What will Gilead’s study of F/TAF among cisgender women tell us about next gen PrEP and next gen trial design

The FDA’s October approval excluded F/TAF as PrEP “for those who have receptive vaginal sex.” Many voices have expressed outrage that Gilead’s strategy for F/TAF regulatory approval left women by the wayside. Gilead had previously claimed finding a relevant cohort of women would not be feasible. Gilead is designing a novel trial, planned to begin in Africa in 2020, to gather missing data about the safety and efficacy of F/TAF among cisgender women. What are the implications of this trial?

On Wednesday, November 13, the FDA’s Jeff Murray presented how an innovative design will enable a relatively smaller trial, and the questions it raises.

Recording and Slides: YouTube / Jeff Murray’s Slides

Next week, on November 11th, 13th and 15th, AVAC and partners will continue the webinar series addressing key issues related to the US FDA’s October approval of F/TAF as PrEP and its supplemental approval directing drug maker Gilead to conduct a trial among cisgender women. See below for webinar details and registration links, and check out the first webinar in this series from last month for more background.

Dubbed Descovy by its maker Gilead, F/TAF has prompted heated discussion on several critical fronts. The recent FDA approval excluded “those who have receptive vaginal sex” due to insufficient data about safety and efficacy among cisgender women. Following this decision, Gilead is going forward with a new trial among cisgender women that will involve innovations to trial design. In addition, advocates have posed important questions about how the safety data compare between F/TAF (Descovy) and TDF/FTC (Truvada) and the implications for marketing and access. To explore these and related questions, AVAC, IRMA, TAG, WRI and The Well Project are hosting a series of webinars.

It’s Complicated- Implementation questions regarding price, programming and policies for Descovy as PrEP

November 11, 10:00 – 11:15am EST
Register here.
We’ll probe what Descovy’s market presence will mean and discuss the advocacy priorities to meet the challenges and opportunities. These questions are informed by the fact that Truvada (aka TDF/FTC) is set to go off patent next year, several generic options are waiting in the wings, and funding PrEP-related services in the US rely on key programs. The presentations will be moderated by Kathie Hiers, CEO of AIDS Alabama, and include Amy Killelea (NASTAD), Tim Horn (NASTAD), David Hardy (HIVMA and Johns Hopkins University), and James Krellenstein (PrEP4All).

Trial Design Takes a Step in the Post PrEP Era: What will Gilead’s study of F/TAF among cisgender women tell us about next gen PrEP and next gen trial design

November 13, at 10:00 – 11:15am EST
Register here.
The FDA’s October approval excluded F/TAF as PrEP “for those who have receptive vaginal sex.” Many voices have expressed outrage that Gilead’s strategy for F/TAF regulatory approval left women by the wayside. Gilead had previously claimed finding a relevant cohort of women would not be feasible. Gilead is designing a novel trial, planned to begin in Africa in 2020, to gather missing data about the safety and efficacy of F/TAF among cisgender women. What are the implications of this trial? In this webinar, the FDA’s Jeff Murray will present how an innovative design will enable a relatively smaller trial, and the questions it raises.

PK, PD and F/TAF: What does an advocate need to know about the pharmacology of safety and efficacy and today’s PrEP drugs

November 15, 1-2pm EST
Register here.
Leading pharmacologists including Angela Kashuba (UNC), Craig Hendrix (Johns Hopkins) and Pete Anderson (University of Colorado) will join in a discussion on the important pharmacokinetic and pharmacodynamic questions related to F/TAF and TDF/FTC. We’ll explore questions about what drug levels matter, and where in the body drug needs to be to protect against HIV.

Check out the first webinar in this series from last month where we explored the background science of F/TAF vs TDF/FTC as PrEP.

As always, the webinars will be recorded and posted on the AVAC website. And we welcome any questions in advance!

Yesterday, the US Food and Drug Administration (FDA) announced its approval of Gilead’s drug Descovy (also known as F/TAF) as daily oral PrEP for adults and adolescents, except those who have “receptive vaginal sex.”

AVAC and allies immediately decried the announcement, which lacked an acknowledgement of the gap in data on those at risk of HIV via vaginal sex. The announcement also failed to include any information about a funded plan and timeline for gathering the data necessary to understand if this drug prevents HIV infection among cisgender women.

The FDA has since posted its approval letter, which outlines a post-marketing commitment ON GILEAD to conduct a trial in cisgender women, with data expected in mid-2025. As Gilead plans and conducts this long-overdue trial, there’s vital work to be done around early and integrated Good Participatory Practice and community engagement starting now, not after the protocol is approved, and sustained throughout the life of the trial.

Join us and other advocates for the first of a two-part webinar series on F/TAF as PrEP. We’ll explore the science and research—and the community response to these developments.

Advocates’ Debrief on the Science of Daily F/TAF vs. TDF/FTC as PrEP

• Monday, October 7 at 9-10am ET
• Co-convened by AVAC, TAG, The Well Project and the Women’s Research Initiative (WRI)
• Recording and Slides: YouTube / Andrew Hill’s slides / Monica Gandhi’s slides

As always, please send any comments or questions.

Please join AVAC, the Treatment Action Group (TAG), The Well Project and the Women’s Research Initiative (WRI) on Monday, October 7 at 9-10am ET for an Advocates’ Debrief on the Science of Daily F/TAF vs. TDF/FTC as PrEP.

REGISTER HERE.

This webinar is the first in a two-part series, responding to advocates’ desire to better understand the research to date on F/TAF as PrEP, especially as it relates to its safety profile [compared to TDF/FTC] and the lack of robust data in cisgender women. This issue came into greater focus during an August 7 FDA advisory committee meeting at which Gilead’s regulatory submission of F/TAF for PrEP was discussed and debated.

On the webinar, AVAC, TAG, The Well Project and WRI representatives will be joined by researchers Andrew Hill (Senior Visiting Research Fellow in the Pharmacology Department at Liverpool University) and Monica Gandhi (Professor of Medicine and Associate Division Chief of the Division of HIV, Infectious Diseases, and Global Medicine at UCSF/San Francisco General Hospital). They will share their take on the latest research, contextualize the August 7 discussion, and help to inform an advocacy agenda for next steps.

For background, check out AVAC’s blog for a recap of the advisory committee proceedings, as well as TAG and PrEP4All’s joint comment to the FDA.

The webinar will be recorded and posted online shortly after its conclusion.

Have a question or comment? Please be in touch!

A few important new resources are up on AVAC.org and PrEPWatch.org. Read on for highlights and links.

Global Guidance

Don’t miss AVAC’s Take on Updated WHO Guidance on Hormonal Contraception and HIV Risk. You’ll learn “business as usual” is a grave concern in light of the World Health Organization’s (WHO) updated guidance on “Hormonal Contraceptive Eligibility for Women at High Risk of HIV”. The changed status of the hormonal contraceptive DMPA stems from a review that was prompted by the results of the ECHO Trial.

F/TAF and Women

In our blog, “A New Oral PrEP Strategy Is On the Horizon, But Who’s Going to Get It?” you’ll get the details on a potential new oral PrEP strategy using F/TAF, which inched a step closer to availability—though not necessarily for all people who need it. The blog provides information on what happened at an Antimicrobial Drugs Advisory Committee meeting on F/TAF for PrEP, convened by the US Food and Drug Administration—and what needs to happen next.

PrEP and the Challenge of Continuation

Watch the webinar, Identifying PrEP Continuation Challenges and Approaches to Support Success, to hear implementers from Kenya (Jhpiego/Jilinde) and Zimbabwe (PZAT) share PrEP continuation challenges, successes, and approaches. And learn more about findings from a recent think tank our Prevention Market Manager project co-convened with a number of partners on defining impact and success in the context of PrEP, and key considerations for measuring and monitoring continued and effective use.

Fellows in 2020

Apply to become an AVAC fellow, or send this application to someone who you know belongs in AVAC’s 2020 class of Advocacy Fellows. AVAC’s Advocacy Fellows Program has been supporting and expanding the capacity of advocates and organizations to accelerate, shape and monitor biomedical HIV prevention research and implementation since 2009. Our Fellows have gone on to become leaders in the HIV movement in their communities, countries and globally. Don’t miss your chance to join the next class—deadline is September 20th!

Earlier this month, a new daily oral PrEP strategy using F/TAF (brand name Descovy), inched a step closer to availability—though not necessarily for all people who need it. It’s a mixed moment. More strategies are good, but it is unacceptable to skimp on research in ways that leave women or any other population out. The history of the AIDS epidemic is, in part, the history of moving ahead based on research in the bodies of people assigned male at birth—to the detriment of essential knowledge about what works for cis (and trans) women and transmen. This blog provides information on what happened at an Antimicrobial Drugs Advisory Committee meeting on F/TAF for PrEP, convened by the US regulatory body, the Food and Drug Administration (FDA)—and what needs to happen next.

What’s the New Strategy?

Gilead Sciences, the developer and patent holder for Descovy (F/TAF), submitted an application to license F/TAF as a daily oral PrEP strategy for HIV prevention. TAF and TDF (TDF is one of two drugs in the combination TDF/FTC that the FDA approved for PrEP in 2012) represent different prodrug versions of the same compound, tenofovir (TFV). A prodrug is a drug that works only after our bodies have processed, or metabolized, it. It gets activated as our bodies break it down. Many drugs just start working without this activation step, but tenofovir is not absorbed well without this step. TAF is similar to TDF in many ways, but TAF gets metabolized inside cells not the blood. Cells are where the drug needs to be to stop HIV from establishing infection. This difference—being activated at the site where protection is needed, versus in the blood—means that people need a lower dose of F/TAF compared to TDF/FTC to achieve protective drug levels. This also translates to a smaller pill for F/TAF.

How Is F/TAF Different from the Already-Approved TDF/FTC?

Gilead claims that the lower circulating blood levels for F/TAF (described above) might reduce the risk of some of the side effects seen with daily oral TDF/FTC for PrEP (as well as for treatment, for which both drugs have been approved). These include bone density loss and kidney function issues. While the side effect profiles of the two drugs are different, AVAC and other activists have pushed against any claims that F/TAF is “better PrEP”. We welcome strategies that reduce pill size and that may lower toxicities and side effects (less tenofovir in the blood could mean less risk of renal toxicity and bone density loss, both possible with long-term TDF use). But, we don’t want Gilead or anyone else to argue that F/TAF is “better” or “safer” PrEP unless the data clearly show that. As we wrote to the FDA, “Any claims of superiority of F/TAF are an overstatement of the data and, more importantly, will cause enormous confusion among both users and providers of PrEP… All labeling and marketing materials should clearly state these as equivalent daily oral PrEP options.” Click for more on concerns about how Gilead described F/TAF from AVAC, and the Treatment Action Group (TAG) and PrEP4All.

What Happened at the August 7th Hearing?

Gilead presented data from the Phase III DISCOVER trial of daily F/TAF as PrEP amongst men and transgender women who have sex with men. It showed that daily F/TAF is as safe and effective as daily TDF/FTC for HIV prevention in these populations. There is no similar efficacy trial amongst cisgender women, but Gilead did present data, including from a small USAID-funded pharmacokinetic study from research NGO CONRAD, that Gilead hoped would allow extrapolation of efficacy to support a PrEP indication for F/TAF in cisgender women. This CONRAD study of daily oral F/TAF in 72 HIV-negative cisgender women measured the levels of tenofovir (TFV) in the blood among participants. In that study, participants taking F/TAF for PrEP had protective levels of TFV in their blood. (This blood level—associated with a greater-than-90% reduction in risk of HIV acquisition—derived from efficacy trials of TDF/FTC in cisgender women.) The vaginal tissue concentrations in samples in the CONRAD study, though, did not allow the FDA to make any conclusions about protective levels for F/TAF. Since there is no consensus about which levels—blood or tissue—matter most in predicting efficacy, the FDA presentation found it could not conclude that this extrapolation was justified.

AVAC and partners, including TAG and PrEP4All, attended the Advisory Committee and submitted both written comments and presented during the open session of the meeting. The key points from AVAC’s testimony are at the end of this update; additional background materials from the meeting, including submissions from a number of organizations and individuals can be found here.

How Did the Committee Vote?

The Advisory Committee overwhelmingly voted to recommend F/TAF for PrEP in men who have sex with men (MSM) and transgender women by a vote of 16-2. But the committee split 10-8 against recommending F/TAF for PrEP in cisgender women. The panel’s recommendations are advisory to the FDA but are usually followed by the agency. This means that the FDA could approve F/TAF as PrEP for MSM and transgender women, without approving it for use in cisgender women. FDA is expected to announce its decision in early October.

What to Watch For

• The FDA decision. Their decision is expected approximately two months from the time of the Committee meeting and vote. Advisory Committees provide the FDA with independent advice, but final decisions are made by FDA. The FDA could accept the Committee’s recommendation to approve F/TAF for MSM and transgender women (but not cisgender women), approve a label for all people at risk, or deny Gilead’s application altogether. Typically, the FDA accepts the Committee’s recommendation.

• Regulatory filings in Europe and Africa, and WHO prequalification and guidelines. The DISCOVER study included sites in Europe, and Gilead will presumably be filing with the European Medicines Agency (EMA) for registration, and/or with national regulatory agencies in Europe.

  Will Gilead file for an MSM and transgender women indication for F/TAF in Africa, and would that make F/TAF use unsafe given the rampant homophobia and stigma still present in many communities?

  If registration will only be in Europe and the US, will Gilead file for WHO prequalification, which would allow F/TAF to be purchased by PEPFAR or the Global Fund? And how would WHO modify its PrEP guidance if F/TAF is approved by the FDA?

• Safety and effectiveness data in cisgender women. Whether the FDA approves F/TAF for cisgender women or not, there is an urgent need to collect more data in cisgender women, as well as other populations that were not represented well or at all in the DISCOVER trial. AVAC has argued for full approval, with a clear requirement for Gilead to develop and implement a robust post-marketing research agenda to provide data on safety and effectiveness among cisgender women. Gilead has heard collective deep disappointment with their decision not to test F/TAF as PrEP in ciswomen—will they now act?

• Pricing of F/TAF. Branded TDF/FTC, or Truvada, is shortly coming off patent in the US, finally opening the US market to generic TDF/FTC. What will this mean for pricing for branded F/TAF? The list price in the US for F/TAF is currently identical to TDF/FTC, but the generic price for F/TAF is unknown. It should be less expensive to produce F/TAF because it uses less active drug. Even so, Gilead will likely price it above, and possibly well above, the generic price for TDF/FTC. For public agencies, which still fund the majority of PrEP use either through programs like PEPFAR, national insurance schemes or health programs, any significant cost difference may lead them to stick with TDF/FTC. Gilead’s pricing of Truvada, which has limited PrEP uptake in the US, has been under criticism and legal challenge from groups like PrEP4All.

AVAC’s Bottom Line

• The available data support approval of F/TAF as an additional non-inferior oral PrEP option. While Gilead representatives and researchers did present data at IAS 2019 that F/TAF was superior in safety and possibly in efficacy to F/TDF, claims of superiority of F/TAF are an overstatement of the available data and could cause confusion among both users and providers of PrEP. An indication that claims superiority could cause actual harm as potential TDF/FTC users delay initiation or current TDF/FTC users abandon PrEP use until F/TAF is later available. We were pleased that in their comments, the members of the Advisory Committee reinforced this view that if approved, F/TAF should not be marketed as superior to TDF/FTC.
• We support labeling that includes cisgender women as a population that can benefit from F/TAF as PrEP. F/TAF and TDF/FTC represent different tenofovir prodrugs. Gilead did not plan an efficacy trial in cisgender women, hoping that bridging data would be sufficient. There are differing views about which biologic samples matter most in bridging across populations, but the data that were presented do, in our minds, support a label that includes cisgender women. While the Advisory Committee did not vote in favor of recommending F/TAF as PrEP for cisgender women, the comments from the committee members (irrespective of how they voted) did highlight the importance of requiring Gilead to collect this data in the most ethical and expeditious manner.
• Any indication should be subject to specific post-marketing surveillance, Phase 4 studies and a robust Risk Evaluation and Mitigation Strategy (REMS). We know from earlier oral PrEP trials [of daily TDF/FTC] that efficacy in cisgender women can have wide confidence intervals. Recent data about lipid and weight-gain side effects of TAF compared to TDF, especially in women and individuals of African descent, make strict post-marketing surveillance critical. And, these post-marketing plans should also include other populations (e.g., adolescents and transgender men) that were not part of the DISCOVER trial.
• Given the fundamental need for additional prevention options for cisgender women, AVAC believes the insufficient process for collecting data in Gilead’s product development plan for F/TAF thus far could be major setback in HIV prevention, and we join the chorus of advocates who are disappointed at Gilead’s lack of commitment to robust testing of this drug for PrEP in cisgender women. This is a unique situation, given that TAF is closely related to TDF, and not an entirely new product. Approving oral F/TAF for PrEP on the limited data is warranted in this case, but should not be the standard by which additional, novel PrEP options are tested and approved. We urge the FDA to hold product developers to a higher standard in drug development plans that will gain sufficient data across a range of populations in a timely and efficient manner, and in advance of regulatory submissions. Robust data across a range of populations at risk of infection must continue to be the standard, so that product development and regulatory approval can lead more seamlessly to acceptance, uptake and adherence by all populations who can – and should – benefit from innovation.