(Author’s note)
8/18/19
United States Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Advisory Committee Meeting
Antimicrobial Drugs Advisory Committee
August 7, 2019
08:30 AM EDT – 04:30 PM EDT
FDA White Oak Campus
10903 New Hampshire Avenue
Building 31 Conference Center
The Great Room (Rm. 1503)
Silver Spring, Maryland 20993
https://www.fda.gov/advisory-committees/advisory-committee-calendar/august-7-2019-antimicrobial-drugs-advisory-committee-meeting-announcement-08072019-08072019
****OUTLINE
- EVENT MATERIALS
- WRITTEN COMMENTS
- AGENDA
- AUDIO RECORDING LINKS
- TRANSCRIPT 1
- TRANSCRIPT 2
- TRANSCRIPT 3
- TRANSCRIPT 4
****1. EVENT MATERIALS
Event Materials
Lindsey Baden, M.D. – 18 U.S.C. 208(b)(3) Waiver for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (361.57 KB)
https://www.fda.gov/media/129235/download
Lindsey Baden, M.D. – Disclosure Document for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (49.87 KB)
https://www.fda.gov/media/129236/download
Barbara Gripshover, M.D. – 18 U.S.C. 208(b)(3) Waiver for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (197.43 KB)
https://www.fda.gov/media/129237/download
Barbara Gripshover, M.D. – Disclosure Document for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (52.15 KB)
https://www.fda.gov/media/129238/download
Errata to the FDA Briefing Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (111.42 KB)
https://www.fda.gov/media/129608/download
FDA Briefing Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee
https://www.fda.gov/media/129607/download
Gilead Sciences Briefing Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee
https://www.fda.gov/media/129609/download
Webcast Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (80.04 KB)
https://www.fda.gov/media/129614/download
Committee Roster for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (28.58 KB)
https://www.fda.gov/media/129610/download
Final Agenda for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (23.97 KB)
https://www.fda.gov/media/129919/download
Final Questions for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (13.07 KB)
https://www.fda.gov/media/129920/download
Final Meeting Roster for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (28.16 KB)
https://www.fda.gov/media/129921/download
FDA Presentations for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (906.50 KB)
https://www.fda.gov/media/129922/download
Gilead Sciences Presentations for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee
https://www.fda.gov/media/129923/download
****2. WRITTEN COMMENTS
Antimicrobial Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments; Docket ID: FDA-2019-N-2779
https://www.regulations.gov/docketBrowser?rpp=25&so=ASC&sb=postedDate&po=0&dct=PS&D=FDA-2019-N-2779
Comment from (Dr.) Peter Havens (Medical College of Wisconsin)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0002
OPINION: FOR (“in adolescents, if F/TAF is approved for PrEP in adults…to avoid the bone toxicity caused by F/TDF use in adolescents and young adults”)
Comment from Jonathan Winston ()
https://www.regulations.gov/document?D=FDA-2019-N-2779-0003
OPINION: FOR (“favorable renal safety profile compared to Truvada”)
Comment from (William McColl) AIDS United
https://www.regulations.gov/document?D=FDA-2019-N-2779-0006
OPINION: FOR (“concerned that PrEP be widely extended to gay men of color, to women especially women of color and pregnant women, transgender men and women, adolescents, to communities, especially in the South, that experience HIV health disparities, and all communities at greatest risk for HIV infection…AIDS United has recently engaged in working on the issues related to HIV and Aging. Improvements to renal and bone density would create significant advantages for people seeking to prevent HIV to maintain use for longer periods of time.”)
Comment from Damon L. Jacobs
https://www.regulations.gov/document?D=FDA-2019-N-2779-0005
OPINION: FOR (“Two … friends … older adults … discontinued on Truvada because of … interact[ion] with their other medications. Their providers … interest in … Descovy … awaiting FDA approval …[also] International AIDS Conference … data … indicat[ing] that Descovy has a longer half-life than Truvada, and therefore could be more forgiving with missed doses”
Comment from (Dr. Christopher Hall) San Francisco AIDS Foundation
https://www.regulations.gov/document?D=FDA-2019-N-2779-0004
OPINION: FOR (“as an additional PrEP option will expand the number of individuals who will choose to use PrEP as an HIV prevention method…[and] in the DISCOVER trial…F/TAF … shown to be non-inferior or.. at least as good as Truvada for preventing HIV acquisition… in addition…Black and African Americans face over three times the rate of kidney failure in the U.S. compared to Caucasians5, choice of a PrEP alternative with marginally improved renal safety profile may predispose engagement — based on both real and perceived advantages…[also] a more streamlined renal function monitoring algorithm with use of F/TAF for PrEP, and in turn an ability to follow more individuals on PrEP with decreased laboratory expenditures, less intensive lab monitoring, and fewer staff resources dedicated to closer follow-up demanded by present use of Truvada”
Comment from (Craig E. Thompson) APLA Health & Wellness
https://www.regulations.gov/document?D=FDA-2019-N-2779-0007
OPINION: FOR (“F/TAF … an additional option …[to] increase the number of at-risk individuals who decide to use PrEP, and thereby contribute to national, state and local efforts to end the HIV epidemic…APLA Health believes the results of the DISCOVER trial will encourage greater uptake of PrEP among a broad range of populations including young gay and bisexual men, women of color, transgender individuals and older at risk individuals, all of whom are concerned with taking medications for longer periods of time”)
Comment from (Moises Agosto) NMAC
https://www.regulations.gov/document?D=FDA-2019-N-2779-0009
OPINION: FOR (Concerns about … side effects … discourage many individuals who would greatly benefit from PrEP … especially true in communities that already have great distrust of the medical industry.Descovy provides another tool in our HIV prevention toolkit and can avoid the impact of harmful side effects from current medications… would help to reduce barriers to widespread use of PrEP …”)
Comment from (Dr.) Karam Mounzer (University of Pennsylvania)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0008
OPINION: FOR (“The advantages of TAF vs TDF for PrEP may be more prominent among older candidates, especially among those with osteopenia/osteoporosis and/or chronic kidney disease (CKD)…(also) pharmacokinetic analysis showed that the uptake of PBMCs with TFV-DP was faster, higher and longer with FTC/TAF compared to FTC/TDF, rendering TAF a potentially more forgiving PrEP agent for individuals with intermittent compliance”)
Comment from (Bruce Richman) Prevention Access Campaign
https://www.regulations.gov/document?D=FDA-2019-N-2779-0011
OPINION: FOR (“F/TAF … as effective …Truvada… for PrEP, but with fewer side effects: smaller changes in kidney biomarkers and slightly less bone loss. F/TAF will offer an important option for people… considering PrEP but … concerned about the perceived side effects of FTC/TDC, especially those who have compromised renal function.”)
Comment from (Prof. Quarraisha Abdool Karim) Centre for the AIDS Programme of Research (CAPRISA)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0013
OPINION: FOR (“Adherence to daily, oral formulations of tenofovir/emtricitabine and monthly dapivirine rings have proven to be challenging for young women … access to new more potent drugs and formulations that are less user dependent is urgently needed. One such option is FTC/TAF (Descovy®) – a potent and safer alternative to Truvada® (FTC/TDF)….[and] In the absence of clinical trial PrEP efficacy data of Descovy® in women, on balance, the combination of safety data of FTC/TAF from treatment trials that included women; comparable Descovy® and Truvada® non-human primate efficacy data with vaginal exposure; and protective drug level data in women provide evidence in support of the prophylactic use of Descovy® in cis-women. Due to its potency, smaller drug load, longer intracellular half-life and lower systemic circulation of the parent drug tenofovir (TFV), FTC/TAF offers an improved systemic safety profile…. Lastly, iiii Descovy® in the medicines patent pool …will enable rapid access at affordable prices for women in Africa and other developing countries within a relatively short space of time following licensure for PrEP … in … USA.”)
Comment from (Dr.) Elizabeth Bukusi (University of Washington)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0014
OPINION: FOR (“For the women …Descovy may offer some important advantages over Truvada. Complaints … from women on Truvada … included … concerns about the size of the pill and the stigma associated with…connection to ART for HIV treatment …[and]With the shifting funding cycles, … cost of …pill[s] …important reason for investment of Governments who have to carry more of the funding of drugs for ART for both HIV positive and negative individuals. The lower costs for Descovy would offer an advantage for already constrained budgets within the Ministries of Health. (plus) From … pharmacological and medical point of view, … evidence show[s] possible better bone and renal safety which may further reduce care cost”)
Comment from (Prof.) Nelly Mugo (University of Washington)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0015
OPINION: FOR (“The Kenya National PrEP Scale up Program data shows high PrEP initiation among young women and very low retention after month one and worse still at month 3. Women …[in] qualitative interviews speak of the challenge of using … large tablet, … resemblance to ARVs, … blue color contributing to stigma and making it difficult to comfortably use PrEP in the community….FTAF …an option that [could] overcome… these barriers.”)
Comment from (Dr.) Sharon Hillier (University of Pittsburgh)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0010
OPINION: FOR (“Even though Truvada has an excellent safety profile, Descovy does have a superior profile in ways that matter to women-both in safety and pill size. Treatment studies of Descovy have included women and there were not gender disparities in response to HIV treatment. …women should not be left behind. If Descovy is approved for men, it should also be approved for women.”)
Comment from (Prof. Quarraisha Abdool Karim) Centre for the AIDS Programme of Research (CAPRISA)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0012
OPINION: FOR (see above)
Comment from Lynda Dee
https://www.regulations.gov/document?D=FDA-2019-N-2779-0021
OPINION: AGAINST (“Thirty-two years after the approval of AZT in 1987… It is an outright disgrace that [cisgender] women are once again so blatantly excluded from HIV trials…the Sponsor did not study cisgender women at risk for HIV in the DISCOVER trial…It should also be noted that insignificant numbers of transgender women and African-American MSM were included in DISCOVER even though these are the populations that are at the highest risk for HIV transmission….the FDA…is also at fault here for not requiring the sponsor to study cisgender women in DISCOVER…it would be a violation of the agency’s clearly defined statutory mandated duty to approve Descovy at least for cisgender women without sufficient safety and efficacy data. … Truvada provides a reasonable alternative here until the Sponsor actually studies safety and efficacy in significant numbers in this population. Descovy PK data in women has been disappointing from the onset… Claims of Descovys superior safety profile and smaller pill size pale in comparison to the risk of Descovys inferior efficacy in cisgender women.”)
Comment from (Mitchell Warren) AVAC
https://www.regulations.gov/document?D=FDA-2019-N-2779-0019
OPINION: FOR (“The available data presented in the application do, in our opinion, support approval of TAF/FTC as an additional, non-inferior, safe and effective daily oral PrEP option among men and transgender women who have sex with men…if the F/TAF for PrEP label is not extended to include cisgender women, there will be multi-year delays and denial of access of this additional form of oral PrEP … The systemic PK data in the sNDA do, in general, support an initial broader indication of F/TAF for PrEP for cisgender women…..this indication should also be approved but subject to … Phase 4 studies and a robust Risk Evaluation and Mitigation Strategy (REMS)…includ[ing] other populations (e.g., adolescents and transgender men) that were also not part of the DISCOVER trial.”)
Comment from (David C. Harvey) National Coalition of STD Directors (NCSD)
https://www.regulations.gov/document?D=FDA-2019-N-2779-0018
OPINION: FOR “Descovy presents an opportunity to expand PrEP access across the country…
Comment from Drs. Jared Baeten and Connie Celum
https://www.regulations.gov/document?D=FDA-2019-N-2779-0016
OPINION: FOR (“Factors that have decreased PrEP use … include size of the FTC/TDF pill, fear of side effects, challenges with habit formation to daily pill-taking, uncertainty about the need for HIV prevention, lack of access, and stigma in many varieties…. very low level of new infections … in.. DISCOVER trial, and … favorable safety profile of TAF…[it’s] a natural extension of FTC/TDF as PrEP… for anti-HIV activity they are identical and … pharmacology supports FTC/TAF as equivalently effective for HIV prevention regardless of gender or route of sexual HIV exposure…. favorable safety profile of FTC/TAF may be appealing to persons who have been hesitant to take FTC/TDF PrEP, and that profile (and the potential for lower cost of goods with a smaller tablet) may permit even easier PrEP delivery in places like East and Southern Africa where much of our work takes place. ”)
Comment from (David C. Harvey) National Coalition of STD Directors
https://www.regulations.gov/document?D=FDA-2019-N-2779-0020
OPINION: FOR (see above)
Comment from (Prof. Linda Gail-Bekker) The Desmond Tutu HIV Foundation and Centre
https://www.regulations.gov/document?D=FDA-2019-N-2779-0017
OPINION: FOR (“Descovy (DVY) … stands to provide improved bone and renal safety profiles…Despite no direct studies in cis-women, analyses of Gilead clinical pharmacology data demonstrate … no clinically relevant difference in the PK of FTC, TAF, or PBMC-associated TFV-DP between women and men taking DVY…. [and] DVY more rapidly achieves PBMC-associated TFV-DP levels above the protective threshold compared with TVD…in women …higher PBMC and vaginal tissue concentrations of DVY than TVD suggest … there may be … advantage for individuals with less than optimal adherence, which has historically been a challenge for the women enrolled in earlier PrEP trials, such as VOICE and FEMPrEP….safety data … derived from women with HIV-1 taking DVY-containing regimens…support … safety of DVY for PrEP in women at risk of HIV-1…Unique to women is a finding of less nausea among those treated with DVY-containing products than among those treated with TVD-containing products, suggesting … potential additional benefit of increased tolerability for DVY over TVD in women…In addition, the smaller, non-blue colour is important in young women …[for whom] size and colour of the TVD PrEP has negative, stigmatising impact.”)
****3. AGENDA
https://www.fda.gov/media/129919/download
FOOD AND DRUG ADMINISTRATION (FDA)
Center for Drug Evaluation and Research (CDER)
Antimicrobial Drugs Advisory Committee (AMDAC) Meeting
FDA White Oak Campus, Building 31
Conference Center (Rm. 1503)
10903 New Hampshire Avenue,
Silver Spring, Maryland
August 7, 2019
8:30 a.m.- Call to Order and Introduction of Committee
Lindsey Baden, MD Chairperson, AMDAC
8:35 a.m. – Conflict of Interest Statement
Lauren Tesh Hotaki, PharmD, BCPS, BCIDP Designated Federal Officer, AMDAC
8:40a.m. – FDA Opening Remarks Jeffrey Murray, MD, MPH Deputy Director Division of Antiviral Products (DAVP )Office of Antimicrobial Products (OAP) Office of New Drugs (OND), CDER, FDA
8:50a.m. – APPLICANT PRESENTATIONSG ilead Sciences, Inc. Introduction
Diana Brainard, MD Senior Vice President HIV and Emerging Viruses Gilead Sciences, Inc.
DISCOVER Study Design, Treatment Population, and Efficacy Results
Scott McCallister, MD Executive Director HIV and Emerging Viruses Gilead Sciences, Inc.
DISCOVER Safety and Extrapolations
Moupali Das, MD, MPH Executive Director HIV and Emerging Viruses Gilead Sciences, Inc.
Clinical ContextR ichard Elion, MD Director of Research Washington Health Institute
Clinical Professor of Medicine George Washington University
10:15a.m. – BREAK
10:25a.m. – Clarifying Questions
11:05a.m. – FDA PRESENTATION NDA 208215/S12 –Descovy PrEP
Peter Miele, MD Medical Officer DAVP, OAP, OND, CDER, FDA
11:45a.m. – Clarifying Questions
12:25 p.m. – LUNCH
1:30 p.m. – OPEN PUBLIC HEARING
2:30 p.m. – Questions to the Committee/Committee Discussion
3:00 p.m.- BREAK
3:15 p.m. – Questions to the Committee/Committee Discussion (cont.)
4:30 p.m. – ADJOURNMENT
****4. AUDIO/VIDEO RECORDING LINKS
A recording of the webcast can be found at the following address:
•Start of Meeting to Morning Break: (corresponds to Transcript 1)
https://collaboration.fda.gov/p02b424sg3c4/
•Morning Break to Lunch Break: (corresponds to Transcript 2)
https://collaboration.fda.gov/ponp3o5rrn6k/
•Lunch Break to Afternoon Break: (corresponds to Transcript 3)
https://collaboration.fda.gov/p6cwctro9plz/
•Afternoon Break to End of Meeting: (corresponds to Transcript 4)
https://collaboration.fda.gov/p8xr2oc44100
****5. TRANSCRIPT 1
I would like everyone to mute your microphones if you’re not
already done so.
If there questions for the press please address them to Allison and Charlie.
My name is Lindsay Baden and I will be sharing today’s meeting.
I will now call up the Antimicrobial Drugs Advisory Committee Meeting .
We will start from the left to
go around the table.
John Farley, Debbie, Jeff Murray, Jeffrey Murray, MD, Deputy Director, Division of antiviral products, DAVP, Office of Antimicrobial Products, OAP, Office of New Drugs, OND, CDER, FDA , Wendy
Carter, Pete Neely, training
team, Jenny thing
, Laura Cheever
, Shawn,
George,
Barbara,
Michael Green,
[ Indiscernible ], Lauren Tesh Hotaki, PharmD, BCPS, BCIDP, Designated Federal Officer, AMDAC , Lindsey Baden, MD, Chairperson,
AMDAC,
[ Indiscernible ], Tim Burgess ,
Jennifer lie,
Tom Giordano,
Dimitri,
Sally,
Don Smith
, Matthew gets
Moupali Das, MD, MPH, Executive Director, HIV and Emerging Viruses, Gilead
Sciences, Inc.
, [ Indiscernible ],
.
>> I believe we have someone on the phone.
There is some feedback >> Can you hear me back.
>> This weekend.
Thank you.
For topic such as those being discussed at today’s meeting there often a variety of opinions some of which are quite strongly held.
Our goal is that today’s meeting will be a fair and open forum for discussion of these issues and that individuals can express their views without interruption.
Thus is a gentle reminder individuals will be allowed to speak into the record only recognized by the chairperson.
We look forward to a productive meeting.
In the spirit of of the federal
community act in the sunshine act and react that the advisory committee members take care that their conversations are at the topic at hand take place in the open form of the meeting.
We are aware that members of the media are anxious to speak to the FDA about these procedures however FDA will frame from discussing the details of this meeting with the media until its conclusion.
The committee is reminded to please refrain from discussing the meeting topic during breaks or lunch.
Ink you >> And I think everyone for making the time to be here to participate in this discussion.
We know how busy everyone is.
I will ask Dr.
Lauren Tesh Hotaki to read the conflict of interest statement.
>> The FDA is committing
today’s meeting under — all members and temporary members are special government or federal employees from
different agencies.
The following information on the status of this committee is combined to federal ethics and conflict of interest was covered by but not admitted to these 18 section 208.
FDA’s determined that members in voting members of the committee are in compliance with this
conflict of interest laws.
Members and temporary voting members of the committee have been screened for potential financial conflicts of interest of their own as well is sold imputed to them and their
spouses and minor children.
Based on the agenda for today no financial interest supported by the committee members are temporary voting members conflict of the suits interest has been issued in accordance
with 18,
—
[ Indiscernible ]
>>
Take you.
We will proceed with the FDA opening remarks from Dr.
Marie >>
Good morning.
The division of extend this warm welcome to the committee and to the audience to discuss our new supplemental
application for DESCOVY for HIV infection and we are happy to be talking about expanding the HIV convention [ Indiscernible ] today.
Some of you on the panel and perhaps in the audience may have been here in 2012 in this very room when the advisory committee voted on
whether Truvada should be
approved for prep.
That’s for seven years and that brings us to today’s topics.
There are similarities in differences between the two products.
Both are [ Indiscernible ] that contain
emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets).
Both are approved for HIV treatment and also approved a single agents for the treatment of chronic hepatitis the uncle however there are also differences specifically as they relate to the bioavailability of tenofovir alafenamide 25 mg tablets) in the fixed dose combination.
They deliver lower levels of plasma and lower
level, higher levels of — there is also difference in tissue in order to submission.
This is a safety profile but did not result in efficacy difference for HIV treatment.
The other difference is true but is already approved for prevention and DESCOVY is not.
To support that applications of
the clinical trials — which allowed for a broad and the case and for at risk individuals.
Today were dealing with one clinical trial.
What are some of the regulatory considerations about the basis of supporting and approval.
The number of clinical trials needed to support and approval depends on the regulatory situation.
For new molecule entering the market general two or more drugs are expected or two or more trials are expected.
However for a new and related indication for previously approved obvious only one trial is needed to support approval.
Likewise if there is a new [ Indiscernible ] twice-daily to once daily and you cannot make up form of kinetic link is supported by one trial.
Or for new population were PK is different usually we rely on one clinical trial.
For DESCOVY FDA’s initial drug element advice was that clinical trials should be conducted in a relevant populations and that of PK link alone would not be possible.
So for this application I said we have one trial in MSM and transgender women and none in women at risk.
So the primary issue for today and what you will be asked is a question is given the uncertainty around the protective Korolev can extrapolation be used to further expand the indicated
population?
With that being said this application is a special case in the development of for HIV prevention.
I have the following caveat the approach for DESCOVY may not apply to molecular entities because at
this point — can be leveraged.
We asked the committee today for their advice on how this data can be
assessed.
Ink you >> We will now move to the applicant presentations.
Of the FDA and the public believe in a transparent process for information gathering and precision making.
To exercise transparency the advisory committee and FDA believes that it is important to understand the context of the individuals hesitation.
For this reason FDA encourages all participants including the applicants nonemployee presenters to advise the committee of any financial relationship that may have in a sponsor including entity, equity interest and
those based on the meeting.
Advise the committee at be do not have any such financial relationships.
If you choose not to address this issue or financial relationships at the beginning of your presentation you will not preclude you from thinking.
Will now proceed with Gilead presentation at the Brainerd.
>> Good morning.
Ending the HIV epidemic requires not just highly effective treatments for people have already been
impacted.
It also additional options for preventing new
infections.
My name is Diana Brainard and I leave the HIV and emerging viruses group at Gilead Sciences, Inc.
infectious disease physician and I have worked as a clinician and scientist in both the U.
S for people living which is IV and tackle the the epidemic.
It is a pleasure and honor to be here today to work with this committee to bring forward another HIV prevention option that will help us achieve our shared goal of HIV elimination.
Seven years ago as Dr.
Murray mentioned about it was approved to prevent sexually acquired HIV infection.
And remains today the only approved therapy
for HIV preexposure prophylaxis.
Provider is the fixed dose combination of two HIV reverse [ Indiscernible ] inhibitors.
Emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets).
Provider is approved as part of the complete regimen for the treatment of HIV and adults and adolescents.
As well as for prep.
[ Indiscernible ] for the treatment of chronic hepatitis Be.
DESCOVY is the fixed rate tablet of
— is approved as a single agent for treatment of chronic hepatitis B.
We are proposing an indication for DESCOVY co-for adults and adolescents based on the data we are discussing today.
Tenofovir alafenamide 25 mg tablets) and do not revere but they have vastly different metabolisms.
TFS does that one 12th of TDF because of the difference in half-life.
TDF is rapidly converted to TFE
resulting in high plasma
.
>> DESCOVY lower level of circulating not revere translate of your chronically revenant adverse
renal.
The half-life of pre-exposure prophylaxis allows more time to enter perverse
blood and — intracellularly TAF — where it achieves higher
levels of
on the level of interest to all correlates with antiviral activity.
The kinetic differences between Trent 27
TAF and — after a single dose DESCOVY achieves intracellular Tenofovir Disphosphate above PBMC within two hours.
This threshold is relevant for prep based on his correlation using Truvada data from a trial in men who have sex with men with a 90 % reduction in risk of HIV acquisition as compared to the Siebel.
In contract Truvada takes approximately three days
for the mid-level to recess [ Indiscernible ].
And the state levels remain lower than those for DESCOVY.
One steady-state is achieved with either DESCOVY or Truvada drug is stopped Tenofovir Disphosphate start to decline at a similar rate.
However since levels are so much higher with DESCOVY as compared with
Truvada they remain above this EC 9460 days with DESCOVY compared with 10 days with Truvada.
This suggested to us that DESCOVY could be highly effective for prep and the safety advantages observed in people living with HIV taking this cove could also be realized among those at risk for HIV infection.
In 2015 when the Discover study design was coming together there was uncertainty around whether drug levels in the genital tract or peripheral blood nuclear cells vest correlated with protection against HIV.
The higher levels of Tenofovir Disphosphate and PDMs these with this cove could potentially confer in efficacy advantage and offer a more forgiving regimen for prep provided these levels correlated for protection.
However if genital tract tissue levels drive of up efficacy DESCOVY could be less effective for prevention.
Data from healthy volunteers so that rectal tissue levels are tenfold lower following DESCOVY administration compared to turnabout up.
All hypothesis was that prevention at efficacy for oral drugs would be best measured by prefer for your blood mononuclear cells drug levels rather than tissue how much of it levels.
And that therefore this cove would be at least as efficacious as Truvada.
In spite of this difference in rectal tissue levels.
This hypothesis was based on advances and the understanding of mucosal transmission of HIV.
HIV must first reach the epithelium to reach the sub epithelium and it is general belief that a single cell first becomes effect did and initiates
subsequent events.
Kemah kinds [ Indiscernible ] attracts PDMs
the — circulation to the tissue.
This then results in a small population
of initially affect did CD4 T cells located in the sub epithelium.
The recruitment of target cells for HIV, the CD4 cells from the periphery is critical in order for systemic infection to occur.
Dissemination of these recruited and now infected CD4 positive T cells occurs as they entered the prophetic system to travel to regional infidels and spread throughout the body.
Detection against systemic HIV infection can occur via both topical and systemic modalities.
Topical anti-retro virus such as investigational do not revere gel allow for the diffusion of drugs into tissues within the genital tract.
Efficacy depends on reaching therapeutic levels intracellularly within the local city for positives T cells.
These methods had generally been less effective in prop delivered systemically.
To her body and DESCOVY distribute rightly throughout the body and can offer a greater degree of protection.
They can both reach the genital tissues through the blood supply where they can then access resident lymphocytes and importantly as well PBMC is that contain the active metabolite of both Truvada and DESCOVY Tenofovir Disphosphate also can reach the genital tract and can be among the cells recruited to the site of initial infection as well as into the regional training Cliff notes so as to prevent systemic infection.
While there is no been clear evidence of a correlation of her Benton efficacy of Truvada for up with tissue levels efficacy strongly correlates with drug levels of
Tenofovir Disphosphate within tran33s.
A subset of participants in the iPAQ study and then men who have sex with men of to bottle versus placebo
have Tenofovir Disphosphate — because of the wide range of adherence in the tried and due
to correct comparison could be made it was possible to construct a relationship between PBMC, Tenofovir Disphosphate and risk reduction with respect to HIV incident.
It was with these data that Dr.
Anderson established the correlates of protection for 90 % risk reduction for Tenofovir Disphosphate levels at 40 fmol and show that there is a range of protection above and below that level.
These data are not well recognized and have cited in the most recent CDC prep guidance issued on July 18th of this year.
When the DESCOVY study was being designed the scientific and clinical understanding of HIV prevention was less mature.
At that time Truvada for prep was only approved in adults.
DESCOVY was under review by the FDA for the treatment of HIV.
We knew that rectal tissue levels with DESCOVY were tenfold lower than those achieved with Truvada.
If the primary driver for prevention efficacy with orally administered to not for their prodrugs is local level tissue levels in Truvada should be better than DESCOVY F preventing HIV infection.
However if obtaining high levels in tran33s is important at the DESCOVY should be at least as effective as Truvada.
This question was addressed in the phase 3 discovered trial.
To discover trial, a phase 3 study was conducted to assess the state the and efficacy of DESCOVY for HIV prevention.
This was a double-blind active comparator noninferiority trial comparing DESCOVY to the standard of care for prevention Truvada.
The study and rolled over 5000 men and transgender women who have sex with men.
It was designed and conducted in close collaboration with FDA and the community.
Importantly the study met its primary endpoint demonstrating noninferiority of DESCOVY to Truvada through the prevention of HIV infection.
Among individuals randomized to DESCOVY seven acquired HIV infection.
For an incidence rate of 0.
16 per 100 person-years.
And the Truvada group there were 15 infections resulting in an evidence incident rate of 0.
34 per 100 person-years.
The incident rate ratio, the prespecified method for determining noninferiority was 0.
47 with an upper bound of the confidence interval less than the prespecified margin of 1.
62 prespecified control secondary safety endpoints were met.
Demonstrating superiority of discovery to defraud the with
respect to markers and renal toxicity.
These data demonstrate that DESCOVY is highly effective at preventing HIV acquisition and demonstrates safety benefits over Truvada.
What we know now is that both the body and DESCOVY are highly effective for prep if taken.
Adherence is the key determinant of efficacy.
A correlate of protection has been established for Tenofovir Disphosphate
levels in tran33s.
The discover trial that lower levels of Tenofovir Disphosphate with DESCOVY versus Truvada are not relevant for HIV protection.
And that the seven fold higher Truvada Michael for a potential — these results support the conclusion that PBMC drug levels are the efficacy of orally administered to not revere prodrugs.
This finding is an important consideration for the extrapolation of the discover results from six men and transgender women to women.
Today clinical trials within men have had heterogeneous is efficacy results reflecting highly variable adherence.
Data from clinical trials demonstrate that when controlling for adherence Truvada is equally efficacious in women and men.
There is a biologic rationale for this finding.
The biology of HIV as well as the intracellular antiviral activity of Tenofovir Disphosphate are independent of gender .
HIV replicates within CD4 positive lymphocytes with must be recruited to the site of initial infection in order to successfully lead to specific systemic transition.
Adequate drug levels within the recruited cells are necessary and sufficient to mediate detection against HIV infection.
Multiple lines of evidence support reaching the efficacy results for DESCOVY for prep from the men and transgender women in discover to assist women.
The efficacy and therapy have been well established in over 2000 women and are comparable to results in men.
DESCOVY and Truvada both inhibit HIV replication and CD4 T cells to the same active metabolites, Tenofovir Disphosphate.
Extensive pharmacology assessments have demonstrated that the levels of Tenofovir Disphosphate are similar irrespective HIV status or gender.
Taken together this data support the use of DESCOVY for HIV prevention in women.
There is similar support for the extrapolation to adolescence.
DESCOVY and the three other DESCOVY obtaining single tablet regimens are all indicated for HIV treatment in adolescence.
Based on the safety and efficacy established in this group.
HIV behaves similarly independent of age and therefore the extension of safety and efficacy of discovery for prep can be based on similar former code Connecticut and adolescence as
well as a similar mechanist with the stress.
HIV infection status has no relevant impact on these parameters.
Taken together these data support the use of discovery for HIV prevention in adolescence.
Based on the data from the discovery studied the established safety and efficacy of DESCOVY for HIV treatments across men, women and adolescence and pharmacokinetic bridging the following additional indications is proposed for DESCOVY.
DESCOVY is proposed for the the reduce risk of HIV at at risk adults and adolescents wing at least 35 kg.
You will hear from Dr Scott McCallister who will
provide an overview of the phase 3 discovered trial and
efficacy results.
Then Dr Moupali Das, MD, MPH, Executive Director, HIV and Emerging Viruses, Gilead Sciences, Inc.
to have Dr.
Rick Elion has a long-standing history of providing HIV treatment and prevention services to individuals in the DC area for marginalized communities.
He will provide clinical context
for the results of the DISCOVER trial.
We have Gilead professionals to address these questions.
In addition we are pleased that Dr.
Peter Anderson is here today to address questions around adherence.
Dr Anderson is a professor of pharmaceutical sciences at the University of Colorado.
His laboratory specializes in the assessment of drug levels in dried blood splashed and they performed nearly 4000 dried blood spots in discover as part of our adherence discussions.
I would like to welcome Scott
McCallister.
>> Thank you Diana and everyone.
I am in infectious to lease infectious with a long history of clinical care with patience of HIV.
The section I will describe is a tree on
population and efficacy results.
Each of the nearly 2700 MSM or transgender women receive one tablet of active drug and one placebo tablet.
The primary efficacy endpoint analysis was time phase and was conducted when all participants completed 48 weeks in the study and how that completed 96 weeks.
The primary endpoint will the HIV incidence rate for 100 person-years study.
The study was blinded to investigators and study participants until the final person enrolled completed 96 weeks.
At the next scheduled visit individual participants are unblinded and offered to switch to open label to Scobee, blinding is ongoing
and not yet complete.
Eligibility criteria was decide to ensure that the study enrolled population at high risk HIV infection.
All participants required to have at least one of the two
followings risk criteria.
Two or more episodes of condom was a no sex with more than one partner in the 12 weeks before enrollment or diagnosis of rectal gun a real, rectal for media, or syphilis, in the 24 weeks before enrollment.
All needed to be HIV and hepatitis B negative prior or current use
of PrEP and a washout of drugs
was required.
DISCOVER are mostly urban and specifically chosen to be in Logan location
— able to enroll people with significant sexual risk of HIV acquisition.
We also selected size with the cultural competence to enroll and retain people of color and transgender
women.
Ultimate 35 DISCOVER , summer hospitals and some private practices and some local transmit infection
clinics.
The site was responsible to determine the best recruitment practice within their own community.
All of those who met eligibility criteria were allowed to enroll.
It was our goal to allow each person to be a risk of HIV infection to participate.
When we designed to DISCOVER — that included the right design
elements, comparable sexual risk criteria, optimal HIV testing and SDI testing.
So our study would yield reliable results.
We also discuss design issues with both site investigators and with community members in North America and Europe to ensure that the study was practical and aligned with existing clinical this.
Community members encouraged us to establish advisory boards for ongoing dialogue with them.
As a result three community advisory boards were set up, one that was DISCOVER specific and two that with broader HIV issues.
We drew valuable input from the interactions during the trial, during the design phase and recruitment and during the study conduct.
The primary efficacy endpoint was based on the number of HIV infections diagnosed in this cover divided by person-years of exposure in the study.
Noninferiority of DESCOVY was assessed by instance rate divided by the rate in the
Truvada.
Read derived 890 40 margin of 1.
62 of the TBD affect in three prior our CTS.
If the upper bound of the incidence rate racer in discover was less than 1.
62 DESCOVY would be noninferior to
Truvada.
The incidence rate ratio analysis of primary endpoint was a robust means of evaluating the effectiveness of DESCOVY ensuring that the result was due to the drugs used in the buddy and that the treatment population was a sufficient risk of HIV.
At each visit we assessed general safety, including graded adverse events, adverse events leading to discontinuation, serious adverse events and general safety labs.
There was renal lab testing at each visit, bone mineral testing
every 48 weeks and SDI testing from three anatomic sites also at each visit.
We used an analysis cascade or six prespecified safety endpoints where there was a possible difference between the arms due to lower levels of plasma TF the and those untapped.
The safety cascade began with changes from baseline in bone
mineral density in both the hip and spine.
If there were significant differences favoring DESCOVY on each of these we then evaluated the
specific renal proteins, the
data to microglobulin [
Indiscernible ].
With continue significant differences favoring to Scobee we moved to evaluate [ Indiscernible ] with
general urine proteins, all
purchases
—
at each visit all participants received HIV risk reduction education, adherence support and condoms and lubricant from site staff.
In addition opt in and opt out text messaging could be used to remind the individual to take their study minutes daily.
With actual words used in the text chosen by site participants.
Adherence is a critical determinant of prep efficacy so we measured it in multiple ways.
We employed two subjective test, the company to iPad-based questionnaires and counts from returned bottles.
Both at each visit.
We used one objective test, of dried blood
spot to determine TFV-DP provide of chronic adherence in the
past eight weeks before the collection date and we looked at a randomly selected subset of 540 participants about 10 % of the discover population.
In addition to the randomly selected subset we also analyzed dried spots in a case control the amount of analysis of the diagnosed with HIV and DISCOVER with matching controls for each.
In our case control study we compared every individual diagnosed with HIV on study and match them with
five uninfected controls.
The matched controls were specifically chosen to be geographically linked, to have similar time on study drugs in DISCOVER and to have comparable sexual exposure as evidenced by the on study diagnosis of a rectal STI.
From the group of uninfected study participants who were a match for each case five were randomly selected.
Once all controls were selected dried blood spot analysis of the Tenofovir Disphosphate were tested on the date of HIV diagnosis and also on one visit prior.
More than 5800 people were screened for discover.
364 did not meet eligibility of criteria including 49 tested HIV-positive.
5399 were randomized but six in HR were
not treated leaving 26 94 treated in the disco the arm
and 2694 2693 in the two but
arm.
Of those who were randomized and treated in the buddy the
median age was 34.
12 % of the population were emerging adults below age 25 and not jet
at peak own mass.
The racial breakdown across the 11 North American and European countries 84 % self identified as white,
nine % as black.
25 % reported being of Hispanic or Latin
ethnicity.
74 participants or 1 to 2 % of the population self identified as a transgender woman.
From responses on the confidential cost questionnaire the self-reported sexual orientation was or homosexual
in 91 to 92 % bio sexual in 6 to 8 % and heterosexual in one
%.
Baseline sexual behavior data from the confidential cost now showed that the treatment population was a significant risk of HIV infection.
50 % to 60 % had at least two condom was receptive and sex partners and the 12 weeks prior to study entry.
9 to 13 % reported rectal gonorrhea, rectal comedy
chlamydia or syphilis in the past 24 weeks.
Two thirds of discover participants had you dressed to be additional drugs and nearly 1/4 reported binge drinking.
Defined as six or more drinks on at least one occasion and occurring at least
monthly.
A total of 23 % had used Truvada for prep in the past and 16 to 17 % were on it at study entry.
While on study discover participants maintain this high level of sexual behavior on all risk levels.
The average under for condom was receptive and sex partners at baseline and continuing throughout the study.
Similar between the arms.
They also had high rates of sexually transmitted infections.
57 % of those on the study were diagnosed with gonorrhea or chlamydia from at least one of the three anatomic sites tested.
And including syphilis the overall rate on study or any one of these STI is range
from 139 two 145 per 100 person-years in DISCOVER.
Overall 42 % of participants had a rectal STI on the study.
Most likely due to condom was
receptive sex and 60 % had a urethral STI associated with condom was inserted of sex.
At the time of the primary endpoint analysis 16 to 17 % of participants discontinue study
drug in DISCOVER.
The most common reason for discontinuation from study drug
war participant decision, or loss of follow-up 6 to 7 % each.
Only 1 to 2 % of study participants contacted you’d drug to to an adverse event and the other reasons for discontinuation work less than one % each.
As Diana described the study met its primary efficacy endpoint for noninferiority.
Over 8700 person-years on study across the two arms a total of 22 HIV infections were diagnosed.
Seven in the disco we arm, 15 in the Truvada on.
Corresponding to HIV incidence rate of .
16 and person-years respectively.
The rate ratio where point 16 is
divided by .
34 is primary endpoint analysis the rate ratio of .
47 represents a 53 % reduction in HIV instance for the discovery arm relative
to the trip are arm.
The upper bound of the confident interval around .
47 is 1 lower than the lower point six to speak specified noninferiority margin thus establishing the noninferiority of discovery through to about
four prep.
We category —
prior to unwinding a three position panel concluded that five of the 22 HIV diagnoses most likely occurred prior to Tenofovir Disphosphate entry between the screening and randomization business.
The five with suspected baseline infection are shown here in the back section at the bottom of each bar.
Just above our the 17th individuals, six in disco we and 11 you to AVITA required HIV while on study.
The impact that the five suspected baseline infections had on the primary efficacy endpoint we went on to to conduct a sensitivity analysis.
By excluding the five individuals with suspected baseline infection one in discovery arm and the towbar arm the incidence rate ratio in the sensitivity analysis is 0.
55 The confident interval around it extends to 1.
48 which is still low the prespecified 1.
62 noninferiority margin.
Therefore even excluding the suspected baseline infections and the sensitivity analysis the incidence rate in the
DESCOVY arm noninferior to the Truvada aren’t.
We next looked at efficacy analysis by baseline subgroups.
In this forced plot the HIV instance for the two arms are shown again at the top in just left of center.
The rate ratio and surrounding 95 % interval is
show shown on the far right.
There incidence rates for both demographic and baseline risk behavior subgroups.
For each of these subgroups the incidence rates are low and consistent
with the race that the rates of the overall study.
The incidence rate ratio demonstrate that the effect of DESCOVY or Truvada was consistent with the rate ratio in the overall study across all demographic and baseline risk behavior subgroups.
In this diagram are genotypic resistance data of the 22
individuals diagnosed with HIV.
19 has samples that could be successively amplified and evaluated.
Of these 19 only for had genotypic resistance detected to either of the study drugs.
All four occurred in the Truvada arm, all forward M1 84 with resistance to FTC and all four occurred with the suspected race line infection.
Each of the four individuals of in 184 were able to be successfully suppressed on ART,
three with the DESCOVY regimen.
Our adherence results demonstrate that there was a very high level of adherence across the arms.
With self-reports from the confidential cost questionnaires about 80 % reported that they took their study miss more than 95 % of the time across all study business and similar across arm.
With pill counts from returned bottles of study drugs about 70 % appeared to be using their study miss more than tiny more than 90 % of the times.
The levels of TFV-DP from red blood cells from dried spot tested also demonstrate that was a high level of adherence in Ciswomen you both study arms.
On the nearly or thousand blood spots tested in the random subsets 80 to 90
percent had TFV-DP consistent with taking four more tablets per week for both arms.
In contrast very few, just 5 to 9
% at any visit had TFV-DP associated with taking less than two pills per week.
In the 22 HIV cases were compared with uninfected control the dried spot data analysis there provides a clear explanation for the difference between those with HIV and their matched controls.
Low or no adherence was the most significant risk factor are associated with HIV in the study for both arms.
In the case-control study drug adherence as measured in tried spots was significantly lower among those who became infected as compared to match controls.
Most cases had TFV-DP in red blood cells consistent with using the study drug wasn’t two doses per week while more than 20 % of the controls had TFV-DP associated with higher levels of adherence.
Finally less move from the TFV-DP in red blood cells which provided this measure of adherence.
Over to the levers in tran33s which provides a measure of efficacy.
The data from dried blood spot showed a high and comparable level of adherence across both arms.
The levels of activated drug, TFV-DP in PBMC was not across the arms.
One study state was achieved the medium TFV-DP in PBMC was sixfold higher in the
disco we TFV-DP then in the
Truvada arm.
The amount of activated drugs in the PBMC was consistent with established PK data from multiple clinical studies with TAF and TFV-DP treatment.
Given that 40 Fenton Mills represent the 90 percent concentration or EC 90 of TFV-DP 98 % in the DESCOVY arm
was above — in the Truvada arm hello was about this mark.
In summary that DESCOVY was
conducted in — over the course of the study.
Only 87 hundred person-years to HIV incidence rates were only very low and
the noninferiority of DESCOVY or Truvada was established.
Low adherence was the most significant risk factor associated with each HIV diagnosis.
While M1 84 mutations occurred in the towbar arm there was no resistance to study drugs
reported in the DESCOVY arm.
There was no resistance observed in the discovery arm, for cases of M1 84 reported in the Truvada arm.
Significantly more participants in the discovery arm — I would like
to turn the presentation to
Dr.
Mobile DOS Moupali Das.
>> Good morning everyone.
I am an infectious disease physician.
My career has been devoted to helping and that HIV epidemic by increasing prep
uptake.
For the last six years I have worked exclusively on clinical trials comparing the efficacy and safety of the two to enough of your prodrugs.
The discover trial is the largest discover trial with a single comparison of TAF with TDF.
It offers a unique opportunity to
compare both.
The safety and tolerability of DESCOVY and Taft have been Doorly
established in over 26,000 person years of experience in clinical trials and over 1.
6 million person-years in clinical experience.
DESCOVY has a superior there improve renal and bone safety profile compared with the bottle
variable renal bone and biomarkers correlate with fewer
clinical events.
DISCOVER come from similar safety benefits and HIV uninfected people.
They are the first demonstration that these well understood renal and bone safety advantages of DESCOVY compare with Truvada are also true of HIV uninfected population.
There is a meeting exposure of 86 to 87 weeks in disco we and Truvada.
Verbal mineral sub study had 96 weeks of exposure.
Both DESCOVY and Truvada were safe and well tolerated.
The type frequency and severity of their first events were similar between the DESCOVY and Truvada arm.
Most adverse events work grade one or two in severity.
There was a low percentage of study drug related serious adverse events where adverse events needing to discontinuation in DESCOVY and Truvada.
During treatment one person died in each arm.
The most common adverse events in the DESCOVY or sexually transmitted infections.
Six of the nine most common Aedes were bacterial sexually transmitted
exposure.
This is
—
will come back to the general safety data.
The race of SDI were high and persistent
throughout the trial.
About 50 % of participants had lab diagnose gonorrhea or chlamydia at any of the three anatomic sites at baseline and throughout the study.
Were no differences between DESCOVY and provide a.
Two of the most common AE were rectal gonorrhea and chlamydia.
Approximately 10 % of participants had right of Ghana radio or gonorrhea at baseline.
There were no differences between DESCOVY and Truvada.
The by visit positively race reflect high and persistent sexual behavior with the persistent STI race
reflective of high rates
.
There were different from our treatment trials.
Four of the most seven most commonly prescribed medications are and abide out used to treat SGI’s.
More than half of the
participants received — returning back to general safety the common study drug related adverse events reflect the most common adverse events in the discovery treatment
trial.
20 % of participants in DESCOVY and 23 % enter about a half study drug related adverse events.
, Related adverse events were low in frequency and similar between arms.
The majority were mild G.
I and headache.
Laboratory abnormalities were also in
common in the study.
Greater higher lab abnormalities occurred at a low frequency and number clinically significant.
In the HIV treatment trial and in the Truvada adherence subset the lipid-lowering effect of Truvada has been well documented.
In discover Truvada was also associated with a reduction in lipid parameters.
Total cholesterol, HDL and LDL cholesterol all declined.
The magnitude of these declines is not clinically significant.
Were as total cholesterol, LDL and HDL levels of were generally unchaste in participants taking DESCOVY.
Importantly these changes resulting in no difference in the total cholesterol to HDL levels between arms which is strongly associated with cardiovascular risk.
While both this cove and Truvada were safe and well tolerated DESCOVY was superior to do about it in all
sex renal and points.
Reviewed cases including proximal to be a lot of P including
thank only syndrome.
, We also evaluated total protein area by
dipstick and — in discover after 80 person-years of disk exposure
to study grog —
DESCOVY had significantly — the prespecified time point for the assessment of secondary safety and points.
At week 48 discovery participants also had to the can’t lower —
>> At week 48 20 per percent of participants on DESCOVY paired with 24 % on Truvada developed dipstick put in your area.
One % compared to Truvada, to present develop clinically significant quantitative protein area as defined by the kidney foundation as a urine protein to creatinine ratio of greater than 200 mg.
Graham DESCOVY had superior
—
on the left panel the Truvada group had a look 20 % increase from baseline in tubular
written area while discovery —
>>
The superior real safety of DESCOVY was demonstrated in participants
who are on about at baseline who switch to DESCOVY compared to those who remained on
Truvada.
The discover trial included participants taking Truvada for prep at baseline and do not require a washout of Truvada.
Were a large number of, 905 people who were on Truvada at baseline.
We prespecified sensitivity analysis of the participants on baseline Truvada for renal and points.
As overall discover population those on baseline Truvada were switched to DESCOVY had improvements in renal function to to those who remained on Truvada.
The improvements in JFR and those that switch to discovery was apparent as early as week four and persisted through week 48.
The improvements with DESCOVY
in tubular function.
Those who switch to discovery has significant decline in tubular proteinuria approved tubular function while those who remained under by the had 11 %
increase in rental binding [ Indiscernible ].
These changes became apparent as early as week four and continue to week
48.
Discovery was superior to Truvada on all prespecified biomarkers of renal function.
This was demonstrated in both overall population as well as the Truvada switchers.
We evaluated bone safety with the bone density study.
The median age was 34 so approximately half of the participants were still building to peak bone mass which is achieved in the early to mid 30s.
DESCOVY participants headed increase in bone mineral density from about [ Indiscernible ] from baseline in stable help bone density bubbles on Truvada had declines of one % in both bone mineral density from baseline through week 48.
DESCOVY was statistically superior to Truvada in both the specified and points.
Using the T-scores from the baseline participants were classified into the clinically relevant categories
of bone mineral density, and osteopenia and osteoporosis.
29 % of participants either had osteopenia or osteoporosis in the arms.
After 48 weeks after patients on DESCOVY — SGOT show you there were safety endpoints.
Discovery was superior to do about it in all six prespecified Alpha control bone in real safety endpoints at the week 48 endpoint.
We continue to follow long-term renal and bone safety in the
discover study participants.
Both DESCOVY and Truvada were safe and well tolerated.
The rates of serious adverse events or adverse events leading to discontinuation study drugs were low and balance between RM.
The magnitude of the differences in the early safety endpoints between arms is similar to what is observed in HIV and help be comparing DESCOVY to Truvada.
Confirm that the DESCOVY superior safety in PrEP .
This is a significant development from a clinical perspective so we can now offer a similarly efficacious and safer drug as another choice for HIV uninfected people were simply at risk for HIV acquisition.
The efficacy and safety of DESCOVY for women, men to have sex with men.
The excessive clinical
—
we have over 108 thousand person-years into about a for prep and 6500 person-years for DESCOVY for prep for discover
trials.
Both drugs were highly effective for treatment and prevention.
Efficacy is driven by Tenofovir Disphosphate or PBMC.
The 90 % lower plasma levels for DESCOVY compared with Truvada is associated within an improved bone and renal safety profile.
The pique of DESCOVY or Truvada is independent of in transit and extras it factors this means that the pique of plasma to not
for fear is not affected by sex at birth, gender identity, or sexual orientation.
HIV infection status also does not
affect pique.
Tenofovir Disphosphate levels
are comparable with DESCOVY in
DISCOVER and the level in SI Ciswomen in contrast the
Tenofovir Disphosphate — efficacy is high in both women and men on PBMC regimens for treatment.
Also with Truvada.
The key metabolite for both Truvada and his cove associated with safety is plasma to
nonsevere.
Plasma TFV-DP
—
these renal improvements are consistent with the trial results on those on baseline Truvada who switch to DESCOVY.
Women continue regimens who switch to DESCOVY at clinically significant improvements in osteopenia and osteoporosis within 48 weeks.
At baseline a third of women on Truvada based regimens for HIV treatment had osteopenia or osteoporosis.
When he switched to DESCOVY have a spine osteopenia and less osteoporosis at week 48 compared to those who continued on to Rodda.
These results were statistically significant.
Discovery is also an efficacious and safe treatment for HIV and adolescence.
DESCOVY is approved for eight IV treatment in adolescence when at least 35 kg in combination with third agents and discovery Regimens.
It has similar safety benefits compared with Truvada in adolescents with HIV.
Truvada has been approved for (PrEP .
To this .
As a sub for HIV infection status is not affect PK so we would expect high levels in adolescence if they were taking for prep .
50 adolescence who initiated or DESCOVY for HIV
treatment were also evaluated.
The mean age in the study was 15 years and over half of the participants were female.
Discovery was highly efficacious in adolescence for
HIV treatment.
With DESCOVY the levels in adults without HIV adults and adolescents with HIV are similar across all three populations shown on the
left.
Plasma TFK PK is consistent with results from prior studies.
Truvada has — importantly due to the 90 % lower plasma
—
Allison participants continue to build bone mineral density similarly to an eight sex and race match population.
DESCOVY is noninferior to Truvada in HIV treatment and prevention
efficacy.
There comparable to Ciswomen and adolescence.
The efficacy and safety of DESCOVY for prep can be inferred for Ciswomen .
Taken together and the excessive efficacy and safety data support the purposely inclusive indication.
We have planned multiple effectiveness studies of
discovery for prep.
We consider numerous approaches to studying the efficacy of DESCOVY in 2015 we were discarding the trial.
Ciswomen
.
A superiority trial for DESCOVY over Truvada was also not reasonable as both are oral daily pills differentiated primarily although not exclusively on safety.
Lastly we considered a noninferiority trial.
Unlike discover where we pulled effects from three
randomized trial with similar efficacy the five randomized controlled trials in women lacked a consistent treatment of fact from which we would contact a noninferiority margin.
Using only the two trials with the highest efficacy in women taking Truvada who were able to estimate that a non-inferiority trial would require enrollment of about 22,000 women in the high incidence reason.
This would require approximately 8 to 10 years to conduct.
The design of the trans-35 DISCOVER was not approved for adolescence until 2018 so we would be comparing the safety and efficacy of two investigational agents.
More importantly we had different data that adolescence require a higher visit frequency to maintain adherence and made benefit from age-appropriate targeted intervention to maximize recruitment and
potential in clinical trials.
The efficacy and safety of discovery for prep in women and adolescent can be inferred from the totality of evidence for HIV prevention are extensive safety database for HIV treatment.
Clinical data are now needed to inform providers and individuals at risk for HIV regarding the clinical effectiveness of DESCOVY for PrEP.
We’re dedicated to generating this data and will
be supporting in over 3400 women in the United States and Africa.
They include the evaluation of the safety for prep in pregnant and breast-feeding women and how the improve safety tolerability and smaller size DESCOVY could improve uptake and persistence.
We are strongly committed to understanding how having an additional choice for PrEP with this cove which has an approved renal ample safety profile and pharmacologic profiles consistent with an earlier and longer protection from HIV can help address our shared goals of increasing PrEP uptake in helping to end the HIV epidemic.
Thank you please to invite Dr.
Richard L in to talk about the clinical context.
>> Good morning.
My name is Dr Rick Elion.
My financial conflicts of interest are I do
research with Gilead and [ Indiscernible ].
I am a member of the advisory panel for Gilead and I have no stock or financial interest.
I have been active in the carriage it be patient since I left residency in 1983.
I began in Brooklyn in 1985.
At the time of the HIV testing of that year I have been continuous at the front line for caring HIV patients are seeking solutions and improvements in care for over 30 years.
I watched countless men and women die in my first 10 years of practice.
Advances in treatment and prevention have transformed a hearing job to one of satisfaction.
And director of Caesars at the Washington health Institute to serve low-income population in the district.
And a clinical Professor George Washington University.
We were the site for one of the first prep
demonstration in 2013.
I worked at the Department of Health in the wellness program in DC which of the center of care of
those with SDIs.
I also continue to follow patients as a Washington health Institute some of which I have cared more for 20 years or more.
Am grateful and honored to have the chance to share my first active and my DESCOVY is important to our prevented toolbox.
It is estimated that up approximately 95 % who either don’t know their diagnosis or have been diagnosed and not enclosed engaging care.
While treatment is successful at preventing new infections the bulk of new infections will not be prevented with just treatment alone.
We need multiple options for patients who choose their ideal method of treatment is.
When consumers have more choices at least two greater
treatment.
PrEP is critical to prevent
new infections.
The variety of options throughout each person to choose what is right for them.
Choice is critical for patients as they are much more comfortable and committed to the choices they make rather than being told what to do.
Biomedical interventions including treatment as prevention and PrEP are among the most useful.
Treatment as prevention is helping the decline of 80 % of new cases in the United States.
Is a future synergies of these apartments treatment for HIV-infected individuals and PrEP for infected individuals.
The announce shown here look at the change in new diagnosis of HIV over five year period in states by PrEP use.
This data is control for rates of Biologics oppression and the states with low prep use at the finding of three %.
You can see about a one % increase in HIV diagnosis.
These are compared to the high prep use group with 11 % of PrEP where you see a five % reduction in new cases.
These race of PrEP are still quite low considering the risk of profiles in the communities.
And could be greater if there greater [ Indiscernible ].
The CDC report makes clear that communities in need are receiving prep.
This demonstrates the imbalance between the potential need for PrEP in certain communities and the use of PrEP.
Don Smith reported on the disparities between the potential members of various populations that were qualified for versus those who are using.
differences are staggering in the communities and can be seen in the slide go roast differences exist for only a fraction of the communities who are benefiting from props ranging from racial disparities in Blacks and Hispanics and men and women.
Adolescence, 15 to 25 years of age who are sexually act of art facing the same disparities.
We know that Truvada for PrEP efficacious in sis men interested in women.
DESCOVY pharmacology consistent across ages.
This notion of forgiveness is critical to this population.
Aside from the potential benefits of a better DISCOVER DESCOVY will be a better medication for people who are building bone mass.
There depositing bone as part
of the normal growth and the loss could potentially have a lasting effect in adolescence were after losing using to about it may not ever reach bone density.
We is the notion of a Z score.
A lo Z score below two is a warning sign that you have less bone mass and/or may be losing bone more rapidly than expected for someone of your age.
Consideration of The scone for age, race and sex is most important during adolescence when Gohmert is that the variability increases.
The scores are stable over three years of rapid bone decline which you can see after stopping PrEP especially in the younger participants is a concern in finding of these analyses.
Disease for individuals on Truvada, told body during the 48 week period of prep and covered with the comparable time.
The clinical significance of this is twofold.
The first is that the bone mineral density based on the Z score does not recover the baseline 48 weeks after PrEP has been discontinued.
Second.
It is a better choice therefore for adolescence.
Offering them the medication that allows the bone to grow at a normal fashion is an important consideration selecting the best medicine for HIV prevention for adolescence.
It is equally important for women.
I previously mentioned the PK event for adolescence.
The PK data that was presented earlier reflect a higher interest are loyal level of TAF and longer period that the level stay above the threshold of efficacy.
60 days versus 10 days.
These represent a significant difference between
TAF and TDF that PBMC have been correlated with level the protection.
This continues to evolve.
The Ciswomen that the failure of higher tissue levels for men was on a detriment to the overall efficacy.
It was likely German by the higher drug levels in the barest components of the PBMC.
The higher levels in the subsequent longer time to load levels fall below threshold infections could [ Indiscernible ] and mirror to
further study.
This would be very important for both adolescence and for women who
are starkly have a greater [ Indiscernible ] due to poor adherence.
PrEP has been approved for women when adequate adherence has been
maintained.
Women make up approximately nine % of new infections I have a great deal of unsafe infection
through unprotected contact.
Women therefore make up an important part of the population for controlling HIV infection.
Are underrepresented in the low use of PrEP.
In 2015 only two % of women who are eligible for prep were on prep.
I work with colleagues at the Washington Hospital Center in the Department of Health in the same by engaging women in PrEP in the STI program known as the wellness clinic and the family planning at Washington Hospital.
We screened nearly 1000 women who are at high risk of sexual practices and only less than one % opted to
initiate that despite free medications and pure support.
Despite her numerous efforts to explain and encourage the adoption of more tools for HIV prevention for women we have been lagging behind.
This data of HIV incidence for demonstration products show the comparable rates of new infections in men and women.
There should be little doubt that PrEP was Truvada was equally well in men and women when appropriate.
This demonstrates real-world efficacy.
There is no data to suggest that this efficacy is different between genders when adherence is somewhere.
These data from world experience support the fact that women benefit from the same fashion with men for help with Truvada in the world world by adjusting clinical trial settings.
As mentioned earlier women had not adopted up in significant numbers.
The reasons for this are complex and involve multiple issues.
The study of African women and men is a
clinical issue for women as well as side effects and if the treatment will work.
Other service pointed out the mistrusts of providers, stigma and fear being out is as needing HIV protection, partner notification and lack of support once partner cost, access to medicine remain key drivers for women’s reluctance start PrEP.
There are multiple reasons in the this is a
mission exercise by women for adopting treatment.
We want to help women make a better informed decision.
DESCOVY bone safety data is clear.
Increase rich increased risk of fraction and people living with HIV who have taken Truvada-based
regimens.
Approximately one in two women over the age of 50 will break a bone because of osteoporosis.
A woman’s risk of breaking a help is equal to her combined risk of breast, uterine and a wearying cancer.
HIV-positive women have a 15 % higher risk of osteopenia at age 50 than men and a comparable age.
DESCOVY is a safe or alternative for women that Truvada who at any risk for risk for bone health and treatment settings.
I have switch women trying to write a
two TAF regimens to alleviate problems.
We know that Truvada for PrEP is equally effective in men and women.
We know that PBMC levels are associated with efficacy for HIV prevention.
There is no established regimen — the low tissue levels were not predictive of us to sex scene
in Ciswomen and success —
the key issue is that hearing the based on the evaluation of DESCOVY for prep and whether the indications to the extent the on the participants within the DISCOVER trial.
There is a history of conflicting data regarding the role of tissue levels.
Versus the role of systemic protection through components of the blood.
This is obviously one of the key questions before the committee today establishing efficacy and safety in HIV prevention for all committees.
The data from the Ciswomen that systemic protection tries efficacy in MSN and transgender women.
There is a call for —
we do know that DESCOVY was safer in men and transgender women and we do know that the improvements in safety with TAF versus TDF as well and we can debate is a significant clinical and if it.
I believe they do from a safety
perspective for both adolescence and women based on the data that has been shown today.
The differences in PK between TDF and the improve profile might improve outcomes by mitigating suboptimal adherence.
This evidence supports the extension of efficacy data for Ciswomen for
women and adolescence.
At the end of the day as a position counseling women for the need for HIV prevention and prep I cannot stress enough how detrimental it would be to give men a choice of what they for medicine not offer the same choice to Ciswomen who should have the same options available to CSS men and trans women.
They should not have to wait for approval which could take at least four years for TAF for PrEP.
That women decide if the — there is reasonable certainly based on the Truvada prevention to extend the certainty for the mail and transgender men in
discover — I’m certain that women in adolescence do not have the choice and cannot use
the safer medical and medicine.
I hope we don’t give those vulnerable populations that message.
And to allow them the option to choose what will be best for them.
I have talked clinicians, in Uganda and they look to the U.
S recommendation without indications for medications.
Providing a safe and effective medication were women make up half of the cases is fundamentally important.
The decisions today have implications not just in the
United States.
Please allow me to keep doing my job of guiding and helping patients to make the best decisions.
Don’t take the choice out of our hands.
The totality of the evidence and the failure will Evan support making this drug available to all those who need it.
Thank you >>>> I would like to thank the applicant for a very thorough presentation on a tremendous amount of data.
Before we have clarifying questions for the presenters we will take a 10 minute break.
Please remember there should be no discussion of meeting topics during the break amongst yourselves with any members of the audience.
We will resume at 10:25.
****6. TRANSCRIPT 2
We have about 50 minutes for clarifying questions for the applicants presentation.
We may not complete all of the clarifying questions, in which case we will resume after lunch, after we have a chance to have the agencies
presentations.
In the clarifying question process, for those of you who are new to joining us, what I like to do is try to build on themes.
I really asked for committee members to please use the honor system and how we do the clarifying question process.
When we start, if you’re interested in asking a question, signal Lauren or I who will add you to the list.
If the question is asked and there is a follow-on that builds on the theme, very much
like to build on the theme
, please take your card and turn it on its side.
That will indicate you want to build on the theme so we can have a series of questions on the same topic and not be bouncing around with every other question going back and forth between topics.
I just asked the committee members to build on the theme and not put that away so you can ask another question faster.
We will try very hard to get to all the questions as quickly as possible.
I would like to, as much as possible, build on themes because that’s more efficient.
So we will start with I think the member on the phone.
The first clarifying question.
>> Yes or.
The question is, what if any are the laws determining bone density, and renal safety related to the adherents and failure?
>> I am going to ask the doctor to come to the podium and speak to the longer-term bone and
Ringel, renal effects of DESCOVY use .
If you have an additional question we will take it from there.
>> Basically, the ability to steer on multiple incidences, occurring multiple incidences.
>> The failure to what to adhere.
>> Okay .
We will present the safety data first in terms of the long-term effects, then we will talk about adherence, our, how
adherence is related to efficacy.
>> [Echo] >> To the colleague on the phone if you can mute, we are getting feedback.
>> The bone mineral density biomarker in the renal tubular biomarker is a function by markers chosen for evaluation in DISCOVER are associated with clinically meaningful differentiation over the long-term.
First we will look at own and then we will look at
renal .
slide one up please The early declines in bone mineral density between weeks 24 and 48, widen over time through three years of follow-up.
In a representative example of BMD from twofold trials in regiments in HIV treatment.
On the right you can see the separation in the BMD curves is associated with increase in discontinuations
due to to bone adverse events.
This is over a three-year time.
of data from the HIV treatment literature.
Slide two an analysis from the euro Sita
cohort with 619 fractures in
86,118 P why a follow-up.
This was adjusted for demographics in the HIV specific variables and comorbidities, having ever been
on TDF versus never been on TDF, was associated with a 40% increase of fracture risk.
Being currently on TDF versus never being off of it, was associated with a 25% risk.
You may ask what does this mean for
people on prep like PrEP ?
This is data from published earlier this year in terms of an
analysis of trials done to support the US services preventative task force recommendation with a grade A from PrEP for HIV prevention.
Here we see both TDF trials and
Truvada trials.
The follow-up was significant shorter than we have in the treatment literature, however there was an increased trend towards fractures in those receiving
TDF or Truvada.
Now we will switch to renal situations with bio markers.
A similar pattern exists for the tubular markers which are early markers of proximal tubular dysfunction.
The early changes, as early as before, and the line separate over time with longer-term follow-up to weeks 48 and week 96.
They continue to separate through week 144 .
On the right-hand side you can see there were no
discontinuations on people on DESCOVY containing regimens but the toxicity is evidenced by increasing adverse events from renal causes leading to discontinuations in a stepwise faction through week 48 through week 144.
With respect to how this is relevant for people with PrEP, we turn to this year earlier.
Here we see that either TDF or Truvada PrEP is associated with an increased risk of renal a ease
.
In summary , AE’s, we chose these biomarkers because we are aware of the clinical meaningful differentiation in terms of renal and bone safety over long-term follow-up .
And continue to follow the Testaments and discover to follow them over long-term.
>> With respect to the adherents question, I will say there have been multiple clinical trials as well as real-world data sets demonstrating the close correlation between efficacy to Truvada for PrEP and outcome .
Slide five.
This figure demonstrates across multiple different clinical trials and will world data sets that the higher the adherents within the study or within the [indiscernible] within the trial looking at adherence
participants based on plasma, levels, intercellular drug levels, the higher the advocacy with respect to risk reduction for HIV acquisition.
We saw a similar relationship within the discovered trial with respect to nonadherence to either
Truvada or transient, DESCOVY being the primary factor associated with HIV infection.
>> If I may, on the bone, do you have any follow-on questions?
If not we will have some follow-on in the room.
Dr alien on slide 105 showed TDF in adolescent bone development.
Do you have similar for TAF quick >> To review the data we have with task, TAF containing regimens in adolescents.
>> So first I will show you the data in adolescents with HIV.
Slide one up.
DESCOVY or TAF does not have the same impact on bone marrow density as does Truvada.
Here is bone safety in adolescents , adolescents with HIV.
You see both the spine and total body
cut continue to increase and grow and there is minimal changes in disease force which reflect age, race and gender matched populations.
In the Tran 12 study we included
people who were 18 and older did the age range was 18 to 76 .
however we did look at the bone mineral density in participants stratified by age less than 25.
Slide number two up.
This is comparative data between DESCOVY and Truvada ,
less than 25 years and then greater than 25 years with spine.
You can see the participants on DESCOVY continue to have the same
increase in spine bone mineral density where those on Truvada had significant declines which is particularly relevant to this population .
similar trends were observed with hip in terms of continued growth on DESCOVY or stable on DESCOVY but declines on Truvada .
>> Is this consistent with the findings and PrEP that Elian showed .
>> With this data compared to age matched controls, HIV uninfected, not on a compound, is the bone development on TAF equal , or is there a difference?
Because comparing it to TDF, one may accept the
decline in say it is not [indiscernible].
>> If we go back to slide number one.
These are participants with HIV.
So there is that consideration.
But this is people who are on Truvada .
You are asking about the Testaments on TAF .
>> Persons on TAF and am interested in the TAF comparison, not on a tenofovir
dear compound.
Because we don’t have any data
without HIV, this is with HIV.
The dotted line are the matched by age, race, gender and population.
You can see in the dotted lines between zero and week 48, there is no difference in the blue dotted line which is a spine score and the pink dotted line which is total body.
>> Those would be age matched control that’s what I thought you said, I just wanted to make it clear that best as we can tell there is no aggregation of normal bone development, as best as you can tell realizing they are HIV-infected, to be on this for long-term.
>> Exactly, thank you.
>> Was there a follow-on question?
>> My follow-up was related to the adherents question rather than bone.
The previous slide, the backup 32 showed the relationship between adherents
and efficacy.
One of the, one of the considerations is the relationship between the adherents and the efficacy on Truvada continued regimens versus TAF .
Sing in women and men, that informative thoughts as to the local tissue concentrations.
So looking at the film PrEP , versus the [indiscernible] populations, if you can go into how levels of adherence which then presumably correlate with PBMC concentrations, correlating in women versus men.
>> So the level of adherence, measured across the studies varied.
They were not all uniformly assessing adherence through the same mechanism.
However the Association between adherents and efficacy by these measures, whether it was Tenofovir, Plaza levels or Tenofovir within the peripheral blood cells, that relationship held on across men and women.
The study shown here represent some of the larger studies conducted to date.
But since Truvada the prep was approved seven years ago, there is an even larger data set that had accumulated.
The slide one please.
The CDC recently updated their website with new data on efficacy and analyses across all available data.
And concluded that adherents is highly correlated with outcomes for both men and women.
And that the efficacy of Truvada for prep is estimated to be 99% for men and for women, who are using Truvada for PrEP consistently .
>> If I can follow up on that , I guess my question goes into people who are partially adherence, to the degree it is
knowable, as partial adherents, as effective in women as in men?
I think indirectly the question as partial adherents you would think from pharmacokinetic, some of the concentrations of TF V and [indiscernible] which may not be sufficient, will it protect men and women equally.
There may be concerns about tissue.
Again partial adherents protecting women as equal as men?
Certainly there will be a relationship in adherence.
>> There was some recent data presented just a few weeks ago at the IAF conference from the [indiscernible] study which was a larger study conducted in Africa in men, looking at, it was looking at different interventions to increase adherence.
But in terms of the clinical outcomes of that trial, slide three please.
Among the 400 women aged 16 to 25, enrolled in this study, there were four infections with overall incidence rate of one, per 100 person-years.
They use dried blood spots which is the methodology from the study, as well as from Discover trials and they found that the
infections have closely correlated to these measurements of adherence using the dried blood spots, which is to say two of the infections occurred with no detectable blood level and the other two occurred in the setting of adherence consistent with less than two doses per week.
So this suggest that in the setting of low adherence there is no relationship.
>> The adherents question relates to the other question, the argument that there is high levels of Tenofovir active component and that is a correlate of protection.
My understanding is the data, those data were generated from people who were less adherent
and more adherent to the Tenofovir drug.
Is it the PMC data, are they not simply adherence if you measure Tenofovir and hair or some other body component, and do not arrive at the same conclusion that Heyer is a core elective protection for HIV
protection.
It gets to the strength of those data which are critical to this argument the company is making.
>> Sewed Tenofovir knife estate when measured in red blood cells as the stem would be dried blood, is a measurement of adherence alone.
And can be analogous to measuring Tenofovir and hair levels or
plasma, the advantage of the Tenofovir in blood cells is it
allows for an integrated affect of efficacy over a longer period of time, similar to a hemoglobin A-1 C did nevertheless it doesn’t speak itself to efficacy.
But we know for Tenofovir prodrugs to be administered, the drug is acting within the T cells which are component of peripheral mononuclear cells .
we also can draw the correlation between the level of Tenofovir by phosphate within the red blood cells, and with the
corresponding level is within PBMC based on phase 1 studies and healthy volunteers that Dr.
Anderson did to validate that analysis.
And so the dried blood spot data adherence data can hit thresholds of adherence, and based on the phase 1 study done where they did, were able to match the adherents bands exactly to how many doses were given per week, they can then correlate that to the expected intracellular PBMC levels.
We correlate that with efficacy because that’s where we know the diet
, the virus replicates.
>> Only based on adherence as I understand it.
How do we know that somebody with the exact same adherence, let me ask you differently.
How do we know that the levels in PBMC are the critical determinant of prevention, not of treatment efficacy of someone with HIV, but have prevention.
You have an established that in my mind.
>> So we know that Tenofovir ,
Truvada for PrEP is equally effective in men and women.
And adherence is the primary driver
of that efficacy.
When we look at the vegetal and rectal
tissue levels of Truvada .
I will try to slow you that slide in one minute, what we can see is the rectal levels of Tenofovir by phosphate following Truvada use are 100 fold higher than they are in vegetal tissue.
If genital tissue, rectal tissue, I will put slide one up.
These are the data I just spoke to with the 100 fold higher rec tool Tenofovir levels as compared to vegetal levels in the setting of Truvada , with healthy female volunteers.
So if genital tissue levels were driving efficacy, then you wouldn’t expect to see equal efficacy in men and women.
You would see disproportionate efficacy but we don’t.
We also know from the DISCOVER trial that DESCOVY is highly effective at preventing HIV acquisition in men who have sex with men, and transgender
women.
And slide to add in the DESCOVY data in the vegetal and rectal compartments.
What you can see is for DESCOVY , rectal compared to vegetal, told levels are tenfold higher and within the rectal compartment Truvada achieves higher levels
than DESCOVY .
So again comparing Truvada to DESCOVY, if rec told levels were driving efficacy, you would expect Truvada would be better than DESCOVY .
But that is not what we saw in the trial.
We saw they were non-inferior.
And we saw that adherence was the primary driver of efficacy.
So we know that we have these high rectal levels, we know that
vegetal levels with Truvada are lower.
But we know Truvada is highly effective in women who take the drug.
And therefore that provides evidence if you
will, that the active Tenofovir by phosphate and the circulating PBMC is driving the efficacy, and not the tissue level within the homogenate of the tissue.
>> We have several more follow-on questions.
Dr >> I actually thought was follow-on but related to the size.
A couple of statements regarding the size between Truvada and DESCOVY , how much difference in size, having an impact on, you know somebody taking it easy to take it somewhere else.
>> So DESCOVY is substantially smaller than Truvada because it catches a smaller dose.
25 milligram versus 300 milligram.
Slide one please.
Obviously not to size, but you get the relative comparison between the size of the two pills.
Size has been cited in patient surveys as a factor that is seen as favorable.
>> We are still doing follow-on’s.
>> My follow on his back to the PBMC question .
I think the data we have seen where you tried to show the correlate with efficacy was based on the [indiscernible] study with men.
We get into the Tran 12 study trial with DESCOVY.
And then where we didn’t see Truvada being effective do we know that also works for women in other trials or just in those two drugs?
>> There are other trials besides partners prep, that showed efficacy in women.
For example TDF number two was a study conducted in both men and women.
In the TDF to study if you look at the as treated population that sensors people after they have no longer been taking the drug, for at least 30 days, then the efficacy and the men and in women is comparable.
>> Actually my question was do
you have the TFE PBMC data and women know the marker Rebecca Sissy was in the trials, of efficacy was in the trials, that was my question.
>> Within partners PrEP , we had adherents but I don’t believe there was Tenofovir by phosphate levels with the Tenofovir levels .
We can take a look and see if we can find a specific data regarding Tenofovir by phosphate levels in clinical studies within women.
What I would say, I want to reemphasize that the connection between adherents and the Tenofovir by phosphate is in TDM sees, made based on, in PBMC is on the dried
blood’s not assay.
I will have Dr.
Anderson come up to speak to this so he can walk through the connection how the Tenofovir by phosphate corresponds to the level.
Because it seems like what we are talking about is Tenofovir
bi-phosphate in the PBMC’s driving efficacy.
You don’t actually measure the PBMC during the study for adherence, you measure the dried blood spot and then we know from the validated assays what that level correlates to with respect to Tenofovir bi-phosphate in PBMC .
>> I will also say we know across men, women, HIV affected, HIV unaffected that the Tenofovir bi-phosphate levels are consistent .
>> Good morning, [indiscernible] consulting honorary for my time here but I do not have a financial interest .
in the outcome of this meeting.
I wanted to explain the relationship between DBS concentrations and efficacy as well as PBMC concentrations in efficacy , if I could have slide number two up.
DBS was used in the Discover study.
As an adherents biomarker.
What we measured is enter cellular red cells.
The reason is the halfway in the red cell is 17 to 20 days.
So that means the concentration will be proportional to exposure to the drug adherence.
A proportional relationship.
So it’s a wonderful marker for assessing and quantifying adherence.
If I could have slide three please.
The way that we operationalize this is dried blood spots coming to the lab we take a punch.
So we normalize the amount we essay.
And then validate the method, to get it
resolved.
And then we have to understand what that resolve means.
To do that we conducted several observed dose in PK studies and how participants with DESCOVY versus Truvada
and gave them very and , varying adherence rates.
We could tell then the concentration, what the adherence, when we first made that standard relationship.
And then we wanted to know do these bands of adherents relate relate with this one.
And they do.
So these results are from the open label extension that show HIV incidence in the dried blood spot level.
And the difference adherence bands along the top, less than two doses per week on average .
2 to 3, and then greater than for.
People that have blood spot levels greater than four, people that had blood spot levels from 2 to 3 had approximately 90% reduction in HIV incidence related to not being on PrEP .
Holding those dosing categories in mind, this is very similar to what we see
in PBMC’s , slide to please.
So these now just switching the mind from diet, dried blood
spots, these are the active site now.
Case-control from the randomized controlled trial.
And the relationship between drug concentration and PBMC , and efficacy compared to placebo.
Now looking at the bands along the top, these are PBMC concentrations from directly observed dosing
studies showing two doses per week as well as four or more doses per week.
And we saw approximately the same efficacy relationship in the PBMC’s .
Those that were in the roughly 2 to 3 dose range, 90% reduction.
Those in the for more essentially 100% reduction.
HIV incidence is sort of the connection that we make through adherence us, through adherence is the point brought up earlier, making a connection through the adherence.
The differences we know that is the active side.
>> [indiscernible] >> You’ve sort of drawn a line between >> Please talk closer to the microphone >> You’ve drawn a line between the levels from the dried blood spot test, and PBMC levels .
And the correlation with
efficacy data.
And I guess, sort of my thesis is, because PBMC’s or T cells are the site
of replication in the virus, and that TAF has good intracellular levels in PBMC’s that the efficacy would be
expected as good or better.
But the connection between the PBMC levels in previous PrEP trials, depends on the fact, the pharmacokinetics of Truvada .
So whatever the actual target cell that is necessary for effective PrEP is, we know it correlates with the PBMC levels .
Not that PBMC’s are the actual target that makes PrEP efficacious.
How do we know that the correlation between PBMC levels and sell X, is the same with regard to the pharmacokinetics of these two different drugs?
>> So we know cell X is APB for positive T cell.
That is the only cell in which HIV will replicate to spread infection.
Now that CD positive T cell could be within the tissues.
Or it could be within the peripheral blood mononuclear cells recognizing that these are not distinct subsets, but that there is circulation around the body in trafficking of cells in and out of tissues.
I will put slide number two up
please.
And then cc 15 and back please .
just reviewing again how infection is established.
Infection is the initial established in postal transmission by the infection of a local cell.
But in order for infection to disseminate, two different things need to happen.
CD4 T cells need to be recruited to that site of initial infection, so a founder population can be established.
And then the founder population
needs to disseminate the of the lymphatic system.
And we know from nonhuman primate studies, that these CD4 T cells that form the founder population are coming from the peripheral
blood mononuclear cells.
So, we know that when you’re talking about systemic oral drug, that systemic drugs load both peripheral blood on mononuclear cells, but also drug circulating throughout the plasma.
Slide to please understanding how that infection is occurring with
systemic therapy or oral Tenofovir Pro drugs, drugs are
loaded in this peripheral blood mononuclear cells that are circulating in the body in trafficking to different locations, including the lymphatic tissue and including tissue particularly when there’s a chemo kinetic sentinel .
but also TAF in the case of DESCOVY and Tenofovir in the case of Truvada are also circulating throughout the blood and distributing throughout the body .
And so as those drugs get into the tissues, they are also able to load resident cells.
And provide protection that way.
So there are really two different ways that systemic oral agents should provide protection against HIV
infection.
Topical agents can also provide protection, but the way they do that is not by sitting on top but diffusing into the [indiscernible] and in the case of Tenofovir gel for example, they still have to get
into that CD4 T-cell.
That is the only place that HIV replicates.
That is independent of female, male, Regina or rectum.
>> I would agree with most of what you say.
I just have to disagree with the idea that there is an instant tastiness, instantaneous dynamic with cervical and other submucosal populations.
The phenotype of resident memory T cells in different tissues has been demonstrated to be different.
And there are high CCR five resident lymphocytes in vegetal tissues for example that is different, cervical vegetal tissues, and the subregional tissue is also thought to play a role.
And all I’m saying is unless one actually knows what the pharmacodynamics of G these different compounds intracellularly, different resident populations, there is not recruitment until after the virus gets there.
And there is infection locally of cells to come into the site of infection.
So the level of intracellular drug in the lymphocytes that are going to be affected immediately after exposure, is what is relevant .
that, no one has really been able to measure from what I understand.
>> Unfortunately, it is 11:07 AM
.
We need to go to the agency’s presentation.
I would have you respond but this is a longer discussion.
I think as I anticipated we almost got through one round of questions, one question.
So I will be very interested as all of the committee members on further discussion of this, I think you understand the key issue and perhaps over lunch you will further clarify how to educate us on the rationale.
We need to move to the agency’s
presentation.
And clarifying questions to the agency.
If there is time we will come back to further clarifying questions, of the applicant, after lunch.
>> Thank you very much.
>> Dr Millet thank you for presenting on the agency perspective on some of these key issues.
>>
Good morning.
I am Peter merely.
I will be presenting on behalf of the FDA review team far [indiscernible] for DESCOVY , preexposure and PrEP indication.
Here is my agenda A brief discussion is proposed by this application then move on to subcontracts and background.
In particular discussion of the issues we have been having here with regard to the role of the tissue concentrations in HIV prevention.
I will summarize the FDA findings in the DISCOVER trial with women who have sex with men.
And what’s being proposed in this application as part of [indiscernible] and data submitted for that approach.
>> This application proposes a new application for DESCOVY or
TAF , for up Rolexes to reduce the risk of sexually acquired HIV one and at risk adults and adolescents.
>> To be clear there is indication applying to adult and adolescent men who have transit and gender sex with men.
And women who have sex with men.
The indication is similar to the currently approved indication for PrEP
for Truvada .
The indication is listed for you here.
As you know the date of the agency
reviewed as part of the PrEP indication for Truvada consistent with data from the phase 3 blind placebo-controlled trial in
transgender Wender, women.
An adult heterosexual men and women and HIV discipline relationships as part of the PrEP trial.
As well as data from the phase 2 open label trial and adolescent MSM.
>> As you have heard already there are some differences between TAF and TDF , both drugs have been approved.
But compared to Tenofovir 300
milligrams and TDF of 25
milligram.
It resulted 90% lower plasma levels in the Tenofovir .
These differences in the plasma exposure to Tenofovir that makes those differences and the safety profile observed between
TAF and TDF .
, There is a reduction.
>> That said, there have been published single-dose comedies that suggest that it achieves
lower [indiscernible].
As measured in homogenates.
>> Why is this important, as you have heard in the previous discussions, the relative importance of mucosal tissue versus systemic drug concentrations to PrEP efficacy is unknown .
Importantly the minimum drug concentration in mucosal tissues if relevant would be considered protective against HIV-1 infection is also unknown.
>> That we have some indirect observations that might support a role for mucosal tissue
direct concentrations in PrEP efficacy.
As mentioned before tropical microbicide experience, vegetal mucosal
tissue at high enough levels with very limited systemic exposure can reduce the risk of HIV-1 infection.
As you have heard and other oral doses, exposure and Vaginal tissue versus rectal tissue.
This differential drug distribution has concerns in combination
with adherence may have computed, contributed to mixed efficacy results in the PrEP trials in Cisgender women .
That is a controversial topic.
It has been greatly debated the last few years did the end result is we are not entirely sure to what extent this differential may have on the efficacy.
In other words, suboptimal adherence given in women than in men.
>> These concerns have practical implications.
The CDC PrEP guidelines for example
acknowledge the lack of scientific consensus on protective contribution of drug exposure in specific body tissues.
The CDC addresses this issue by reporting the time to achieve maximum intracellular concentration of TF the DP in
PBMC’s studies and some state guidelines have also followed suit in the tissue differential also discussing the time to achieve protective concentrations.
For example New York state prep guidelines recommend a
seven-day lead-in of oral PrEP use for protection from Angel sex.
In contrast they recommend 20 days of protection with receptive Vaginal six.
And the consensus with the PK was the prime motivator or driver for PrEP efficacy .
>> As we know there are no gender differences with respect
to PK for TDF.
Given that there is a lack of consensus regarding the contribution of level tissue versus the systemic exposure for PrEP efficacy.
And these are lower mucosal tissue concentrations
with oral TAF versus TDF dosing.
The FDA determined that fully powered clinical trials would be needed to support efficacy of [indiscernible] is the active control here >> Back to the application.
The data submitted to support PrEP
for DESCOVY consist of one phase 3 double-blind active controlled RCT in the MSN/TG W DISCOVER study.
>> To support an indication of cyst gender women and adolescence and asked drug collation approach is used it
>>[Captioners transitioning] >> >>
At each follow-up as you heard they receive risk reduction counseling and adherence counseling as well as STI screening at all three anatomical sites, oral, rectal and urine.
>> A primary efficacy endpoint was the essence per 100 person-years one or subject reached a minimum of 48 weeks of follow-up at least 50% had reached 96 weeks of follow-up or permanently discontinued from the trial.
>> For the relative risk analysis #based on historical data from the three clinical
trials for prep and MSM.
Based on equal weighting of trials and HID incidents of 1.
44 was assumed for the control arm of F/TDF with the confidence
interval of 2.
60 4 analysis with the discover trial was a ratio.
The square root of the lower bound of this confidence interval provided the noninferiority margins so
the square root of 2.
64 is 162 5390 subjects were randomized in discover.
Six subjects were randomized but not treated with a safety population of 5387.
Full analysis used for the primary efficacy analysis consisted of subjects randomized in treated HIV-negative and one follow-up HIV test during the trial and
that population was 5335.
The baseline characteristics were the #[ Indiscernible ] 34 years.
99% of subjects were MSM and 1% were transgender women.
84% were white, black or mixed black race made up 9% of subjects and Hispanics 25%.
Baseline 60% of subjects reusing Truvada for prep and 44% were uncircumcised.
Meeting duration of exposure was 86 weeks balanced between the two arms.
Adherence to study was hired by multiple measures in this trial.
>> For the primary efficacy analysis a total of 22 HIV infections were reported.
Seven Indy F/TDF arm with an infection rate of 1.
06 and 50 in the F/TDF arm for HIV infection of .
342 rate ratio was 0.
68 with confidence intervals shown here.
The upper bound of the confidence interval was below the prespecified margin of 1.
62 in the discover trial we received a report of
additional [ Inaudible-Static ]
one more HIV infection inclusion.
>> Data indicates F/TAF provides a similar level of protection as F/TDF of rectal acquisition of HIV.
If we consider other potential HIV
transmission in men we do not have any direct evidence to support the efficacy of F/TAF for this low risk transmission.
We can assume insert if sex was occurring at the trial and subjects reported a mean of four, unprotected inserted anal intercourse partners prior to screening.
60% were diagnosed with gonorrhea and chlamydia likely from unprotected anal intercourse.
Given the low rates of HIV infection >> I’m going to switch gears and talk about safety as
observed in the discover trial.
Both F/TAF and F/TDF were well tolerated and no notable differences between the two arms of adverse events or laboratory abnormalities.
The most common AEs were sexually transmitted infection is [
Indiscernible ] diarrhea at 16%, nausea and 7%, headache at 7% and fatigue at 6% with comparable rates between the
arms.
6% of subjects in the F/TDF arm were considered serious adverse events and 5% in the F/TDF had serious adverse events.
The majority were not considered related to study drug.
We observed low rates of adverse events [ Indiscernible ] into percent Indy F/TDF arm.
The most common adverse events leading to drug discontinuation with gastrointestinal disorders which led to drug withdrawal less than 1% of subjects in each arm.
We look at G events overall and they attended [ Indiscernible ] with the startup syndrome described in previous trials of F/TDF PrEP.
These issues did not have a major impact on bodyweight.
There was a mean increase of weight from baseline of 1.
1 kilograms for F/TAF and essentially no change in weight in F/TDF.
>> Looking at renal safety, when we looked at the meeting absolute change in serum creatinine there was minimal change in either group at weeks 40 way #[ Indiscernible ] the mean change and estimated GFR from baseline.
The blue line shows the changes which essentially stayed consistent with baseline whereas in the F/TDF group there was a decrease from baseline over the course of the trial which became apparent as early as
week four.
The distribution of urine poking to creatinine ratio PCR categories was a key alpha protected safety in point
in this study.
PCR is generally regarded by the empty division of cardiovascular and renal products is a useful laboratory assessment.
The proportion of subjects who had no significant baseline and went on to develop [ Indiscernible ] higher in the
F/TDF group.
Conversely the proportion of subjects who had significant proteinuria at baseline which will only 25 per arm and had improvement in their category was higher in the F/TDF group and 57 versus 44% respectively.
>> These differences were statistically significant at week 48 however the differences were not significant at week 96.
We observed a greater frequency of treatment emergent proteinuria by your dipstick in the F/TDF arm a 24% versus 21 percent for F/TAF.
Most abnormalities were grade 1 and saw no difference in the frequency of potent area between the two arms.
We saw little differences in the frequencies of treatment emergent laboratory abnormalities as it pertains to serum creatinine.
2% for F/TDF and 1% for F/TAF overall and no differences between the groups with respect to hyper phosphatase man.
>> Very little difference between the groups in the frequency of treatment emergent adverse events related to renal safety.
This one case of [ Indiscernible ] syndrome as well as a case of nephrotic syndrome in the F/TDF on.
The cases in the F/TDF arm [ Indiscernible ].
When we looked at other adverse events as grouped by high-level terms whether for renal failure or impairment, electrolyte analysis, renal function and urinalysis, we saw no differences between the groups.
>> There was little difference between the two groups in the renal adverse events that led
to drug discontinuation.
>> In summary, for adverse events treatment emergent lab abnormalities related to renal functional safety we observed no major differences between the groups in this particular subject population.
I remind you as with Truvada approved labeling for discovery carries a warning for the onset of worsening renal impairment.
Moving onto bone safety.
The mean percent change from baseline at week 48 in hip and spine were a key alpha protected safety endpoint.
As shown in the table they were differences between the groups at hip and spine and it weeks 48 and 96 essentially no great change in the trend [ Indiscernible ] at each site for the F/TDF arm.
These differences were statistically significant at both time points.
>> Consistent with other tenofovir product labeling we conducted an analysis of the percent change from baseline using the following cutoffs, 7% for hip and 5% change from baseline for spine as we [ Indiscernible ] considers clinically meaningful.
We saw no difference between the two arms with the hip either decreases or increases and no difference between F/TAF and F/TDF between decreases in spinal BMT but a greater proportion of subjects in the tenant on the had a 5% or greater increase from baseline at week 48.
>> The applicant has shown your results from a categorical analysis regarding the change of the BMD clinical status from baseline to week 48.
We concur there was a greater proportion
of subjects in the F/TDF arm that had status a week 48 and a greater proportion of subjects in the F/TDF on that had an improvement of the BMD status in the hip at week 48.
When we did the same analysis we saw the differences in the proportion of subjects at week 48 and there was a greater proportion of subjects in the F/TDF arm that showed improvement.
>> When we turned to adverse events as reported in the discover trial during the course of the trial was a no differences between the two groups with respect to fractures most of which were traumatic and occurred at a relatively low rate of 2% or pathological fractures as well as in reports of back pain,
spinal pain or bone pain.
Was on the differences between the two groups with respect to what the investigators themselves reported as bone density decrease, bone loss, osteoporosis or hyper phosphatase man.
>> We looked at the meeting change from baseline in passing lipids and an overall trend to decrease it best in cholesterol and LDL in both arms but the magnitude of the decrease from baseline was greater for F/TDF and a spider decrease from baseline and fasting triglycerides with F/TAF.
However is important to note we saw no differences from baseline for the ratio of total cholesterol to HDL either within groups or between
groups.
That said the F/TDF group had a consistently higher incidence of abnormalities related to total cholesterol LDL or triglycerides across all toxicity levels.
>> We conducted a categorical analysis of a shift from baseline LDL categories as adapted from the NIH national cholesterol education program.
We found a greater proportion of subjects in the F/TDF group had worsening LDL category at week 48 compared to the F/TDF group, 17 versus 10% and a good proportion of subjects in the China group had improvement in their LDL category compared to F/TAF, 40 versus 28% respectively.
These findings did not translate to any major differences between the two groups with respect to adverse events and clinical adverse events which were very low in the trial anyway.
While the proportion of subjects who were on lipid modifying agents at study entry was balance between the two arms, a slightly greater proportion of subjects in the F/TDF arm initiated these ages during the study at 2% versus 1% .
In summary both F/TAF and F/TDF were well
tolerated and safe.
Differences between the groups were observed for various indices namely changes from baseline in renal biomarkers, bone mineral density and fasting serum lipids consistent with previous trials that compared TAF to India.
In general F/TAF and F/TDF had similar profiles including low rates of serious adverse events or adverse events leading to drug discontinuation.
>> I will now turn to our discussion of the indication
for PrEP in sis gender women.
Prep indication is challenging.
Previous clinical trials in women have demonstrated
variable efficacy of oral F/TDF .
FDA recommends designs in women because the termination of a not appear any margin is not readily feasible.
>> In this application 2X compilation strategies are proposed.
When is the extrapolation of F/TAF efficacy from MSM in the discover trial to support indication in sis gender women.
One must demonstrate exposures including plasma as well as diphosphate concentrations.
The second approach is to extrapolate efficacy and as you have heard this approach makes use of
published value as derived
[ Indiscernible ].
For this approach one must demonstrate diphosphate concentrations in systemic BK but also in cervical vaginal
tissue.
With respect to the first approach, we don’t expect there is going to be in the clinically relevant differences in the PK PPM say associated
between men and women.
For reasons that have been discussed of any matching systemic drug exposures alone may not suffice because of the unknow contribution of mucosal tissue concentrations to PrEP efficacy .
For the second approach where we try to extrapolate efficacy to support F/TAF, while there is some overlap regarding systemic drug exposures the applicant has
cited [ Indiscernible ] for PrEP efficacy.
Two things to consider.
This threshold concentration was associated with adherence to three to four doses of FTS per week specifically from the IprEx trial.
This concentration has not been validated as a PK surrogate for all populations.
The concern with relying on the PBMC threshold concentration is that may not accurately reflect the drug concentrations at the tissue level.
We know with F/TDF with multiple dosing we can achieve this threshold
concentration of 40 femtomoles.
We know this concentration in PBMC correlates to a rectal tissue concentration of greater than 100 vegetables per milligram or greater than the lower limit of quantification.
In contrast a single dose can reach this PBMC concentration of 40 femtomoles in a matter of hours.
The vaginal tissue concentration can be reported as below the level of quantification.
In both scenarios we achieved this threshold concentration being proposed as a circuit in PBMCs with diverse results in relevant tissues and concentrations.
The more conservative approach is to try to match PK both systemic and tissue to support and extrapolation of F/TDF in women as opposed to F/TAF in the same population.
For the systemic part we know TAF [ Indiscernible ].
With regards to tissue concentrations we know a single dose TAF TDF results and concentrations mostly below the level of quantification.
We don’t know is whether multiple dosing achieved different results at the tissue level and to that end data from an external study
in healthy female volunteers was submitted to support the latter part of the extrapolation.
This is the study design conducted in two parts including a single dose and multiple dose where subjects were treated for 14 days with F/TAF or F/TDF.
We are going to focus only on the approved doses for F/TAF and F/TDF.
Multiple samples were collected for pecan plasma, PBMC, rectal and vaginal biopsies and focus on the biopsies and the evaluations for Dr.
Le diphosphate concentrations.
One thing about this design is each woman contributed cervical vaginal tissue samples and only one given time point.
That is because tissue samples were collected at different clinical sites at different time points.
Rectal tissues were collected four hours post dosing administration.
Vaginal tissues collected at four hours post dose following single dose administration and following 14 the administration.
The measurement were tissue homogenous and assuming it tissue density of one gram per mL final sample concentrations in the lower limit of
quantitation of 0.
3 nanograms >> Here are the results we obtained.
Following single dose administration of F/TAF or F/TDF 83% of tissue samples were below the lower limit of quantitation at four hours.
Following multiple doses a significant proportion of tissue PK samples were also be out here.
Concentrations were higher for oral F/TDF dosing only four hours post dose.
They were mostly unquantifiable at 24 and 48 hours and unclear if this isolated finding it four hours translates to comparable
or higher Dr.
Le diphosphate concentrations in vaginal tissues beyond four hours after administration.
>> This table represents the results from the multiple dose part of the study.
It is busy so I will walk you through it.
If you look at the first row and the column for F/TDF 62% of vaginal tissue samples in the F/TDF arm were below the level of quantification.
None of the tissues in the F/TDF arm were
Dr.
Ofotokun Indiscernible ].
Similar results were seen with cervical tissue biopsies and is for the rectal tissues the results confirmed the previous reports dosing with oral F/TDF results in higher tran [ Indiscernible
].
For 20 hours at 48 hours the majority of the tissue samples for the vaginal cervical tissues were below the level of quantification and we were not able to determine and medium level for these tissues any degree of confidence.
In conclusion, F/TAF and F/TDF
afford similar protection against sexual acquisition of HIV-1 infection.
Both are safe and well tolerated.
F/TDF dosing results are smaller it
changes compared to [ Indiscernible ].
No major differences were noted with respect to the side effect profile during the course of the study.
Clinical data regarding the use of F/TAF in sis gender women are lapping
>> This application proposes a PrEP indication based on efficacy data be tenofovir
diphosphate concentrations.
The relative importance of mucosal tissue versus systemic drip concentrations remains unknown.
>> That concludes my presentation and I will take any clarifying questions from the committee.
>> Thank you.
We will now take clarifying questions for the agencies presentation and I think [ Indiscernible ] has the first question.
>> A question that may also overlap with the question [
Indiscernible ] you state TAF FTC is effective in preventing HIV in MSM and transgender women but we have never seen the transgender female data broken out in any way, do you have a sense of what that looks like or better question for the sponsor?
>> The applicant is free to chime in, first it was a very small proportion of transgender women enrolled.
I believe about dirty percent opted out early during the course of the trial.
None of the HIV infections were seen in the transgender women.
>> Any pharmacokinetic data on tenofovir versus Truvada in regards to whether any of those transwomen were using estrogen?
>> I would defer to the applicant as to concomitant medications being used by the
transgender women in the study.
We have seen reports about the
effect of PrEP with feminizing
hormone therapy.
No clinical action studies
have been conducted with TAF.
I don’t know for clinical pharmacology reviewer would like to discuss this topic further.
>> There is no clinical interaction study being conducted with TAF and feminizing regimens and drug interactions are likely to be minimal however, some studies suggest estrogen can change [ Indiscernible ] of leukocytes and analogs.
The study conducted was [ Indiscernible ]
receiving feminizing regimens that the paper published recently by [ Indiscernible ]
showing minimal changes to an for the transgender woman and
minimal changes [ Indiscernible
].
The sample size is very small.
The study showing the lower concentration of tenofovir diphosphate is mostly driven by the higher the ATP levels in rectal tissues but we don’t tab
any data [ Indiscernible ]
>> I would ask applicant, this is clarifying questions to the agency.
We realize applicant has important data so if you can keep a list of these questions and then we will come back and engage your data set after we clarify with the agency.
>> I will hold for that.
>> If we can see slide 46 again, I just want to make sure you understand, I think it was the last slide in your presentation the one described as complicated.
My question is simplistically for BLQ you want it to be lower because that is the percentage above a level that is quantified and not really telling us what level is present, it is just whether anything can be quantified or not.
I want to make sure I am reading this correctly.
I see at four hours F/TAF in the vagina appears to be better than F/TDF and and cervical tissue it appears to be better
and at 24 hours, F/TAF is not as good but neither one are very good in
both [ Indiscernible ] and have 48 hours basically they are all not good.
We are also demonstrating F/TDF doesn’t have that level of protection overtime either.
If mucosal levels are important, this slide does not demonstrate that because you are not seeing a difference that benefits F/TDF which Artie has a drug indication and has shown to be efficacious, is that correct?
>> I don’t know we can say what is better than the other, the tissue samples were just not quantifiable.
But I agree with you the TDF samples were also not showing much.
It may be an issue with the assay or the cutoffs we used to determine quantifiable.
I don’t know if the clinical reviewer has any other input here.
>> [ Indiscernible ] >> Can you tell me which number
it is?
Slide 79 .
Slide 80.
You can see [ Indiscernible ]
which makes it difficult to
compare across studies.
In this [ Indiscernible ] we
have a higher [ Indiscernible ].
The difference can be due to tissue biopsies and because it is converted from the nanogram per mill to [ Indiscernible ] per gram, if you have a smaller sample size it is possible to
have LLQ values.
Related to the [ Indiscernible ] may not have the long-term stability data
and also [ Indiscernible ].
It is probably related to the
[ Indiscernible ].
>> In thinking about this problem of understanding whether the drug levels in the genital compartment are the actual proxy for protection, have you looked at the trials were the only difference in treatment was TDF [ Indiscernible ] in a difference in plasma, genital discordance and suppression.
We know some women on suppressant therapy can still also have HIV present in the genital tract and that may be an additional way to get a differential
impact of TAF versus TDF in the genital compartment.
Can you come in from the agency perspective about how we should view the appropriate nests of an application for a drug intended all the way out to have an indication in men and women coming in with clinical trial data only for men with an expectation [ Indiscernible ].
I am concerned because often women are excluded because about possible pregnancy and of the reasons in this fee is to make a potentially concerning precedent.
Thanks >> We have not looked at that
data.
At least I am not aware if the company has that information.
The second question, ideally the agency would like to see clinical trials in the populations for which the labeling is going to be indicated.
We recognize conducting trials in women in the current landscape with
Truvada approved is challenging.
I think our first initial hurdle was to agree on
a trial period.
That ultimately was decided to be conducted in MSM and transgender women.
Discussions about a trial with women were had with the applicant and again we noticed there were
challenges and difficulties in the agency itself was struggling with the appropriate study designed to recommend for this population.
It was never really agreed-upon this particular application the way it appeared would support the
indications being requested.
At this point we are trying to work with what was submitted to
see if we can justify an indication across the populations based on a study conducted in one particular
population.
Going forward we are not recommending this particular approach.
As Dr Murray noted, this particular case is unique because we are talking about basically [ Indiscernible ] for the same drug and we have an approved drug already for Truvada and
all those populations but ordinarily we would not rely on a single trial in one population to support an indication across multiple populations.
>> An .
Giving your review of the sum total of the data, what is your impression with the agencies impression of a marker of protection in the vaginal compartment?
Has that emerged or is that still unclear given the state of the data?
>> That remains very much unclear.
I want to emphasize it is not one or the other.
It is not necessarily mucosal tissue versus systemic.
There may be a contribution of both and that is what we don’t understand.
If vaginal tissue concentrations are relevant, are they acting as the primary line of defense in the systemic acting as a backup?
I think that was a theory floated by Dr.
Anderson but we don’t know at this point.
The only thing we can measure are these tissue homogenates.
Some said this have looked at mononuclear cells within the vaginal tissues themselves and have had mixed results with respect to differences with the vaginal compartment and the rectal compartment.
I think the field itself at least to us is a bit mixed or conflicted.
The first question you asked is very much unclear in my opinion.
>> Part of the challenge, and other members of the committee have asked this, the vaginal
compartment, there are menstrual cycle issues, microbiome issues, behavioral issues that are different than other compartments and it may be adherence or PBMC concentration that may be all that matters or there may be an interaction with his other factors in trying to understand from the data available to determine if perhaps adherence is all we need which is in part which is what is being suggested but I am struck by voice and the other trials that did not show even results a protection although explanations, there it always worries me when there are lots of explanations and we are asked to embrace the positive but not worry about the negative and assume it should just work the way we want it to.
I guess my question is, should we just assume the vaginal compartment is an extension of the systemic
compartment in this setting?
This will be asked of the applicants later which is building on the conversation.
>> I think it would be challenging to do that now that we know the pharmacokinetics are very different between TAF and TDF.
I think part of the difference we see systemically may be extended to the compartments in question for various reasons, TDF itself may be cycling in the G.
I and achieve a high protection in the rectal tissue for example.
I don’t know we can confidently say we can extend systemic to tell us what is going on in the vaginal tissue.
>> My other follow-on, I will continue to follow on in this line of questioning.
>> Kind of along this line of
discussion was the significance of the time for achieving
protective concentration that was different with TDF for different populations.
What is different for men and what is different for women.
I think the guidelines varies from different state regions of the country based on the time for protective concentration for
TDF.
Do we have a sense of that variability with TAF?
>> I think the guidelines are being conservative because of this uncertainty around the role of tissue concentration.
I think CDC has presented the data for prescribers to be aware of and some state guidelines have pushed that further into prescribing
recommendations.
And trying to be the most conservative, for TAF we don’t have any information like that.
It depends of whether you believe systemic PK is the driver or protection, in which case you probably don’t need this lead-in time but if you believe it all that tissue may be contributing to PrEP efficacy, I don’t think we have any data to help us with what is going on with TAF, at least in the vaginal tissue.
>> Dr.
Swaminathan? >> These are drugs that stop viral replication, these are not disinfectants.
The applicant has a valid point that it is T
cells that are the issue.
Is it useful to look at drug concentrations of homogenates of biopsies which are primarily
everything but lymphocytes?
>> In retrospect, but probably not, going into this what we had with these single reports out there that was surprising to the community that TAF was acting so differently in local tissue compartments.
It is probably what drove us to be conservative and request a clinical trial to begin with.
If it had been established systemic PK were the main driver, we probably didn’t need the discover trial.
There was a fair amount of uncertainty as I tried to describe to you both in the literature and the guidelines.
conducted and I will say rectal tissue concentrations with TAF are lower compared to TDF in the discover trial shows comparable efficacy results regardless but we don’t know the minimum concentration.
It may be whatever concentration is being achieved with TAF in rectal tissue may suffice, we don’t know.
But you are right I don’t know tissue homogenates is the best measure to give us some valuable information at
this point, I don’t know.
[ Indiscernible ] >> Switching topics, you mentioned the idea that penal transmission or acquisition seemed reasonably protective
against here.
Did the sponsor gather data on types of sex?
Is there any signal the acquisition is more likely in
men who reported [ Indiscernible ] or so much overlap between the two in in the single person you can’t distinguish that?
>> My impression within each individual there is a variety of sexual practices that we can’t decipher if there was a subgroup that was thickly practicing insert effects.
Pretty much all of the HIV zero converters for practicing anal receptive intercourse but they also had reports of inserted sex in their.
There are individuals who reported for the most part inserted sex showed up with rectal STIs.
Again all of these reports are
self-reported.
Like I said I don’t think we had any direct evidence but given the low number of HIV infections and the fact we presumed a lot of these individuals for practicing insert effects the protection did defer to them as well.
>> [ Indiscernible ] >> Just a brief follow-on.
If I remember I think about 60 some percent were uncircumcised, any circumcision signal?
>> It was 44%.
In terms of baseline characteristics and HIV infection we didn’t see any correlation.
>> I do remember the confidence interval outside the U.
S lot higher, is circumcision involved in that?
>> I would have to defer to our statistician.
>> Please state your name at the microphone.
>> [ Indiscernible ] there is no such baseline characters that have a great impact on a final result.
>> [ Indiscernible ] >> A question about a citation you have in your briefing document, a mallet analysis that compares TDF that compares tenofovir and Truvada
versus DESCOVY and the safety data presented talks about statistically significant margins of safety, are any of these from your perspective clinically significant?
>> I think in the clinical setting, probably not but over the long term they might be.
I think the current average use of PrEP at this point is 6-12
months.
We didn’t see anything different between the two arms in terms of clinical events.
>> If you stratus by the adverse events by age is there anything that flushes out in terms of this being more common among older adults?
There are some 60 and 50-year-olds in the study.
>> There was a small number of older participants.
We didn’t see any differences come up on either end of the spectrum.
>> Dr.
gets? >> My question relates to the nature of risk population and the expected rate of HIV in the patient population.
I not was projected at a rate of infection that was somewhat higher and I wonder if someone from the agency could run through the calculations that predict what the expected rate of HIV infection was in
the actions [ Indiscernible ]
.
Having confidence of the projections of what the expected rate of infection is I think is important.
>> You mean without PrEP?
This wasn’t a placebo-controlled trial.
To that and I think you are asking [ Indiscernible ] I think the applicant did do a comparison to local geographic areas in the U.
S epidemiological data looking at concurrent HIV incidence not on PrEP and I think there were four to five incidents per 100 persons.
At least in the U population of MSM in the geographical areas where the study was conducted the incidents was much higher.
>> And the STI rate?
How does that influence your thinking of being in a high risk population?
>> Dr.
Murray has published a meta-analysis looking at various PrEP trials and tried to correlate the STI rate at least four rectal gonorrhea and the predicted HIV incidence would be.
As you heard there was a high amount of STI’s going on in this trial and based on the correlations we have looked at, that should’ve correlated to an HIV incidence of I believe six.
>> Six what? >> Six per 100.
>> So tenfold higher.
I have a follow on to Dr.
send Barry’s comment.
The issue of the trial in cisgender women you mentioned a noninferiority margin so can you help us understand, doesn’t mean it is not possible or how would you frame [ Indiscernible ] what might look like for us to understand the challenges in a [ Indiscernible ] trial.
>> The challenges we have [ Indiscernible ] and then we have one trial that could show statistically significant
protection in the [ Indiscernible ] trial that showed a point estimate that favored efficacy.
When you have such divergent results from historical trials it becomes a challenge to come up with a margin.
I don’t know if the statisticians want to discuss this but that is basically the main conundrum.
We would not be able to adequately construct a margin with such divergent variety in previous trials.
>> So in the MSM trans population we have consistent results with Truvada and it is easier to design a trial that shows consistent results.
In cisgender women where the data are very uneven it is difficult to have a trial but we should assume it should work.
I’m just trying to follow the logic of that being put before us.
>> I think a noninferiority trial would be difficult to construct.
That said there might be other possible study
designs such as comparisons to local HIV incidence in the population of study in the
community a study.
These are novel study designs we are grappling with ourselves in the agency given that we have a product on a market that is highly effective.
>> Dr.
Gripshover? >> What about a switch study?
Is that something the FDA would consider would be appropriate?
We have women already taking Truvada for PrEP.
Would that be a study design that could be
considered.
You may not have a high incidence rate but at least you are comparing it to an already approved drug?
I’m curious what the agency would think if that is the study design that would work.
>> I don’t know what the comparison would be in a switch study other than safety.
We haven’t really considered a switch study.
>> Dr.
Green? >> This is a direct follow-on.
So you can’t easily come up with a strategy to give a noninferiority study but there is no reason to presume if you did a head-to-head it would be superior and it also seems like it would be unethical to do a placebo study so we may be back
to the argument of the sponsor that there is no feasible way to assess it so we have no choice but to make a decision using extrapolation.
I don’t know if that is your intent to say but I’m hearing that.
Tell me why that’s not true.
>> I think you hit the nail on the head.
The question is how confident do we feel the extrapolation approach would be reasonable to extend the
indication?
At this point we hadn’t really discussed in the alternative study designs so that may still be on the table.
It is not a question of whether we think this is appropriate but whether in the absence of other supporting data we feel confident this might work.
>> Dr.
Ofotokun? >> I don’t seem to by the argument we can construct an inferiority margin around the data we have for women because we know from looking at the data and the studies in PrEP in women the reason were efficacy was not demonstrated that way was because of poor adherence so in studies [ Indiscernible ] the drug was effective and we can construct a margin around a study [ Indiscernible ] that
ever been done and construct an inferiority margin in the study design.
I remember the sponsor had a series of planned studies in women so how are they planning to do that if it is clinically
impossible to have a sample size calculation.
>> I will answer your second part first.
We have not seen any of these proposals and agencies the applicant has proposed.
My understanding is these aren’t going to be efficacy comparisons.
They may be safety demonstration projects.
The first question I would defer to our statistician about construct [ Indiscernible ]
>> [ Indiscernible ].
>> Dr.
Smith, you have a follow on?
>> There is a lot of work going on to develop new agents for prep for preexposure prophylaxis.
It is not clear to me whether you are saying from now on no studies will be done in women because we can’t define the margin and therefore we can’t do a noninferiority trial in the current PrEP is so effective .
I don’t understand the implications of the
decision for future trials.
Given that, it may be difficult to find a high incidence population of women in the U.
S It is certainly not the case in the developing world and I think in fact in the world at large, women are the largest number of new infections so the need for effective prevention options for women is even greater than for MSM although
not in this country.
If we are saying from now on we would do the studies and men and some PK studies to extrapolate to women, that doesn’t sound like a good scientific approach so I’m trying to understand the
boundaries you are drawing and how that will apply in the future.
>> We are not saying that at all.
There is a path forward in terms of superior designs.
[ Indiscernible ] the challenges we have drugs that is similar in terms of administration and
dosage.
If you’re looking at long-acting agency can’t do a superiority trial so that is what we have been advocating.
This is a particular circumstance that is complicated because we have two
similar products.
This PK extrapolation being proposed is not meant to be precedent-setting for future trials in women at all.
>> And we do need to remember the business at hand is the current application.
There are broader questions I think are appropriate for us to highlight as we have been doing to set the stage for data in the future that are needed to make informed choices so your points are very well taken.
I’m not sure it will result agency policy going forward but I think the points have been heard.
Sankar Swaminathan, did you have a follow on?
>> Can you clarify from an agency perspective how much of a study needs to be done in the U.
S an indication?
>> The guidance is we can accept clinical data from form studies if the [ Indiscernible ] why the data or applicable to the U.
S case 60% of the subjects were in the U.
S covered.
There is not that preponderance of foreign data but for PrEP in general and for example in women studies will be conducted [ Indiscernible ] the mechanism of transmission of HIV in the mechanism of action for the drug should be the same regardless of the geographical populations.
>> Other questions with the agency about their presentation and their analyses of the data
submitted?
If not, it is 12 20 p.
m are supposed to take a break.
I don’t think we have time to delve into another line of questioning but I think to the applicant I think you have heard issues around and perhaps after, we would do the open public session and come back to clarifying questions to the applicant but data on the efficacy entrance and data on the inserted male partner if you have it was some of the issues raised I think you have the data and we just wait for the committee to see comments around the design issue around
the cisgender female will be helpful for the committee to hear your thoughts.
You touched on them but I think they are central to our discussion.
After lunch we will have the open public session and resume the disk unction with the applicant and the agency after the agency has finished their clarifying component.
We will now take a break for lunch and reconvene in this room at 1:30 PM sharp.
****7. TRANSCRIPT 3
It will allow centers to enroll more clients especially those at higher risk HIV acquisitions.
For I continue for transparency the SAF has received problematic support from Gilead County for less than four % of his annual revenues in the fiscal year.
This statement is to write in my own professional medical review in the position of foundation and leadership and has not been influenced by Gilead was staff.
SAF enrolled 59 participants.
We understand that early Rios demonstrated very low results in the
Truvada group.
In addition preliminary discovery data suggests better renal and bone outcomes for the participants on an act.
But we agreed that the improve outcomes are likely marginal yet based on remote, motivators including those at most at risk may be more likely to engage with PrEP as more ages with improved side effect profiles are approved for
reviews.
Additionally , a strategic priority of the foundation is to center is PrEP services on communities disproportionately based on the incidence rates including black Americans.
And rolling persons in such prep show the need for
treatment.
The approval may enhance problematic capacity to provide standard prep services that CEOs like ours.
Those affected by local or other structural
factors such as depicted here.
Innovation of an express model of screening supporting conical
prep follow-ups in PrEP patients.
Clinical management of Truvada for PrEP patients baseline and episodic
monitoring every 3 to 6 months.
With conventional use of
F/TAF we believe that we can project a more inclined function in turn inability to
follow, lesson to sublet
monitoring and pure staff — with all the social classes held unchanged if approved for use and prescribed for a
portion of our.
Patients .
Thank you for your time and attention.
>> Thank you.
Will speaker numbered two bugs step up to the podium and introduce yourself.
Please state your name and any organization you’re representing.
>> Thank you for the opportunity to speak today on behalf of the national Center for health research.
And Stephanie Fox analyze scientific and medical data to provide objective health information to policymakers.
We do not accept funding for medical device company so I have no conflict
of business.
However it only provides benefit if it is effective and safe Esther Vona for each population for which is indicated.
Otherwise you to can be unnecessarily increased risk for HIV.
The discover trial phone similar rates of protection against HIV infections amongst participants taking both drugs.
While the trial seems well designed to demonstrate comparative effectiveness of the drug it is still a single trial replication is the key to scientific evidence and independent trials can result in different infection rates due to differences in demographic or profiles of
patients or other factors.
For example study participants were more likely to be white, older and better educator than the general U.
S that is at risk for HIV.
Which is the target audience for the drug.
This population may consist with people who are currently using Truvada their questions about the generalize of liability of the population that consider using the drug.
It is important to study the general U.
S at risk for HIV.
The study also found improvements for biomarkers related to kidney health and bone density suggesting that this could be safer than Truvada.
However there is only relevant if it translates into clinical medical difference related to kidneys or bone fractures.
Which were similar in both treatment groups in the
clinical trial.
The trial suggest that the benefits outweigh the risk for men who have sex with men however the benefit risk ratio was muscular for transgender men women.
This into a part of the relatively low number of transit gender might women in the trial.
The high dropout rate.
The FDA is a considering this for transgender women and the efficacy of the drug for transgender women should be analyzed.
This is important considering the recent findings
that formalized therapy can affect trucks.
Similarly there is insufficient evidence that the drug is effective and safe
for prep for ciswomen
gender women.
Similarly the benefits for adolescent boys differs from that of men and should be considered separately.
Finical trials demonstrating effectiveness and safety persists gender women and adolescents are needed if the FDA is considering approval for
them.
We understand the desire to provide a new prep treatment indicator for a broad population.
Especially when the new treatment may be expected to lead to risk for kidneys them bone density.
It is an appropriate and potentially dangerous to approve this drug for subgroups of patients that have not been adequately studied.
The law require substantial evidence that benefits outweighs the risk in the subpopulation and the new indication clinically.
Thank you >> Thank you.
>> Will speaker number threes come to the podium and introduce yourself.
>> Thank you so much.
My name is Jeremiah Johnson and I am the HIV project director at treatment action group in New York.
We appreciate the hearing is being held today considering how centrally Gilead has control this entire process on development all the way to do it laying it for decade for the medication all the way to centrally controlling the DISCOVER trial without the input of the community.
We believe it is a string important that this regulatory agency in the community begin given time to have a transparent discussion about this and to take control of the process again and away from an applicant that has a vested interest in maintaining a $2 billion a year market in biomedical convention in the
U.
S GAGAS.
Within my six remaining minutes I will go over three main points in a small amount of time.
So please pay attention.
To start we are going to be talking about in terms of representation within discover and the broader body of evidence that we have as part of this as DA discussion today.
We have number of concerns about Gilly is active campaign against his own product Truvada and what will
be generic TAF-FTC an overstatement of efficacy and
safety benefits that can be compared to that.
Have a general discussion about the lack of transparency in the
whole process and a rush process when involved in four discusses that clearly the community was not adequately consulting on early on in the process.
I will not go into this like too much.
Obviously the trial participants within the DISCOVER do not represent the broader epidemic that we see in the United States and
around the world.
With 99 paying system under men.
Were not seeing a body of evidence amongst all population that needs to be considered in terms of efficacy safety for scale of a new option.
Right now you’re hearing at the podium and there is a lot of discussion online right now and a lot of debate amounts community advocates about what the does the state of Maine and what should we be advocate and that we don’t have sufficient data.
For no good reason to we have insufficient data.
Some believe that we have to continue to advocate for an
indication for us ciswomen because they are not beneficial to the bottom line to do the follow-up efficacy research in order to get an indication for ciswomen and if we miss the opportunity there will be different PrEP for different populations.
We are concerned that we’re sending a message that we’re sending a message that if we don’t do adequate research within these populations that you don’t have to do that and you can get a broader indication anyway.
That is an enormous problem so it is up to the FDA today and going forward in this discussion whether you believe the information and the evidence presented thus far is indicative of a broader indication or a narrow indication.
What must be clear is that ciswomen cannot be left behind or other populations that are been left behind in the entire process.
If it is not approved there must be guarantee, it there must be requirements that the company
contains the efficacy, exit efficiency so that they are not left behind in the process.
It needs to be contingent on open label studies that continues to give us information for the population.
This must have been and this committee must be responsible for the deficit that has taken place.
We must see that for all of the communities that are highly prioritized within the epidemic.
We’re not prioritized within the treatment.
Will .
They are also trying desperately to even in this
room today boldly assert that it is a safer option when in fact we do not see clinically different outcomes in the DISCOVER trials and continue to downplay increases in weight and challenging issues around lipids that certainly indicate that it is not necessarily a safer option.
It is important that this regulatory body operate with the highest level of scrutiny with the labeling, marketing and educational materials that come out of the applicant should an indication be provided for DISCOVER .
Quickly these are slides that Gilead will not be presenting to date that we saw from the DISCOVER trials that they was a significant increase in
weight.
The stresses the need for additional research in this population considering that the DISCOVER was not representative of these populations.
Ultimately we had to ask what is the Russian this entire situation.
There is not one peer-reviewed publication that is, of the DISCOVER trial.
Their full transparency and we just aren’t as to see some of the information from the trial.
This is coming after a delaying tactic development.
We’re frustrated as community members that Gilead continues to centrally control this process, the FDA does not and the community has not been adequately involved so going forward this body needs to send a clear signal that any manufacturer engaged in the field of biomedical research must do a better job.
If they actually have to adhere to GPC and work with community from the start and they actually have to allow this regulatory body to come up with a robust research protocol that covers all populations and not just their bottom line.
With that I will close and just say that we require a robust post marketing research following this discussion today with the labeling and all materials need to be under high scrutiny and that we need a clear message from the F DA that this process will go better in the future with future modalities.
Thank you >> Thank you.
Will speaker number four speak up to the podium and introduce yourself.
Please state your name and the organization you are representing for the record.
>> Hello my name is [ Indiscernible ] and I’m
cofounder of the
— I wanted to review , next slide please.
DESCOVY is a correlation of two different drugs which was first approved in 2015 as part of Jen Boyer for HIV treatment
and emtricitabine 200 mg.
Act [ Indiscernible ].
This is alleged to convey certain safety benefits compared to PDF.
I think that one of the things that it’s important to realize in the entire process is that TAF is not a do drug despite being FDA
approved
in 2015.
Gilead first file a patent application for TAF cleaning priority all the way back to 2000.
Using the codename at the time was GS 7340.
All the back in 2001 regarding the metabolism of GS 7340 now known as TAF.
What we should be asking ourselves is why in 2019 are we discussing a FDA application for TAF and why don’t we have better data on assist gender women.
Has been developed when it was supposed to be developed we would’ve had
an F/TAF.
Is go through the development of TAF.
As Gilly had begun early phase 1 and two trials in 2001 and 2002 filed in IMD with the agency for the development of TAF back in January of 2002.
In October 21st 2000 force they discontinue development of TAF.
On October 2010 to restart development of TAF.
What was the reason for this top and
start approach to drug development.
You don’t have to look to me or Jeremiah or anyone in this room to actually understand what Gilead was during.
The former CEO, Dr John Milligan was one of the reasons we were concerned about development TAF was we were trying to watch to Botta versus [ Indiscernible ] and have our own study was the safest thing
on the market was the best at the time.
We are receiving mixed messages.
For those that take TAF every single day I am highly disturbed by the applicants behavior by delaying a drug that was going to produce some safety benefits to protect their bottom line rather than detect the public health.
I only wish that the FDA would share the same billing but is that the FDA reports Gilead decision to delay.
Worst of all I was quite surprised
Until this year.
Would also recommend the [ Indiscernible ] get the patent term adjustment allowable under U.
S touching the entire period of Gilly as delay as the testing phase.
This will prevent Americans from accessing generic drugs for additional five years.
This is the disturbing presence that the FDA is rewarding the decision of a Corporation to delay the development of a drug that is
now purporting is safer than
TAF-FTC.
We are pleased with a Catch-22.
On one hand we deny the ability for art DESCOVY from telling a
broad indication for and no efficacy data for this population or we choose to deny the extension of that indication and that unfortunately in today’s environment we are basically worked to deny women the choice to make the decision of the drug that they would like to take.
I believe personally and not representing my organization that it is the right choice is to extend the
indication of
F/TAF .
Ciswomen women get HIV.
The idea that the applicant will decide not to provide high-quality evidence supporting efficacy in the population is disturbing.
The fact is that this agency may be forced to grant a broad indication with no efficacy data is also disturbing.
This can never happen again.
I want to make that incredibly clear.
Ciswomen, meant to have sex with men all of us deserve medical technologies that are skimming up to fight one of the deadly police pandemics of our time.
They deserve high quality treatment.
We should not encourage companies to delay high-quality evidence for the the point of ologies.
Thank you.
>> Thank you.
Will speaker number five step up to the podium and introduce yourself.
Please state your name and any organization your representing for the record.
>> Hello.
June Gibson my brothers keeper located in
Jackson Mississippi.
My brothers keeper as a community based organization to reduce health disparity in the United
States by the well-being of minority and marginalized populations through leadership in public and community health like this is collaboration and practices.
We do it through a radio program and services including
our community-based programs and a center for research evaluation and power for change.
One of our most prominence will be open hours healthcare Center.
That is our primary health care clinic.
The center is in and a visit innovative that offers underserved, underserved population with an emphasis on
the LGBTQ+ population.
We offer an array of services including women’s health, family planning, men’s health, HIV care, mental health, preventative screening and transportation and emergency assistance.
When you look at our HIV and PrEP Mississippi we
have struggle but we have been able to accomplish some things.
If you look at our linkage for HIV testing and linkage to care where either exceeding or meeting the national goal.
However we continue to do struggle in retention and care in fire
suppression.
The PrEP data is the open hours healthcare Center.
This is a particular interest because we provide 75 % of all of the PrEP in the state of Mississippi.
As you can tell it is sparse.
We’re not in the entire state.
You can have one rest but that really optimizes and says who we are reaching the we have more to do.
There are multiple reasons why we are not able to do this in Mississippi.
We have done assessment by patients and our staff and of course there is a lack of access.
There is a prevalent thing that is around the country.
We also have stigma which is in every form of care that we provide.
There is also some other cancers that are, route our assessments with our patients.
Not only is there local recession of risk and you would think you Mississippi that is the thing but it is.
There’s a concern about side effects.
When you live in that state like Mississippi side effects are huge because we are already existing with so many other negative health outcomes.
On ways see the commercials that talk about the benefits of the medication and how wonderful they are and that last 50 seconds when they run through all of the side effects
that is what we hear.
And I hear it in particular when you think about Truvada because my dad is on the analysis.
My Alice is on dialysis.
So is my cousin.
We’re living the side of text and we need a safer option.
We need a safer option for no other reason that we have gone through enough.
We have high diabetes race, high blood pressure race, kidney failure, you name it we have it and all of this combined with
HIV.
We need DESCOVY for PrEP so we can increase utilization.
If we gave free pills every month that is accessed but access is not indicative of utilization.
So we need to have a safer option for our community.
In particular with African-Americans.
We live these health disparities.
We live the side effects and we are women in particular who may have a low perception of risk it seems as if we are taking to Botta we are trading illnesses.
I get rid of one to get another.
That is not something that we want.
Particular for adolescence and including
parents with adolescence they generally want the best for their children and they really don’t want to think about their kids having sex but we know that that is the real thing.
If they see the advertisements for Truvada and they see the side effects it gives the impression that they are going to expose their children to something that is going to give them a lifelong problem and when you’re in the state of Mississippi you see your family in a dialysis clinic.
If you had the opportunity to as a stop by the dialysis clinic.
Will see that it is filled with African-Americans.
As it relates to adolescence I actually have a call tomorrow for a parent.
Her six-year-old-year-old came to us and tested positive for syphilis and chlamydia.
She called one month later wanted to take him off of PrEP because she is so concerned with the health issues and the side effects associated with PrEP.
You and I we understand the correlation between syphilis and HIV but that is not her reality.
That is not her perception.
We all live within our perception because that is our true reality.
I will like for PrEP, for DESCOVY to be approved for prep between African-American women and
adolescent.
>> Thank you.
Will speaker number six please step up to the podium and introduce yourself.
Please state your name and the organization you are representing for the record.
>> Good afternoon.
And Kirk Myers in the prosperity in Dallas Texas.
I am the founder and chief executive officer of a AIDS prevention agency.
We provide services that address health, social and economic disparities amongst black Americans with an emphasis on the [ Indiscernible ] community and their families.
I am also a black man who has had sex with women and was living with HIV for over 26 years.
Through my lived experience and managing my disease and managing my agency dedicated to decreasing new incidence of HIV and AIDS through various prevention programs I know the delays and deliberations that are surrounding the prompt approval
of discovery for black women, trends individuals is out of sync with our real-world reality.
This captures the reality amongst my people especially those black women and trends individuals individual overrun by the socioeconomic health disparities they confront daily.
Some people have privilege on their side for time-consuming contemplation
the prompt approval of DESCOVY for the approved use of HIV for PrEP my community makes immediate choices on a day to be basis that ultimately can result in the acquisition or spread of HIV aids.
Therefore I urge the prompt approval of DESCOVY for the proposed use of HIV PrEP because it is right to give lack women, MSM the option to make a safer and effective choice on it daily basis to predict as a go about their
lives as usual.
While I work as a CEO or the street level of a sex worker I will be standing as an authentic voice to compel the advisory committee to consider the fact that I have immediate access to those who would benefit from DESCOVY for the proposed use of HIV.
I have organized community forms, focus groups and one-to-one individuals to speak with authority that this drug is wanted.
The young women gave me and confide in me have expressed [ Indiscernible ] that has the ability to protect them from HIV and AIDS with more side effects.
Finally if anything is right at this historical moment in HIV prevention it is options to go beyond the past practice of normalizing the majority and
ignoring the mud minority.
Without this option expediency , desperation and ignorance will continue to drive up the statistics of new incidence of HIV and AIDS.
With all due respect I am asking the advisory committee members to join me in doing the right thing and insist on the prompt approval of DESCOVY for
prevention of I’ve HIV for
transgender individuals who respect will speak out and share our testimony that this is the right stuff to take.
For the more we implore that this drug be approved not just in men and trans women but women need this drug and it will not be in the interest of public health to have this drug approved without including
women.
For to be stigmatized as a drug everyone deserves the same choice in prevention options as the rest of us.
Is a black man living with HIV in America for the past 26 years there has been this divide between black men and black women and when we look at options this is the best option for all of us possible.
I am not a scientist.
I do not have all the beautiful sliced to compel you to do anything that I can tell you from the grassroots level and street level that this drug is needed and if we only approve it for one indication it will create further stigma that we do not need.
Thank you >> Will speaker number seven step up to the podium.
>> I am into war and I am the executive director of New York-based organization focused
on accelerating the delivery of drugs.
I should note I was a member without any conversation of the independent data committee of the DISCOVER trial .
I stood here as some of you in this room did as well seven
years ago.
The task was easy The data was robust, the evidence was clear and I am delighted that that committee then and the FDA shortly thereafter follow the evidence and approved Tenofovir Disphosphate near .
I wish the task was as easy to date.
While the evidence is clear today we sent in an evidence free zone which has been well discussed
today.
Is the dynamics his face and I hope we don’t to return to ever again.
I have some thoughts about that toward the end.
The data or the data We must act on that most urgent data point presented at that is an epidemic that continues to multiple places in multiple populations.
What we do today matters.
Not just in the United States but particularly for
women at great risk in Africa.
Recognize full well that that is outside of the approval of the FDA and committee.
Your job is to look at safety and efficacy for the U.
S this room today recommendation made in this room by the FDA will resonate and influence the global response.
I realize that is a heavy burden but one that is real.
I am going to stick a few minutes to go through the two courses that you have on
the table.
Is very clear to me and the organization that I believe that the data presented in the application supports a noninferiority claim for PDF for oral propped for men and transgender women.
I emphasize that is noninferiority.
The DISCOVER that we assign for
noninferiority we met the test.
Not only as you make your vote today on the committee but as the FDA works around the labeling for Gilead that this be clearly registered as a non-if the area oral propped option.
Any claims of superiority I think are unfounded.
Yes there is a different safety profile.
I cited to date that it may be safer on some levels but concerns in hours with weight gain.
We need to be very clear so there is no computer to PrEP users today or users of tomorrow that we are somehow promoting one as a safer more effective drug.
This is a noninferior oriole oral drug.
One is more challenging young women.
Data was not collected in the efficacy trial.
We can quarterbacking why that was and
why decisions were made.
The best time to debate that is not sitting in an FDA hearing to consider drug approval.
The should’ve been open conversation that we had with the company, with FDA and community groups far and wide to discuss the best pathway for product development.
I do trust that that is the case and Dr.
Murray described that for next generation new chemical entity
prep agents that is not a change with what we discussed today is not creating a new status quo.
We recognize that this is a [ Indiscernible ] and based prep and I use my comments in that regard.
If F/TAF is not approved for women the only one that will pay the price is women at risk
of HIV.
Gilead will not suffer nor will others.
That said we have to be clear that safety and efficacy matter.
Based on the data is ended today and I just say in addition to not taking money from pharmaceutical companies I am not a status mission, try
list, ethicist or scientists.
There is a very clear rationale for F/TAF to work in women.
I believe that is critical to approve.
That said I believe the prep indication is to come with an incredibly strong robust and enforceable postmarketing surveillance, research agenda and a risk evaluation and mitigation strategy that makes it very clear that over the next 12 to 24 months Gilead will be responsible for collecting in collaboration with other research groups the effectiveness as well discussed efficacy of prep in women is hard to measure currently with oral propped, not impossible but hard to do, let us focus on effectiveness and ensure that FDA postmarketing ensures that we have that.
I will say in our work in Africa particularly as reported in a number of studies the pill size does matter.
It is one of the leading reasons why women in programs in Africa
do not continue the medication.
Your decision will matter and a smaller drug, not necessarily
safer or more effective will be of enormous benefit.
I want to emphasize again in closing that the education prescriber information is afforded materials that are not part of any materials that is monitored by the FDA but with community and put.
In an active way to ensure that the language used to describe this indication as a noninferior product for all populations clearly describe clearly enforced and robustly done.
So we do [ Indiscernible ] to approve for population
F/TAF for PrEP.
This is a signal of delay and distrust of the research community and product development.
At the same time committing together that we are not changing the rules for future products of new PrEP agents that we ensure that we have better conversations early in the process so that products coming to this committee and to the FDA are done with the most robust and complete package possible.
Thank you very much >> Thank you.
Once again the open public hearing speakers have presented us with
incredibly powerful insights.
In the challenge at hand before us and we thank all of the speakers for sharing your thoughts and convictions and insights and balancing this
very difficult problem.
To open public hearing portion of this meeting is now concluded and will no longer take comments from the audience.
Will no turned our attention back to the business at hand which is a evaluating the data presented before us and we will continue with our clarifying activities with the applicant.
Prior to the applicant [ Audio lost ] as I look at all of the materials we have received seem to be defined by a weight greater than equal to 35 kg.
That is not how I have thought of about adolescence.
I want to know if there is an age parameter or simply a way to parameter.
Is a 15 to 17 the end of sufficient weight or is it down to 10 or five.
I just want to know if there are any parameters around the adolescent category.
>> I think we’re sticking with weight.
It becomes tricky to decide what age one should be starting to use — >> 10 then?
>> If it is purely weight it could be a big 10-year-old or 36 kg.
>> We know the safety and have the dose down to 35 kg and exactly in a physician or person of adolescent age should consider it is probably up to them and when you put an age in their it boxes you and.
>> I thought about it was 15 or 17.
Is that purely weight-based? >> Thank you for the clarification.
I wanted to make sure that I was reading weight as the determinant and not other factors.
Okay? Back to the applicant wanted to clarify some of the concepts from this morning that you needed your input and then we will come back to the many questions we have on the list from the panel members.
>> Thank you.
We have for clarifying answers to prior questions.
The first is around the data for DESCOVY in vegetal tissue.
I want to walk through what the available data are and someone has a clear understanding of the dater and the literature.
There been three different studies of DESCOVY in vegetal tissue.
One was a single dose study of DESCOVY and the discussion of that manuscript they compared the results with another study that the same group conducted several years prior with about a.
The second study was done with a single dose of DESCOVY and Truvada within the same study.
The third city was done by the same group and multiple doses of DESCOVY and Truvada looking at
vegetal tissue levels.
Slight to.
Here are the results for most studies.
In the first study looking at DESCOVY best tissue levels following a single dose of DESCOVY the tissue levels of AC was reported as 132,098.
This was compared in across study comparison to the Truvada levels which were noted to be 1.
3 to 1 those with DESCOVY.
The second study that was done with a single dose of Truvada or DESCOVY in the same trial demonstrated that after four hours all of the samples with Truvada Cold War below the quantification and 69 % of the samples with DESCOVY was below the quantification.
The conclusion is that multiple dose data are needed.
In the setting of multiple doses which is indeed the more relevant setting to assess tissue levels for daily administered drug four hours after dosing of DESCOVY or Truvada levels were
2.
6 fold higher with DESCOVY as compared to Truvada.
FDA presented these data in their presentation.
At 24 hours and 48 hours after dosing stopped there were comparable and low levels between DESCOVY and Truvada in the battle tissue.
I would like to now put these special tissue data into context with what we know about
rectal tissue data.
The vegetal tissue or just now a graphical representation of the data I showed you as a four hour time point in the table where you can see that DESCOVY achieve slightly higher levels than Truvada four hours after dosing.
As compared to rectal tissue levels the first thing to note is that Truvada achieves about 10 fold higher levels than DESCOVY in the rectal tissue.
It is also relevant to note that the rectal tissue levels with Truvada are somewhat of an outlier as compared to the vegetal tissue levels with both DESCOVY and Truvada and the rectal tissue with DESCOVY.
This has been hypothesized to be related to the low bioavailability of Truvada and the fact that there may be drug delivered through the directly through the G.
I rectal tissue with Truvada.
If done stone to a lesser extent with DESCOVY which has higher viability Billy.
This is up hypothesis without clinical or scientific proof.
Nevertheless what we know about Truvada is that despite the lower levels in the battle tissue as compared to the rectal tissue levels with Truvada Truvada PrEP is highly and equally
efficacious and then women.
The lower levels in vegetal tissue correlate to having efficacy in the setting of Truvada for PrEP use in women.
Similarly we now know with the Discover co-trial is that despite having tenfold
lower levels of [ Indiscernible ] both drugs demonstrate that they were highly effective and DESCOVY was not inferior to Truvada at preventing HIV acquisition.
These data contribute to increasing body of understanding the systemic drug levels of what is driving efficacy and advocacy is not related to particularly
homogenous tissue levels.
I can keep going to the other issues or we can stop for comments.
>> Thank you.
Your point is well taken.
Since this is such a an important issue comments from the committee to better understand these data since
these are a critical element.
>> Lori.
concern is there are extremely
large small numbers.
I need some help understanding how generalizable these results are to the larger population.
I am unable to that based on the data presented.
>> So in terms of the generalizability all tissue level studies that have been conducted have generally been less than 10 participants per group occasionally somewhere between 10 and 15.
This is just related to the nature of the invasive nature of conducting the studies and the requirements for biopsy.
In addition we haven’t seen any of data looking at tissue level data in prevention studies because taking biopsies in the setting of individuals who are at risk for HIV infection could actually increase their risk and those data are not available nor are they likely to be generated.
So I would agree that the data are variable and that they are not a large amount of data, nevertheless when we think about what the state of Maine in the setting of high amounts of clinical data around efficacy of Truvada for prep in both men and women those data can provide reassurance.
>> A little more clarity would help to.
How is it that states are coming up with guidelines on the amount of time needed to obtain maximum intracellular concentrations and pushing in that direction when we are not able to get, we are able to get 14 participants from this study and I might also ask if it would be appropriate to ask the agency to comment on this as well.
>> Yes.
>> So during the lunch break we try to track down the
data that actually we are behind the timeline of recommendation around 20 days.
The data really came back to very sparse tissue data and there are no data that connected 20 days.
One study showed that when assessing national tissue levels in rectal tissue levels over time it seemed that as attend day time period there were stable and study state levels within the rectal tissue of time with Truvada where is the battle tissue levels were still seeing to be increasing and seems like that is the basis for the extrapolation to 20 days required.
But this is never been validated and we don’t know of any clinical data to speak to the time to protection for women.
>> Would you like agency to comment if anyone is aware of the basis for those recommendations?
>> Also if they could comment on their understanding of the uncertainty associated with the concentrations in the tissues given the small numbers.
>> We actually have concerns about the reliability of the data because of the inconsistency and the small numbers and the differences in methodology.
But that is all we have right now.
This extrapolation which has been proposed.
As to the time to achieve protection I don’t believe the CDC has a recommendation in that regard.
What they are stating is the time to treat maximum concentrations.
Some steak islands have interpreted to mean enter protected levels which make sense but I don’t know that the data is robust to that extent but needs conservative levels.
We have not introduce any of that to the [ Indiscernible ], review the data because as it stands right now PrEP is going to be using combination practices so it is counterproductive or counterintuitive to suggest a lead-in period where you come of condoms for example.
So we have not entertain that and we’re not really use the data.
I pointed out that that concerned about the differential distribution is out there and it has guiding some of these recommendations that are being protected by states.
>> To another — I don’t know one of the statisticians can comment but when I hear a number of a temple in crews in the tissue concentrations that content to stick in everybody’s mind but we have to understand the uncertainty associated with that and has a confidence been after the summated so we don’t get home estimated so we don’t get hung up on that number.
This is pretty important point but I will leave it at that and I just want to make that as a final point.
>> This is Jenny from FDA.
The [ Indiscernible ] that we have four tissues with a small numbers and presented as a median in the [ Indiscernible ] because there are a lot of low limit of connotations was observed in those tissue concentrations so this is something [ Indiscernible ].
>> It is just a minor verification about the [ Indiscernible ] tissue concentrations that generated in the rectal and but China.
Can you confirm or clarify to
me whether but China data of
the but China tissue .
I know there different sometimes for you look at the different aspects as opposed to
rectal drug concentration.
>> There is a range of methodologies used with a compartment study.
This is a method with tissues or cells are washed from the cervix and sometimes with or without scraping.
The data that is shared with you is biopsy data, the slide provides a very high level schematic of how these tissue levels are measured and whether it is in the rectum or the but China force after use to take biopsies generally with rectal tissues or biopsies are taking them with basil sampling where it externally limits want to do.
These biopsies consists predominantly of epithelial
cells and fiber blast which make up the majority of the tissue.
I will point to the limitations of the sampling.
Also contained within that biopsy will be a variety of immune cells including relevant CD4 cells and macrophages, [
Indiscernible ] and the tissue block is intubated with enzymes in order to break up the cells
because the ciswomen is released through enzymes.
The amount is quantified using [ Indiscernible ] so the toll TFK PK level that is reported is the Tenofovir Disphosphate across all of these different cell types recognizing that the predominant cells that are contributing to these levels are epithelial cells and fiber blast and it has been hypothesized that part of the reason these battle tissue levels drop off at 24 hours and 48 hours and why there are so many [ Indiscernible ] of the time measurements is because epithelial cells have a more
rapid turnover and therefore the Tenofovir Disphosphate within the epithelial cells which represent a higher proportion of contribution to the levels are turning over and are no
longer having ciswomen as a 24 hour and 48 hour time for it.
That is just a hypothesis.
>>
[ Captioners transitioning ]
>> We did look at the subset of those participants it had PK sampling done at the week four time pound and found there was no difference in tenofovir diphosphate levels within that
population.
This slide shows data on the 18 women who are part of the study that had tenofovir diphosphate levels
measured at week four.
You can see the concentration of tenofovir diphosphate is similar to what is seen in the MSM population despite being on gender affirming have [ Indiscernible ] hormones.
>> Any questions?
I think these are fairly clear.
>> The third issue was providing additional information [ Indiscernible ] >> Just to remind everyone the eligibility criteria for the discover trial were in two parts.
The first piece was requiring two episodes of condom less anal sex with more than one unique partner in the past 12 weeks prior to enrollment where the second criteria was evidence of rectal gonorrhea, rectal chlamydia or syphilis in the past six months past 24 weeks.
I have proportion people in the study and use all reported going to share the data in the people reporting [ Indiscernible ] in terms of the number of partners at screening prior to baseline.
>> The me number of inserted anal intercourse partners was four which is the same as the report of condomless anal intercourse partners.
There were no differences between arms.
All the people infected in the study, the 22 people who acquired HIV had data and biologic evidence of condomless anal intercourse.
>> Just to clarify, so I am understanding these data and
what is implied, data on men who were inserted the not receptive, so purely insert is and what degree of transmission occurred in that population?
>> We don’t have data who were people who were purely inserted but the criteria required receptive evidence of anal intercourse that was unprotected.
There was [ Indiscernible ] evidence of receptive anal intercourse.
>> Follow-on questions or clarifications?
Please continue.
>> The last topic I would like to proactively follow-up is the question about study design issues in CIS women.
As reported by panelists and community members and FDA, there are challenges with conducting a clinical trial in women and superiority store
report two oral drugs that are placebo-controlled trial are not going to be ethical given Truvada is effective in women and we talked about inferiority and the challenges around establishing a noninferiority margin and the FDA perspective on the inability to construct a non-inferior margin because of
the lack of consistency.
We did look at taking the effect from the two most effective randomized clinical trials in women, partners PrEP which was one of the registration studies for Truvada and a Bangkok study which was a study in injection drug users but most of the HIV acquisition in women was through sexual transmission.
Using the treatment effect from those two studies, we calculated a noninferiority margin using the same methodologic approach we used for discover and came up with a sample size of 22,000 in a high risk population and that would take eight to 10 years to conduct which was part of the reason we didn’t initiate that study particularly in the setting of the ongoing discover study however, we also recognized there is been a lot of discussion since 2015 about this conundrum of what could be done to assess the efficacy of PrEP in women and now where we are because of the discover results and because there is highly effective active comparator in Truvada and now
DESCOVY and men as well.
Dr Indiscernible ] has been one of the leaders in this area and we have and participating in discussions as well as with PrEP experts and community members and are some novel tile design methodologies that don’t fall within the standard rubric but I could ask Dr.
Wilson to discuss some of those approaches from a statistical standpoint.
>> Thank you.
Just to clarify the 22,000 Diana referred to would be a study in Africa so you are dealing but by
incidence rate.
In order to find the base noninferiority designed we selected two of the five women’s studies which had the most benefit from Truvada so we cherry picked the two studies to help us reduce the sample size and the lowest we could get it to was 22,000.
Now we are certainly open to more innovative ideas.
Unfortunately for us, [ Indiscernible ] a great talk a week ago and we are very receptive to some of the ideas Jeff proposed and I would like to go through some of these in terms of how a woman’s study could look.
>> All of these are proposals but it was proposed there should be at least two placebo anchors in order to interpret a woman’s study.
The two that come to mind would first and epidemiologic assessment of the perceivable incidents so we
would envision a study in Africa where it would be based on current epidemiologic data what the incident sees [
Indiscernible ].
The second approach to estimate a placebo incidence could be based on the screening period from the study so knowing how long it was from the last test to beginning treatment, that being the risk period, we can look at the subset of women not on Truvada and assess the incidence and that would be a reference
placebo incidence.
The other thing proposed in order to
assess whether a PrEP drug is effective visit should lower the incidence by five to 10
fold.
The idea came from oral contraceptives and oral contraceptives lower the incidence of about 40 fold but we are trying to be realistic.
Just for reference if you look at the discover study where the adherence was very high, we are estimating Truvada lowered the incidence by 10 to 20 fold based on two ways of estimating
the placebo incidence and [ Indiscernible ] 20 to 40 fold.
These are both effective agents.
I like to bring up slide number one which is the noninferiority study we are talking about.
Just with reference to these five studies, the two best studies, partners PrEP and a Bangkok study which had the lowest risk ratio, in partners PrEP we are lowering incidents threefold and in Bangkok we are lowering incidents fivefold.
These are just the point
estimates.
I would also add in our own demonstration project where we have got a lot of real-world data in women, our estimate we are lowering incidents approximately fivefold based on observing and
incidents of .
8 largely from cohorts in Africa where you would expect and incidents [
Indiscernible ].
The fivefold is as far as we are apparently
getting with adherence rates.
Is potentially possible to improve appearance and get greater effect sizes but
clearly the metric for what constitutes good enough efficacy will need to be tailored to the population and adherence we are getting.
>> And other criteria which is an extra criteria and not a different option is that the incidence rate in the experimental arm should be no more than .
5 higher than the active control which would be Truvada and that seems somewhat
reasonable.
Another separate approach was a part [ Indiscernible ] look at the
adherence subset of a study.
In discover if you look at the individuals who are taking two or more tablets a week, we are only seen two infections, one in each arm so we are observing and incidents of last then one in 1000 in adherence subjects and it was proposed that threshold of one in 1000 is a reasonable measure of what constitutes an effective agent.
These are all good ideas and very innovative approaches that we can leverage and work with
the FDA on to try and design a woman’s study that answers the efficacy question and we are committed to doing this.
>> Thank you.
If [ Indiscernible ] in the placebo groups I’m having trouble understanding how you come to a 22,000 person study when we look at the discover which had a one per hundred person [ Indiscernible ] you have a fivefold increase event rate it a threefold increase in sample size?
I’m having trouble understanding.
>> The main thing driving up the sample size is the weaker performance of Truvada in these women’s studies.
In the design of discover, we estimated based on the three historical controls that we would lower incidents fivefold.
When you pool these two best studies you are lowering incidents threefold so it becomes a lot
harder to attain 50% of a week affect.
>> I see your point but I am still concerned with the assumptions but I see your
point.
Other questions Goetz?
>> I want to come back to what you just said, the weaker performance of Truvada in these
women, are you stating that [ Indiscernible ]
>> It comes back to Dr.
Baden’s question as to why the sample size must be so large.
Are you projecting the women you will enroll will be nonadherent?
>> Our interpretation of the data is adherence is a primary driver of efficacy.
As you have seen presented today, there are several thousand women who have been given PrEP and over 100,000 men that have been given PrEP.
If you look at the literature there is a total of six case reports of individuals getting infected while on treatment.
It is highly unusual to get infected while on
adequate adherence and that is why the threshold of what constitutes good enough is you need to have less than one in 1000 individuals getting infected because that is what the current drugs can deliver.
>> [ Indiscernible ] >> Why did the discover study work?
It is a circular problem we are dealing with.
You expected it 10 hold higher-rated HIV then you saw in both arms.
The adherence was extremely high, higher than it was across the board in the previous studies and yet you ended up with a non-inferior drug statistically proven not inferior in this population.
I don’t get it >> My understanding is that you’re perfectly adherent to both Truvada or discovery there is no advantage to one of the other from it efficacy point of view.
That is a hypothesis data from Truvada is we are seeing, and similarly for
discovery we are seeing 2500 infections and individuals are adherent and to find there is a DBS done every three months showing adequate drug levels.
On the other end of the spectrum if you stop taking the drug completely, there is no difference between what the drug can provide because it is not providing any benefit.
To the extent that is a benefit is in the middle.
The individuals who are not fully adherent but are taking some drug in the PK properties of the drug lead us to believe at least from the PBMC levels there could be an advantage to the efficacy of discovery.
These data are somewhat suggestive.
We don’t have enough data to say even in a subset there isn’t an advantage and certainly the study overall has its own superiority but that is a hypothesis that can be tested in the future as well.
>> Dr.
Walker? >> It may not correlate to the discussion going on at hand, and forgive me if you mentioned this, there has been a lot of information presented but I wanted to know, could you go back and let us know some information about these baseline demographics and exactly how the sites were selected?
I’m curious especially within the U.
S knowing HIV is not evenly distributed among states and regions so I’m curious to know how your sites were selected and if you could just give me some details on the states if they were rule or urban and if that led to the disproportion of African-Americans in this study?
>> I will ask Dr.
McCallister to comment and describe our site selection process.
While he is coming to the podium I will say the discover study enrolled 9% overall African-American subjects within the U.
S proportion was 13%.
As I believe was pointed out earlier today, the population we enrolled into discover was largely reflective of people taking PrEP today.
It was not reflective of the people at highest risk for new infections
right now.
This slide shows the percentage of Blacks and Hispanic and Latino individuals enrolled in the discover trial on the left as compared to the percentage of Blacks and Hispanic or Latino individuals taking PrEP today in the U.
S Our proportions were similar for discover for black participants and we enriched somewhat for participants who self identified as Hispanic or Latino.
I will have Dr McCallister speak to the efforts we took to enrolled a diverse range of sites in the study.
>> We did specifically seek outside and a high background HIV incidence areas.
In the U.
S doing, almost all of them were urban centers and they were hospitals in STI clinics and
health departments.
Within the U.
S in discover, we had a large percentage in the Northeast and the Southeast in particular.
One of the findings that has come out, in an attempt to understand what the background epidemiology was of our site was we used CDC data to get HIV incidence rate in these sites and compared it to places where discover was conducted.
>> These data are incidence
rates over time at 25 metropolitan statistical areas inside the United States that overlapped with discover sites and these are incidence rates in MSM in those locations who
were not using PrEP .
What you see is over time the general incidence rate in both the discover sites as well as non-discover sites has gone down a bit but the discover sites where in places where the incidence was higher consistently over time.
>> >> Can you clarify if that comparison was adjusted for the racial and ethnic distribution of the participants matched for what the distribution is in the MSAs?
>> These data on the screen are all the people at risk with an
indication within these MSAs.
When you do break it down racially, the numbers are very close.
They range from 3 4.
2 >> I’m not sure I understand that.
What I’m asking is does this comparison, where you were saying people in high risk areas, are they from a racial and ethnic group that is at high risk in that area?
Have the HIV in Houston is an African-Americans right now.
If he only enrolled white people in Houston you would get a lower rate of HIV incidence, does this adjust with that difference?
>> It is inclusive of all people in these MSAs so the answer is no it is not specifically adjusted for African-Americans.
The rate an African-Americans were the rate in Caucasians from these locations are very close to these numbers.
>> Am I being obtuse?
>> The point has been made.
Dr Indiscernible ].
Dr >> I will follow up on what I think is his question.
You have presented data on say one metropolitan statistical area [ Indiscernible ] the MSA’s from which you recruited patients have higher rates of HIV
acquisition the other MSAs.
When I think the question is, the patients enrolled in the
study, are they representative of the racial makeup of that MSA and this would be predicted to have the higher rates or were there patients enrolled in this study populations of lower risk?
Which gets back to the question of the risk of the population enrolled in the efficacy of the intervention.
>> What I think your question is driving at is how confident can we be that we were in the right population with a high risk for HIV.
To address that I will ask Dr.
Wilson to come to the podium in the two ways we try to estimate the potential placebo rate to understand whether we were in the right population.
>> Just answer the question directly, we did an analysis where we forest the racial makeup in the MSAs to match that in discover and the rate
went down by .
3 overall in 2017 and 3.
5 when you force it to match the
racial makeup in discover.
We have looked at another method of assessing the placebo rate and that is using the rectal gonorrhea approach which I can show you.
There have been eight different cohorts within controlled trials of placebo controls.
Each of the eight black dots on this graph represent a placebo cohort and what is notable is the higher the rental gonorrhea rates the higher the HIV incidence rate in these placebo cohorts and it is a linear relationship.
On this graph we have superimposed the discover data suggest about 20 on the X axis you will see two little dots and these represent data from discover.
Great for Truvada and blue for DESCOVY .
For both arms we have the rectal gonorrhea incidence as well as the HIV incidence.
These two dots with the vertical confidence intervals which are hard to see because
they are so tight are well below what the projected placebo incidence would have been in the gray area is the
95% prediction interval around the placebo rate.
>> Dr.
Smith, did you have a follow on?
>> I had a question about the
MSA slide.
>> We will pull that up.
>> Remind me the years in which the discover trial was actually happening?
>> It started at the end of 16
and largely in 17.
>> Okay.
So incidence was falling in both sets of communities before the start of the study and you really only
have the last two time points that are presumably related to the discover trial?
>> That’s correct.
If I can have the slide on the increase relative to placebo in Truvada with the MSAs.
When we designed the study relative to the three historical studies used for the design, we expected Truvada to lower
incidents fivefold.
1 expected for Truvada versus 6.
96 in placebo from the three studies.
When you look at the actual data from discover we are noticing Truvada is lowering the incidence might 8.
6 fold if you were to use the MSA data, that is this middle estimate of the placebo rate.
The placebo rate estimate to be 3.
8 during the duration of the study versus the U.
S discover where we observed Truvada incidence of 4.
46 active control was substantially more active than we anticipated.
Using the rectal gonorrhea it is actually 19 fold reduction we are seeing with active control Truvada.
Discover was actually a better test of a new agent then we anticipated it to be.
>> Dr.
Das? >> Was it really a better test or just the prevalence of circulating HIV in the populations test might’ve been lower and therefore exposure to HIV may have been lower?
I think you made the case the at-risk behavior was relatively high but how do we know the gonorrhea curves you showed in the low rates in the discover cohort work just because there
was lower exposure to HIV?
>> If you look at the lower
bound of the interval around HIV incidence we projected for placebo so what we projected an incidence likely up of six, the lower bound is slightly above three.
In looking at the conservative miss, there is a big gap between how placebo would have performed relative to have these two agents are performing.
>> Thank you we are close to our break but before we go to our break, one last question on the cis- women.
Separate from this committees deliberation and the agencies action, what is your commitment to studies in cis- women in terms of generating the data that are absent?
>> We are firmly committed to generating data in women and asked shown we have got a number of studies that we are hoping to initiate within the next year.
Is are not traditionally powered for efficacy studies, these are clinical effectiveness studies and they are planned to be conducted both in the U.
S well as in high incidence settings within Africa to demonstrate the safety as well as the clinical efficacy across a broad range of populations.
In addition, we are committed to generating clinical data
with DESCOVY with PrEP using one of these novel approaches if we can come to an agreement on what that approach should be and Dr.
Wilson walked to some of the ideas in active discussions with investigators and experts on how to best get this done and we are committed to do it and planning to incorporate the feedback we received from FDA and from the panelists in this decision.
>> So whether or not there is the indication that is granted, you will conduct studies in cis- women to determine the effectiveness?
>> Without a doubt.
>> It is that the 10s hundreds or thousands?
>> The indication allows us to go more broadly into clinical effectiveness demonstration projects so it clearly allows us ticket to higher number and reach a higher number of women more quickly because we have endorsement from a regulatory agency that this drug is safe and effective in the population.
If we don’t have an indication, we are still generating then in women but the nature of the data has to be restricted until we get the endorsement from the regulatory bodies that we can do these demonstration projects so we are committed and we are going to generate data and I think the proportion and maybe the velocity of that data depends on where we land but the commitment is there and it will
happen.
The time period is just depends.
>> I understand.
We will take a break and resume at 3:15 PM sharp.
****8. TRANSCRIPT 4
We have several committee members to still have questions from this morning.
I will ask the committee members as well as applicants to be as poignant as possible in the questions and the response so we can cover as much ground in the next 15 or 20 minutes before we have to get to discussion about the questions at hand.
I’m going to start with questions from this morning.
Dr Indiscernible ] you are on the list.
Dr >> I have a question that relates to the slide cc 50 which was the plot looking at
the different subgroups.
I know there has been conversation, I know adolescence had been part of the populations you were contemplating including in your request for indication and I wonder if you could explain.
The closest thing we have to adolescence is age less than 25 and one of the only two data points on this curve that show
a favoring to TBD so maybe you can comment on that.
>> I will first make the point there a wide confidence intervals around the point estimate related to the relatively small sample size as compared to the entire study design.
The incidence rate within the population of participants who are less then 25 are higher than the overall incidence rates.
This is related to the relationship between younger age and lower adherence which has been demonstrated in many prep studies and certainly demonstrated in the adolescent study with Truvada and reflects those participants have lower adherence in that age bracket however both DESCOVY and Truvada were highly effective and substantially lowered the risk of HIV acquisition.
>> Thank you.
A follow on to that, safety in the younger ones, I am learned adolescence is defined by weight of the 35
kilograms.
The data you have on [ Indiscernible ] 10-year-olds on Truvada, 12-year-olds?
I want some sense if we may be giving it to our 10-year-olds.
>> We have Truvada, DESCOVY and state [ Indiscernible ] regimens containing Truvada that are indicated for adolescents to 35 kilograms and indications in younger populations based on the data we generated in treatment trials so we have nearly a large body of evidence to suggest DESCOVY therapy is safe and well tolerated in these younger populations even extending less than 35 kilograms.
>> Is that from zero to 10 years old in treatment?
>> In the setting of HIV treatment I think our lowest weight indication is 25 kilograms.
>> Again any labeling is going to need to take into consideration the absence of data.
>> I’m getting a signal the age cut office six.
>> So you have [ Indiscernible ] with indication.
Dr did you have a follow on? Dr.
Gripshover? from thsi moring
(4:00)
>> GRIPSHOVER: Yes, I had one question about weight gain, we did see one slide from the audience earlier, but I know especially in the HIV treatment world where there is a concern with obesity they think some may be related to TAF some also the integrase inhibitors I think they gained one kilogram in the the men it seems like sometimes women gain more weight so I wonder if we can have any data in women on TAF outside of this is if we are trying to extrapolate this to a broader population?
>>BRAINARD: I will ask Dr. Das to come and discuss the weight gain in the discovery study and place it into context around what we know from other PrEP trials.
I’ll also note that the data we have from other HIV treatment setting suggest there are many factors associated with weight gain and integrase nhibitor therapy being one of them and that is seen across different integrase inhibitors.
TAF in and of itself iss not associated with weight gain.
What we see in the HIV treatment staff is TDF is associated with the weight-suppressive effect and when TDF is switched to either a TAF product or a regimen without TAF that doesn’t contain TDF, that can be associated with weight gain.
>> DAS: The difference in weight in the discovery study was driven by the TDF weight suppressive effect that Diana just discussed.
We’ve known about the potential for Truvada to potentially suppress weight since the IprEx trial.
The U. P.I. has weightloss as a known adverse drug reaction for Truvada based on the IprEx trial.
On the left-hand side you see placebo across the top and Truvada across the bottom and you see with IprEx there was a weight loss through week 48 with Truvada and a weight gain on placebo.
This is in median percent changes in weight.
In discover, the Truvada arm looked similar to the IprEx arm with initial weight loss and a little bit of stabilization toward the end and the discover arm the descovy arm sorry looked very similar to the placebo.
The average amount in American age 18 to 40 gains in the year is one kilogram and the placebo weight gain in the IprEx trial and the weight gain in the discover trial on the descovy are are consistent with that. Further. if you look at HPTN 077 at 48 weeks the placebo armed gained about one kilogram.
The Cabo arm in that trial also gained gained 1.1 kilogram.
I think what we are seeing a trials that compare TDF to TAF is the TDF weight suppression or stabilization affect versus the release of that affect in switch with a lack of that affect in the TAF arm.
(7:31)
>> Thank you. Dr.Lee?
>> Can you please go back to slide cc 50 in the subgroup analysis of los [ Indiscernible ] this may have been where the incidence rate
is a little higher perhaps due
to adherence as a reason.
What was the adherence for that group and was it similar to the treatment trials you see in adolescence?
I’m trying to correlate this for younger people and if we would see the same trends.
>> I will ask Dr.
McCallister to address the issue of adherence by age within the discover trial.
I will say overall we have seen lower levels of adherence within studies of PrEP in adolescence and younger individuals and that was one of the drivers for where we didn’t include adolescence was because of the data suggesting they benefit from an increased visit frequency, they are going to benefit from increased interventions to improve adherence and have age appropriate retention and recruitment methodology.
>> So adherence in individuals less than age 25 was lower than in those above age 25.
This is the kill count data broken down by less than 25 years on the left, 25 to 50 in the middle and above age 50 on the right.
These are as you can see far lower for those less than age 25.
Another way of looking at it is true the [ Indiscernible ] data.
We see the same pattern.
Less than 25 using the tenofovir diphosphate levels and if you are in a range of four tablets per week or higher.
Of the 22 infections in discover, seven of them did occur in this group and all seven did not have technical difficulties.
>> Thank you.
Dr early in the day?
>> My questions have been addressed.
>> Dr.
Jia Donna? >> A question for the agency.
Two questions, is it within your purview to say a registration or study should include an X proportion people in [ Indiscernible ] a certain proportion are black African-American from the U.
S is that something you can say or is it up to the sponsor to design that?
>> We can make the recommendation but we wouldn’t want to hold up a trial or an approval if they didn’t meet with the suggested rate would have been in that certain population.
>> Another question is this request to approve based on essentially drug level
extrapolation for women, do you have other examples of when the agency has allowed that to happen?
Can you get any guidance on when that is appropriate or considered inappropriate at the agency level?
>> I don’t think we have any other examples.
>> The tissue level, we extrapolate efficacy for children all the time so we have matched efficacy in different populations based on systemic PK.
I don’t think we have ever made a regulatory approval decision based on a non-systemic type of PK argument.
>> And that prior decision you inferred the correlate of protection so to speak, let’s say an antibiotic level in blood where there is an understanding of the protective moiety is.
>> We have always tried to
match as much bioequivalence, I use that term loosely to the population that had the clinical data.
>> Dr.
Goetz? >> I want to go back to one of the backup slides which had shown
correlation between dosage [
Indiscernible ].
That was in the IprEx study .
What I was interested in is trying to build this bridge which may or may not be buildable, are there similar data that are inferred based on PBMC or RBC studies in women that correlate the same level of protection of two to three tablets per week as being the cut rate?
>> I will ask Dr.
Anderson to address this question about the thresholds for adherence for women and for men.
>> I would say not this level in formal analysis in women.
We just don’t have that yet.
We do have [ Indiscernible ] there is
a very recent study in women, this study is one of the very few studies in women that have collected blood spots and a marker were you can tell different gradients of adherence and this study did collect those.
They had four infections in the study and none of those infections occurred at the middle with the DBS level.
They all occurred at the low level.
>> So aside from this sparse
data set, there are no data at your disposal that will allow us [ Indiscernible ] based on a
biological measure that correlates with drug levels to protection in women and shows equivalence between the level of protection we expected in minute that level and the level of protection demonstrated in women.
>> I think these results on the screen are consistent with what we saw, it is a smaller data
set that it is consistent.
>> I would also say in the partners PrEP study there was an assessment of adherence based on tenofovir blood levels.
Unlike tenofovir diphosphate in red blood cells was is an integrated adherence
, tenofovir plasma levels were say within the last four days so this is a measurement of adherence and less precise but it does offer an objective assessment and it is referenced in the new CDC guidance as a meaningful assessment of what they call recent PrEP use which the correlate is associated with a 90% protection for both when [ Indiscernible ] partners PrEP where they look at both men and
women who had detectable levels the overall efficacy was 92% and and men it was 89% in in women 94%.
This represents a lower level of adherence and for example we saw in the discover trial nevertheless shows there is no difference
between men and women.
>> Thank you.
We made it to the list.
Other questions from the committee?
We are not all satisfied given the nature of the data but are there other questions that can help inform the committee in our deliberations?
>> If not, we will proceed to the questions to the committee and panel discussions.
It would like to remind public observers, public attendees may not participate except at the specific request of the panel.
I would like to thank Dr.
Brainard and the Gilead team for covering an incredible amount of information given the size of the problem, the amount of data could never approach the magnitude of the problem.
We were able to get through about 50% of the slides you prepared.
You have at least 1600 slides, I think we got 150 to 200 in front of us so thank you for preparing the information and sharing it with us.
>> Now we must turn to the questions at hand.
Before we moved to the questions at hand, I have some guidance I would like from the agency and if others have questions, let me
know.
I would be interested in the agencies guidance,
particularly in the cis- women conundrum.
I want to make sure I understand the Robin correctly.
There are multiple studies with Truvada, at least two showed no benefit in two showed benefit.
One led to the indication.
However these data were not strong enough to allow a determination of the study design with the noninferiority margin yet these data are strong enough to guide us with a bridging study to lead to an indication.
Is that the position we are in as we are reflecting on how to move forward with our deliberations?
>> That’s correct even though we had low efficacy in some studies, it was low or no adherence but we think it women are adherent they should be 90% affect.
>> That wasn’t strong enough to set a noninferiority margin so you can have a female trial analogous to a male trial.
>> Noninferiority studies are tricky and are you supposed to use as much is possible.
The problem with not adhere to studies is you need to assume what you saw in the past is going to be repeated going
forward.
For studies in Africa we are not sure what the adherence rate is going to be and that hampers our ability to noninferiority [ Indiscernible ] based on adherence and things we have never really looked that.
>> What tools do you have it brought indications were given to mandate or require future studies versus goodwill and intent to do future studies?
>> I would say this would be a postmarketing commitment.
Requirements are for pediatric studies and safety.
This is really expanding the indication so it would fall under a legal postmarketing commitment but this studies particularly in the HIV arena are almost always completed especially where they are important like this would be to extend the indication to women.
Anybody else want to comment on that?
>> Dr.
green? >> Again I’m going to be the pediatrician.
On the packet to have it looks like application again does include adolescence weighing at least 35 kilograms but I noticed neither question one or two addressed our opinion on adolescence they are not interested in any opinions on the committee on adolescence?
>> We were willing to extrapolate to adolescence based on what is known for PK and safety for the treatment and the fact there is an indication in adolescence for Truvada.
We are willing to make that late [ Indiscernible ] same gender in adolescence because it is the route of transmission we think it could be the variable.
>> Does an indication have to specify sex or can it specify
behavior?
So approved men who have sex with men or can it be approved for men or does it have to be approved for men?
Do you see the distinction I making?
Is that something within the labeling options?
>> Are you talking about MSM and heterosexual men and those have inserted intercourse with women or men who have sex with men?
>> It gets a little bit tricky but if the indication was limited to MSM we would have to think about how the indication would be worded for men in general.
>> [ Indiscernible ] >> Another labeling question, on a label are you able to say this truck has been studied in these populations, there is a recommendation for use in another population based on extrapolation, is that something that can be explicitly put in the label?
>> I think so.
We do that to a certain extent when we describe certain pediatric data.
>> Dr.
Smith? >> Is a possible to discuss MSM indication separate from the transgender women recommendation cry [ Indiscernible ] I have questions about one but not the other.
>> We didn’t plan to have a question answered that way but you might have that as a
comment after your vote but I think if we are prepared to go ahead with MSM I think the agency was prepared to go ahead with the transgender women as well realizing you’re not going to be up to do a power study in transgender women.
Zero conversions out of 74 are probably indicative of some protection in and of itself in the discover trial.
>> But you’re getting it just the power issue given the population sizes?
>> If you look at the IprEx subset analysis that had 200 transgender women defined slightly differently, there was no evidence of impact, statistically significant evidence of protection.
To me it is an extrapolation question.
They didn’t include enough transgender women in
order to do a separate analysis and now asking to make an indication based on the fact that works for MSM.
It was just my question.
>> I think we’re going to ask to have a vote on a package deal and then you can explain why or why not you voted for it or not and if that is one of issues you can explain that.
>> I think we will vote on the questions as written but I think your point is the guiding principle, we can then explain our concerns or reinforcements of how we look at the different
indications.
After we vote, the agency finds our comments even more helpful than our vote.
It is very important that we will vote which looks yes or no but in reality we can express different elements we find reassuring or concerning and what they should pay attention to.
I will be mindful of time, we have about 50 minutes and we have all been very energetic in this complex arena for all the reasons discussed earlier.
In the other discussion amongst the committee before we moved to the vote?
Any aspects of the data or what we are charged with that would be helpful to
discuss or clarify?
If not, I can read [ Indiscernible ] we will be using an electronic voting system.
Once we begin the vote the buttons will start flashing.
It is a new system so hopefully we won’t get confused.
They will continue to flash even after you have entered your vote.
Press the button firmly and that corresponds to your vote.
If you are unsure or wish to change your vote you may press the corresponding button until the vote is closed.
After everyone has completed their vote the vote will be locked in and then displayed on the screen.
The DFO will read the vote into the record.
Next we will go around the room and each individual who voted will state their name and vote into the record.
You can also state the reason why you voted you did if you want to.
We will continue in the same manner until all the questions have been answered.
We when I moved to the first question and I will ask if there are any questions about the question before we vote.
Has the applicant provided substantial evidence of the safety and effectiveness of DESCOVY were preexposure prophylaxis prep to reduce the risk of sexually acquired HIV-1 infection in men and transgendered women who have sex with men.
If yes provide your rationale, if no provide your rationale and list what additional trials are needed.
Please provide additional comments or thoughts in your vote.
If yes you can still have a rationale about studies that are needed.
Any questions about the question?
If not, let’s proceed to voting.
I assume the voting from our online member is being handled?
Okay.
>> For the record the vote 16 yes, to know zero abstention zero no votes.
>> We went out go around the room and state your name and your vote into the record and if you have comments to the agency please share them.
Dr Goetz?
>> I voted yes.
The discover trial supports the approval of DESCOVY .
And I think the word support is entirely appropriate because it certainly supports the efficacy, I use the word efficacy appropriately as well.
I think what is needed to enhance these trials to show the effectiveness in real world populations that expand
transgendered [ Indiscernible ] and other populations and larger populations and African-American men and populations about all patients to be fully adherent to PrEP the population tested here was a highly adherent of population but the real world I’m afraid includes individuals who are less adherent and it is very important to demonstrate the effectiveness in other populations that may face
challenges and certainly long-term safety outcomes to see whether the biologic
signals representing that task lead to clinical outcomes favorable as well.
>> Dr.
Smith I voted yes because I think there is substantial evidence to support an indication for men who have sex with men.
I am not convinced there is substantial evidence for
transgender women and I think additional studies are going to be necessary as my colleague said to understand how this is actually used in populations that aren’t at the highest risk of HIV acquisition and who stands to benefit from it.
Adolescence like men and women in transgender persons all have documented adherence problems with Truvada generally and I think it will be important to
understand how TAF adds protection or not in those populations.
>> Dr.
read? >> I voted yes and my comments have largely been stated but I think they bear repeating.
The data provided do support the safety and efficacy of DESCOVY by demonstrating [ Indiscernible ] in transgender women.
I think though there were a few infections in the
trial the high rates of STI infections and other indicators to support virus characterization.
DESCOVY appears to be safe is demonstrated in discover as well as the extensive experience in people living with HIV.
I think it has been stated that the study population enrolled and discovered did not represent the populations most at risk for HIV and therefore if DESCOVY is approved for use in MSM and transgender women the applicant should be required to collect postmarketing data on safety and effectiveness in those underrepresented populations including transgender women.
As well as people of color.
I think it is important as was raised in the public comment period the labeling and advertising should only speak to the noninferiority, not the superiority of the effectiveness as well as the safety of DESCOVY.
It is important to note the markers for kidney and bone toxicity were biomarkers only and did not indicate a clinical benefit and I also think it is important to not to disregard some of the potential negative adverse events including weight gain.
>> I also voted yes mirroring some of the prior comments, I think the data presented are very strong for supporting the noninferiority of DESCOVY for preexposure prophylaxis in men who have sex with men.
I do want to state again the importance of selling this is a noninferiority book from it efficacy and safety in overselling the safety could create an environment where drug switches are done in a way that don’t reflect the data and create significant disparities in various populations in men who have sex with men.
My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and DESCOVY be a drug for rich purple [ Indiscernible ] people so it is important we don’t oversell the elements of noninferiority.
From the perspective of transgendered individuals, I think more data are necessary.
I think in the same breath that we are going to probably discuss women we should discuss transwomen and trans men and the need and responsibility to get more robust data.
Historically the answer it is hard to do has created a lot of disparity and mistrust in public health and research among transgender individuals so we need to work with the strategies to go beyond that rather than to stay with that and ultimately I think with the caveat of work to do in the transgender population, I stand by my vote of yes.
>> [ Indiscernible ] I agree
with the comments already made.
I am not convinced we have an updated to say anything about transgender women however he did vote yes on that including that language mainly because the biological similarities, anal receptive sex primarily is the risk factor so I agree there is sufficient evidence that probably would be protected with this non-inferior drug.
>> Laura Dodd, I voted no because the question had the term men and transgender women so my concern is really related to transgender women and I agree with the comments so I won’t articulate further.
>> Dr.
Walker? >> I voted no for other reasons that were expressed.
According to the CDC more than 290,000 African Americans with stage III HAV of died since the inception of the HIV epidemic.
Is African Americans were made disproportionate risk for HIV with and bisexual men and heterosexual women being
affected more than any other race or ethnicity there was not substantial or compelling evidence to indicate the safety and effectiveness of DESCOVY for PrEP to reduce HIV infection among this population so that is why voted
no.
Is a public health researcher and a community advocate and an African-American heterosexual woman I have alarming concerns regarding the safety of DESCOVY as well as the sexual behaviors that will result from individuals taking this drug.
There was a lost opportunity to provide substantial data reflective of the community in which is greatest impacted by HIV.
The data from the discover trial failed to provide an update on the prevention of HIV in transgender women.
>> Dr.
Le voted yes with this for the reason the drug combination has demonstrated noninferiority to Truvada and offers an alternative for PrEP which is critical in the data showing why 7% of the CDC estimate of 1.
1 million people with PrEP indication actually receive PrEP.
DESCOVY may offer potential [ Indiscernible ] despite voting yes I do agree we need more information on transgendered women.
>> Dr.
Burgess? >> Tim Burgess, I voted yes.
I think the data from the discover trial met the
noninferiority to Truvada and just that in men who have sex with men.
>> Dr.
Ofotokun I voted yes for the same reasons that have been expressed by my fellow committee members.
I am convinced DESCOVY is not inferior to Truvada and I think it should be emphasized this is a noninferiority study.
Even though I voted yes I am particularly concerned about the low number of nonwhite disciplines in the study and that should be noted and I think if this moves forward the agency should strongly
recommend a postmarketing study that includes all of this population especially black men who have sex with men who are most affected by this epidemic
in the U.
S expressed there is not enough transgender women to make a strong recommendation but I believe based on the data it would be effective in this is that population that should be studied should this approval move forward.
I think we should also emphasize the side effect related to DESCOVY.
It is sold as a safer drug and it may be safer in some aspects but there are other aspects with the lipid profile is definitely something that should be emphasized and I am still concerned the jury is not yet out on the weight gain issue with TAF.
>> Lindsey Baden, I voted yes.
Highlight some key issues.
The continuum of the body of evidence from the prior studies with Truvada with discover is a continuous set of data that work well together and are very reassuring that in MSM it worked very well.
I share the concerns and the population
I thought the data met the criteria for noninferiority and have the equivalent of not severe safety profile for the impact on lipid metabolism and weight gain might balance out the bone density and renal
benefits.
The caveat the study did not include enough transgender women to allow subset analysis, the study was generally well designed including a large cohort and robust follow-up.
If approved label should highlight the noninferiority performance of
TAF and not [ Indiscernible ] not only the potential benefits in terms of renal and bone density but the potential increased risk related to lipid metabolism and rate gain and obesity.
Thank you >> We have [ Indiscernible ] on the phone.
[ Echo in Audio ]
>> Mute your computer while you speak is the advice I am giving.
What you just did work >> I voted yes.
I have concerns for transgender, I think more dated be [ Indiscernible ] yes to the way it was presented.
>> Dr.
Gripshover voted yes.
I believe the discover trial showed efficacy and safety to reduce the HIV acquisition in men.
I think it is a bit of a stretch for transgender women but I agree it is the same biologic release
method [ Indiscernible ] bone marrow density and renal function may be important in young adults [ Indiscernible ] affecting renal function for
the vast majority of people [ Indiscernible ] we need to emphasize this was a noninferiority study
>> Dr.
Siberry Like many before me I think the trial provided evidence for a claim for noninferiority as an alternative both from an efficacy in a clinical meaningful safety standpoint.
The claim would include adolescents.
I strongly support the use of weight without age down to 35 kilos and except the ability to extrapolate for adolescents.
>> Dr.
Swaminathan I agree there was inferiority as far as efficacy the and MSM but the numbers were insufficient to make a clear conclusion about transgender
women.
Nevertheless because of the number of variables that would have to be controlled for the number of patients that would have been required to be enrolled wouldn’t have been feasible and I agree it may have to depend on postmarketing evaluations but the way the question is phrased I agree they did provide substantial evidence of efficacy.
>> Dr.
Cheever? >> I voted yes I believe there is adequate evidence for noninferiority.
I am disturbed this far into the epidemic in this mini clinical trials we can’t do trials on people most at risk and that we really need to look at African-Americans and I echo other people talking about the lack of transgender women represented in this trial.
Once again that needs to be looked at to better understand the noninferiority in that population.
>> For question when it was 16-to but those who voted no there was a large consent the dated to support efficacy however it is in the population studied and limited power in transgender and [ Indiscernible ] safety signal in wait and lipids and those will all have to be carefully followed and monitored in a postmarketing
setting and expanded in the key at-risk populations and it is not inferiority and not superiority on either of the key issues.
Alec and moved to question two.
Do the data from the discover trial in combination with the available pharmacokinetic data and of the previous HIV-1
prevention trials with Truvada
in cis- gender women [ Indiscernible ] if no provide your rationale and list what additional studies and trials are needed.
Also comment on the trial design that would be adequate to expand the indication.
Please provide any additional comments or thoughts on your vote.
Any questions about the question? Dr.
Siberry?
>> Is not asking whether we would support expanding the indication but specifically saying do we think the data are the reason we would expand, am I reading that right?
>> My read of this in the agency can correct me, do believe there dated establishing substantial efficacy and save the in this population and how the information is provided, is that the intent of the question?
Does that answer your question?
>> Yes.
>> If no other questions, let’s vote.
Our online voter is being handled.
One more person needs to vote.
>> Everyone repress your button.
Just keep voting.
For the record the vote is eight yes and 10 no.
Zero abstention and zero no voting.
>> We state your name and your vote into the record.
Dr Cheever.
>> No.
I think the company demonstrated the difference in metabolism between TDF and TAF and we do not know the protective factors for PrEP and how it works in the mechanisms.
We do know we have differences in immunologic male youth between the [ Indiscernible ] so have concerns about what has been shown.
That said I wanted to vote yes because the thought of not having this indicated for women I think will only further inhibits the implementation of PrEP among women.
From a public health perspective it is more harm than good and not approving it for this indication but that wasn’t the question that was asked so that is how I split that.
We have talked about it all day long, the failure to implement PrEP women is huge and we keep glossing over it and I think that is the wrong conversation to be having.
Is about why women in my transgender persons in youth and what we can do to better get them to have protective effects of prep and women [ Indiscernible ] we weren’t having today.
>> Dr.
Swaminathan no.
I would just go to the reasons.
As far as the question as to what the data allowed you to conclude is what is key.
The sales being affected in the vagina and service versus the rectal and penile mucosa are not clearly defined.
Although virus epithelium must affect cells resident in all tissues, the resident target cell population at the time of exposure is the local pool of lymphocytes.
This pool is relatively static and more so in vaginal tissues than the G.
I and replenished by local
expansion.
The PK in PD in this lymphocytes may not be the same as those in the peripheral blood or other anatomic sites.
We just do not know.
The relative efficacy of TAF and TDF made different between rectal and vaginal tissues and between MSN and cis- gender women.
[ Indiscernible ] is not relevant as unlike with [ Indiscernible ] measured primarily in cells infected by rather in both populations of heterogeneous cells from biopsies.
While there is evidence of the safety profile particularly for long-term use this has to be balanced against the possibility of in peer efficacy.
A relative lack of efficacy may translate to a currently incurable infection.
When has the potential choice between long-term morbidity versus immediate risk.
I do not believe we can state with scientific validity TAF [ Indiscernible ] in cis- women for PrEP.
Extrapolation is defensible if there is no scientific reason there could be pharmacokinetic or pharmacodynamic differences between the groups.
That is not the case here and therefore the basis for extrapolation is not obvious.
The absence of clinical data in this group combined with the potential difference in the sight of exposure and other potential gender-based biological cofactors do not allow me to recommend labeling this drug as effective and I do not believe the drug should be approved or labeled without adequate evidence merely because doing the necessary clinical studies
would be challenging.
The alternative is to expose segments of the population underrepresented in studies to ineffective therapy.
>> Dr.
Siberry I think there is good evidence of a biologic [ Indiscernible ] I remain unconvinced we have a good dialogic Corlett for protection.
The reasons Dr Swaminathan said, I think it is inappropriate to extrapolate to women however I feel like we have field women by letting this implication come in without data from women to begin with and I fear failing them again by having an approval for use in men and not women.
That is why I asked for the clarifying question about the question because I think these are two different things and I would be supportive of an indication that includes women with a strong postmarketing requirement for clinical evaluation.
Thank you >> Dr.
Gripshover? >> Barbara Gripshover, I voted no.
I do not believe the data would support [ Indiscernible ] not studied in that population and I don’t think it is clear just
the level [ Indiscernible ]
.
I believe there is a large unmet need of a women [
Indiscernible ].
While I do not like the idea of approving a drug for single population I also think we are obligated to base our recommendations based on data.
Women deserve our best efforts
[ Indiscernible ].
If the drug is approved for MSM I would require us to have an efficacy study in women as part of the agreement.
>> Dr.
Lupole You are on mute if you are talking.
We may have lost the
connection.
>> I voted no as well.
The lack of data and study participants and conflicting data.
It is my recommendation the trial for
this drug in cis- women and [ Indiscernible ] has not been presented to me that it would be safe and effective.
Thank you.
>> Dr.
Green? >> Michael Green, I voted yes but I almost abstained and I almost voted no.
With regards to [ Indiscernible ] the key concern of the FDA appeared to be relating to the tissue level in the vagina and cervix and those associated with TAF were lower than TDF.
There for the absence of the trial in cis- gender females to determine efficacy they are asking us if we can extrapolate to extend approval based on [ Indiscernible ] population.
The data presented suggests low levels both the four hours and 24 hours and 48
hours and yet F/TDF carries an approval in men, women and analytics for preexposure prophylaxis against HIV and considered effective if those taking it are
compliant.
Is not clear low tissue levels have any impact on the effectiveness of Truvada and seems unlike the to me it would for DESCOVY.
Clearly there is not a concern that intracellular levels would be different between men and women.
We heard the agency stated they feel challenged by developing design for noninferiority studies and no reason to expect a positive outcome in a superiority trial and comparison to placebo would be unethical.
I felt it was appropriate to include cis- gender women in the indication especially given the equity issues that have been discussed during this hearing.
Having said that that would be
important to mandate
postmarketing studies in this indication be undertaken by the sponsor and the subsequent studies did not bear out [ Indiscernible ] the label be modified to reflect this if not having the indication removed.
Thank you >> Dr.
Weina but the answer is really maybe.
The reality is we really don’t have a clue which is the appropriate surrogate marketer use.
Is at the tissue level? Potential the PBMC levels?
Is it adherence or more likely something we haven’t even considered yet because we haven’t bothered to count it in some revelation years from now will finally give us that insight.
Right now it seems like the surrogate marker selected depends on which opinion you would like to have supported and the science behind it itch whichever you select and that seems very whimsical.
I reach back to the FDA mission statement and the mission statement is to promote and protect the public out by helping [ Indiscernible ] reach the market in a timely manner and monitor the products for continued safety after they are in use.
This product is out there for treatment and Artie demanded by patients who are subjected to social media pressures and this is only going to accelerate.
I have no doubt this is already being used in cis- gender women in the United States and it is not being followed.
We should follow the FDA mission statement to get this to the market for the broadest population possible and reasonable and monitor the product for continued safety.
Here of course I’m referring to the efficacy because if it doesn’t work then it is putting the users at risk.
If approved for MSM and transgender women it is definitely going to be used either off label or unable in analytics and cis- gender women just because of the perception of better safety.
We may as will carefully guide the post-market surveillance of this product and how well it works.
Clearly when he carefully prescribed and intensive postmarketing required trials.
>> Dr.
Baden, I voted no The question was, do we have substantial evidence of safety and efficacy?
There are no efficacy data presented.
Data are too strong to allow placebo trial but too weak to allow a noninferiority margin.
When his pieces of data the use to say we cannot study this population and I share the open public hearing speakers as well as [ Indiscernible ] we failed
women to be at this point and not have the data to guide decision-making is a shame on all of us.
I feel like Aerosmith.
We are in a desperate situation therefore let’s do something because we can do something in there are side effects to or interventions.
Our interventions are not benefit with no risk and the presumption we can benefit a not have risk is also shame on us.
We need to generate some data to guide the risk-benefit ratio and the road traveled for prevention in women is uneven with high-quality large studies so far as to presume the good data are the ones we should
hang our hat on his sumptuous.
I think given the mixed historical data the absence of data with this particular agent I cannot support an indication which is efficacy.
On the other hand there should be a mandated study, whether is mandated as part of an approval or mandated to get approval.
Both can be done but it should be mandated.
I think once the risen approval it is impossible to undo even if there is no benefit shown.
If there is no approval the pressure is to do the study but then there are women at risk who don’t have this medication and hence we have this population but I voted no because there were no data in the population in question.
Dr Ofotokun.
>> I voted yes.
Taking a look at the data as a whole.
DESCOVY data and the historical data from Truvada.
Based on data in HIV-infected individuals treated with DESCOVY I am convinced the product is just as safe in men and women and the big question is that of [ Indiscernible ] in cis- women.
I tend to have some confidence in the pharmacokinetic data in the
Corlett of Truvada.
[ Indiscernible ] protection, I
seem to believe that in itself provides a strong compelling
data
that TAF [ Indiscernible ] I agree it is a terrible failure the agency as well as a sponsor would come to this committee with lack of data for
women.
I strongly believe like others have expressed their should be a mandated study to look at
women, cis- women [
Indiscernible ].
I also believe DESCOVY for men who have sex with men alone would create [
Indiscernible ].
The equity issue that already exists that either you were going to prove it for the indication for PrEP in men and women or you’re not going to move forward.
I think treating a two-tier prevention and treatment will not be helpful and we should remind ourselves there are more women living with HIV in the world than there are men and the risk of new infection is significantly higher among women if you look at this globally.
I will stop there >> Dr.
Burgess I voted yes but as others have said I nearly voted no and nearly abstained.
I share their concerns about what we think we understand about the punitive mechanism of protection
depending on route of exposure but my overarching concern was about the public health impact of an indication in one population and not in another
population coupled with the fairly compelling articulation of levels in PBMCs as the primary if not total component of the mechanism of protection
led me to vote yes.
I would like others articulate a strong
recommendation for compelled post-market [ Indiscernible ] in women.
>> Dr.
Le ] largely based on three factors.
Data print dating [ Indiscernible ] some safety data from other studies in making this drug combination available as an available option for women and not just for men.
My vote for yes is contingent upon full commitment from the applicant to incorporate a robust package labeling stating efficacy and effectiveness have not been established in cis- women with the use of this product in the vaginal tissue penetration was low and the approval was based on extrapolation of existing data in the other population.
The applicant should commit to conduct robust postmarketing
studies to allow for us to better understand efficacy and/or effectiveness as well as incorporating safety monitoring for weight gain, renal function, plasma lipid levels.
>> Dr.
Walker? >> It was a strong know for me.
No wavering on the fence.
I most highly appalled.
Is about eight women on the committee in the agency and the applicant [
Indiscernible ] or heterosexual women or women in general.
I was highly appalled that more dedication and passion wasn’t put into the study.
>> Dr.
Dodd? >> I voted no and I was not on the fence.
My concern is about confusion or lack of trust that might be generated by an approval that wouldn’t be supported by strong science.
We can’t approve something just because there is a need.
I want to commend the agency for their good discussion about surrogacy.
I think this is often a confusion in the reviews of studies.
There lots of reasons why good Corlett of protection may fail as a surrogate endpoint for the clinical benefit in point, in this case the endpoint is protection.
The Corlett is not a surrogate make.
We have seen dated to support PBMC is a good marker of protection and women
but we have not seen the data and I thought the agency did a good job of providing reasonable arguments about why PBMCs may not be a good marker of clinical benefit.
There probably should be both data related to the biological mechanism supporting additional surrogacy studies.
This looks like or studies on tissue concentrations and additional studies in cis- women with an actual clinical benefit and point of protection.
I’m not convinced there is not a study design out there that would support this.
I don’t know it would have to be something as large as a 20,000 participants study but I think it is time to put some creative heads together and think of some feasible designs.
>> Dr.
Giordano no.
It pains me to say that believe there is the potential for creating one drug for the rich, one for [ Indiscernible ] that is a horrible precedent.
The FDA approval to me means we know this drug is safe and effective.
I’m convinced we note this drug is safe, no drought about that but is it effective?
That remains a hypothesis.
Given there is different biology involved, I think you need efficacy data and it just boils down to that for me.
I think we are in this position and it is absolutely horrible but that is the position we are in.
I don’t envy the agencies ultimate decision but to me there is no way you can say this drug has efficacy in cis- gender women .
Who is to blame for that is not my decision.
>> Dr.
Daskalakis yes.
There are couple of reasons.
We have had success with topical agents that we know of to prevent HIV and we have seen data and
intracellular levels that seem to be protective so that in combination for the role of PBMC level and intracellular level and prevention made me feel I had enough evidence to recommend you consider approval for this drug for cis- gender women.
I would put the caveat that labeling would be critical.
[ Indiscernible ] I also think it would be important to state there is not been it efficacy study done.
From a safety perspective I agree with what everyone else’s said.
I think safety has been demonstrated.
I don’t think the approval of this drug would increase 15 uptake among women.
That is not the problem, at least in the U.
S the pill and a marginal
improvement.
The problem is the patients and providers are unable to do an appropriate assessment who needs PrEP and I’m concerned creating the tiered system will create even more confusion with providers [ Indiscernible ] that makes me concerned.
I think a mandatory study no matter what, whether it is after approval or preapproval requiring that it is critical and that needs to help answer the question about intracellular level versus mucosal level so good science that looks at the role of mucosal levels of tenofonir in women would be critical.
I would also think about coupling the transgender women study against the women study since they are women and that’s probably it to wait to [
Indiscernible ].
Another thing I want to bring it recently is the precedent for extrapolating
data.
We have U health services recommendations
that PrEP [ Indiscernible ] tenofonir could potentially be used as monotherapy to prevent PrEP in women and heterosexual males and females and injection drug users.
I do not see us having a conversation about using [ Indiscernible ]
so we can [ Indiscernible ].
I would encourage the agency to consider looking back at the Bangkok PrEP study and [ Indiscernible ] and ask if we should be asking the same thing about a drug that could cost last then five dollars a month.
>> Dr.
read with a lot of the same hesitations.
Just to be clear I also agree it is extremely disappointing to be in a situation in which there are no clinical efficacy data in cis-
gender women .
A population [ Indiscernible ] however I felt
in this case it was reasonable to extrapolate data from the [ Indiscernible ].
Although cis- gender women were not included it is reasonable to extrapolate safety [ Indiscernible ] I think it is unlike the safety profile would differ.
In the absence of clinical efficacy data in cis- gender women and the question of the relevance
of PK, extrapolation is not straightforward although the collected data regarding PK levels contain mixed results.
It is reasonable to extrapolate
clinical efficacy [ Indiscernible ] on the basis of the data provided indicated
higher levels [ Indiscernible ].
It is also unclear what levels
are required [ Indiscernible ].
I think it would be problematic to approve an indication who have men with sex with men alone and subsequent delay in access for women would be an
unfair situation and I think should be given to the approval with the broader indication to include women or no approval until adequate efficacy can be achieved in that population.
If an indication is approved like others I recommend strongly [ Indiscernible ] performed trials to collect safety and effectiveness data.
Not only is the effectiveness important but the safety profile needs to be further supported.
It is important the company has attested and pledged they will perform these trials and it is up to the agency to require them to do so.
>> Dr.
Smith like we are moving backwards from the 2012 meeting that approved Truvada in which there was a lot of discussion and concern that we had data [ Indiscernible ] now we don’t have data on women at all.
The decision has been made we would do the trial and MSM and figure out what it means for women rather than studying women
themselves.
I find that bad science but also disrespectful in an issue of research equity.
Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment.
I also think because we have Truvada approved for women we are not denying women access to PrEP and it is important to remember that.
What we are doing is saying a second drug that is similar in risk and benefit is available to one population but not another yet based on the data we have and I think that is preferable to approving it, doing and efficacy study, and somebody suggested maybe taking it back or modifying it if it doesn’t work out as well.
That’s a recipe for disaster among the African-American community if we get ourselves into a situation where we are proving something and then saying we weren’t right.
I wouldn’t even think about doing that.
The other thing is even though we think about the fact it may be hard to explain [ Indiscernible ] for this group or that group, I think it the proper studies are done in the short term over the next three or four years to get the kinds of data that are missing, we will be in a position to say whatever is appropriate about women, I think we are going to increasingly in the PrEP field have the situation of some rings are for some people and other things are for other people whether that is [ Indiscernible ] if that becomes approved, that is surely not for all populations.
I know we are nervous about what that means when we suddenly have to
start making decisions but I think this is not the occasion in which that should overrule the absence of data on efficacy for women as the basis for our decision.
>> Dr.
Goetz yes.
I think unlike the other eight people who voted yes, I do not hear a ringing endorsement from anyone of
strong data.
I read the statement [ Indiscernible ] is a livable statement [
Indiscernible ] what we know about surrogate markers, correlates of protection, I think quality is a light word in many regards.
The fact of the matter is we will need a face for mandated clinical trial to substantiates this is an alternative and any guidelines or documents produced by other societies the strengths and weaknesses of this, the conditional nature, and this is an alternative needs to be very clear.
I felt strongly that I’m not sure tissue markers are a surrogate either that has been pointed out by many individuals.
First of all we get very limited samples and secondly the sales we sample are not likely relevant cells so we either need robust data showing across levels of different adherents, inevitably some people are less adherent and we need to correlate if are going to substantiate in any way PBMCs show the correlate between PBMC and protection is similar across the relevant risk groups.
I think that would go a long way to demonstrating what we need to show.
I think adherents is a crucial measure.
What we have in this drug, the population that was extraordinarily adherent.
That is wonderful but we need to be clear and really emphasize adherents throughout this drug [ Indiscernible ] but that is
not to be taken [ Indiscernible ]
>> Thank you.
There you have it.
Eight to 10 vote key principles as I hear it is I will summarize the yes and the no together, the correlate is unclear and perceived differently.
The optics of approval for population A but not population problematic as many deleterious effects it done or if not done and everyone agrees there needs to be actual data so the challenge, and I will be
presumptuous [ Indiscernible ] into the agency and applicant, [ Indiscernible ] there should be a way to do some type of study systematically in a reasonable amount of time if there is collective will to generate data expeditiously and that would [ Indiscernible ].
Many of us believe this would work and should work but we cannot guide policy or regulatory pathway.
We have run 15 minutes over.
I would like to thank five minutes to discuss the last question and that will be an open discussion unless the agency advises me otherwise.
The open discussion is pleats is is whether the data from the discover [ Indiscernible ] I will open the discussion and look for
disagreement that have elements that are analogous to MSM in the sense of the biology and how the drug works in the nature of the exposure.
We weren’t able to extract [ Indiscernible ] presumably there would be some of that in the population in the biology in the prior experiences such that I don’t think it is unreasonable to think it is likely to work in that population but I would like other comments from the committee as to if others agree it should likely work in that population or if there are concerns as to why it may not.
>> Were talking about HIV uninfected men having sex with the discordant partner, female partner.
>> And circumcision has not been addressed but other presented strategies would be maximally encouraged.
>> I agree with your general view that this can be extrapolated but I do think the data should be looked at more carefully from the discover trial.
The enrolled people who had condomless anal sex so I think the collective information about practices you may be able to segregate those practice predominately inserted sex from those who didn’t and
see if there was a difference in the levels of infection in the two arms.
The overall infection risks are probably lower in both arms of that group if you limit it to those but we should ask for additional scrutiny of data.
>> And perhaps new data to look at that population.
Dr Gripshover?
>> I do think the fact 44% uncircumcised this means there was a group that it not yet even used that other protective so I think that is helpful.
>> Given the way the trial was enrolled, the data is just not there so I’m not sure you can actually extrapolate anything from that trial.
>> So what is your view on the applicability to men who have vaginal sex?
>> In my patient population I
have individuals that I have in my patient population that are
at high risk in heterosexual relationships and come to me and are actually on Truvada for preventive reasons but the data is not really there to support it.
It just makes sense based upon the data that is out there so there is an extrapolation because the individual is at very high risk and everything we can do to help prevent it is something worthwhile as long as they are properly informed as to the risks associated with taking the medication as well.
>> If you have MSM you have inserted and receptive, presumably the insert if risk would be similar to the [
Indiscernible ] therefore data suggests it works in that population even though it is not specifically pulled out.
That would be suggestive it is likely to work in that population.
>> Like I was talking about before, suggestive and correlates [ Indiscernible ] >> These are human data in men who are in study on drug and not getting affected.
This is not extrapolating from assays that we are not completely sure what they tell us with the Corlett that we are not sure what it tells us and five people.
>> Sure.
Given the potential outcome of not putting the individual on Truvada when they come to me with exceedingly high risky behavior with multiple unknown partners on a
regular basis, I informed them of the risks associated with it [ Indiscernible-Multiple Speakers ]
>> Just teasing this issue with the issue about the need for a study in women, it seems as if there is another for another heterosexual study like a partners PrEP .
>> Part of a challenge there is treatment [ Indiscernible ] >> But there is still an environment where it is feasible so it Mrs.
[ Indiscernible-Multiple Speakers
].
You get have [ Indiscernible ] the sample size will probably have to be bigger and in fact may be smaller.
>> The point is there are parts of the world in which this could be done just like we do malaria studies and other parts of the world because we haven’t got a whole lot of malaria in the United States to get new drugs approved.
>> Dr.
Swaminathan little more you can extrapolate from.
You have data that in discordant couples where the
woman is positive that
tenofonir works and MSM couples it works and we have evidence that TAF works and MSM couples and now you were just sort of bringing in the fourth variable in the mix of those variables to say [
Indiscernible ] and TDF also works for this situation.
You can sort of extrapolate a little bit more from that but you would expect the person that was protected by TDF in the partner study to be protected by TAF in the future.
>> Another piece of supporting
evidence is the incidence of [ Indiscernible ] in the patient population which I think is 15 to 20% so there was substantive
exposure [ Indiscernible ] and yet if I recollect the data properly all the cases of infection were amongst those people who had receptive anal intercourse so what we don’t know [ Indiscernible ] the presence of the [ Indiscernible ] is a strong piece of evidence in favor of the fact there was a risk.
>> Dr.
Smith? >> I think that touches on a lot of the key issues around this question.
Are there any other issues the agency would like us to address?
If not, I would like to thank the applicant were tremendous amount of data being presented and entertaining a lot of discussion in a challenging area.
And agency for sharing your views and the challenge.
The panel members for robust high-energy day in covering a lot of complex issues and the public as well for sharing your thoughts and I was see if the agency has any closing remarks.
>> On behalf of our division at the agency want to thank the committee for their thoughtful discussion and deliberations today.
I also want to thank the speakers who commented during the open public hearing as well.
I want to thank the company for conduct in the discover study and other pertinent research and for committing earlier in the day to conduct a trial or trials in
women.
Also want to thank the trial participants as well.
Lastly I’d like to thank our staff for their dedication and diligence in conducting the reviews and preparing for this committee.
I want to leave you with a couple thoughts before we end.
Our review of this application continues.
We have not made any final determinations as of today and your comments and the discussions will greatly impact
our final determination.
Lastly, I feel like we should dedicate our collective efforts to ensuring the availability of safe and effective medications for all populations so the next time we meet we can definitively state the HIV incidence in the United States has substantially declined in all populations and we are moving closer to defeating this epidemic.
Thank you very much >> Thank you.
I will now adjourn the meeting.
Safe travels.
>> [ Event Concluded ] >>
Prophylaxis 