FDA Panel Rebuffs Broad Indication for Descovy for HIV PrEP

Kerry Dooley Young

August 08, 2019

A federal advisory panel objected to Gilead Sciences' bid for broad new additional approval of a drug for preventing HIV infection. Panelists chided the company for proceeding despite a lack of data about the drug's effectiveness in women.

The US Food and Drug Administration's (FDA's) Antimicrobial Drugs Advisory Committee ended a Wednesday meeting on Gilead's emtricitabine/tenofovir alafenamide (Descovy) with a split decision.

Descovy was approved in 2016 for the treatment of HIV. It was intended as Gilead's successor to its emtricitabine/tenofovir disoproxil fumarate (Truvada). Generic competition for Truvada could begin in the United States as early as next year.

The FDA panel voted 16–2 in favor of the view that Descovy had been shown to be safe and effective for preexposure prophylaxis (PrEP) against HIV infection in men and transgender women who have sex with men.

But the FDA panel then split 10–8 on the question of whether available data support approval of a PrEP indication for Descovy for cisgender women. The term "cisgender" denotes persons whose sense of gender corresponds with their birth sex.

In the DISCOVER trial, which was the principal trial that investigated the use of Discovy for the prevention of HIV infection, cisgender women were not included. That exclusion angered FDA advisers. The panel's chairman of the committee, Lindsey R. Baden, MD, summed up the views of many of his colleagues at the end of the meeting.

"We've failed women," Baden said. "To be at this point and not have the data to guide decision making is a shame on all of us."

"Bad Science"

Several panelists who voted in Gilead's favor on the question concerning cisgender women said they did so only so as not to deny women a tool for the prevention of HIV infection.

Cisgender women would still have access to Truvada were Descovy to be approved only for prevention of HIV infection in the populations Gilead studied, said FDA panelist Dawn K. Smith, MD, MPH, of the Centers for Disease Control and Prevention.

Smith described Gilead's approach as both "bad science" and "disrespectful."

"Women deserve the same quality of data about the safety and efficacy of the drugs that they are exposed to that men get, and that's not the situation we find ourselves in at the moment," Smith said of the Descovy application.

She argued strongly against the idea of approving Descovy for cisgender women and to then require that Gilead conduct further studies of the drug. There's little to be gained and much to be risked with a broad approval for Descovy on the basis of the available data, Smith said.

"That's a recipe for disaster among the African American community if we get ourselves into a situation where we are approving something and then saying, 'Oh, well no, actually, we weren't right. That didn't work,' " Smith said. "I wouldn't even think about doing that."

In deciding on Gilead's application for Descovy, the FDA will weigh the suggestions from the panelists as well as their votes. The agency is under no obligation to take its panelists' advice, but it often does.

Truvada Data vs Descovy's

At the Wednesday hearing, Smith contrasted the more robust data offered for Truvada's approval for prevention of HIV infection with that offered by Gilead for Descovy.

In 2012, the FDA approved Truvada as the first drug to prevent HIV infection. That approval was based in large part on research funded by the National Institutes of Health and the Bill and Melinda Gates Foundation. Gilead donated the drug.

The approval of Truvada for PrEP was based largely on two studies. The iPrex trial recruited men and transgender women who have sex with men across several continents; the Partners PrEP trial recruited heterosexual partners of HIV-positive men and women in Kenya and Uganda.

"There was a lot of discussion and concern that we had data on African women and not on African American women," Smith recalled about the Truvada PrEP approval. She contrasted it with the Descovy application. "And now we don't have data on women at all," she said.

Gilead has defended its DISCOVER trial design and said it intends to study Descovy's potential for preventing HIV infection in cisgender women. Gilead knows much more about Descovy now than it did when it began its research some years ago, Diana Brainard, MD, Gilead's senior vice president for HIV and emerging viruses, told Medscape Medical News.

"We're going to need to do a different kind of trial," Brainard told Medscape Medical News after the FDA advisory committee split its votes on Descovy. "We need to do that, and we are looking forward to doing that," she said.

In the DISCOVER study, the efficacy of Descovy was found to be noninferior to that of Truvada. In a prespecified primary efficacy endpoint analysis, 22 HIV infections were diagnosed. Seven of these were in the Descovy group (incidence rate = 0.16 infections per 100 person-years); the other 15 were in the Truvada group (incidence rate = 0.34 infections per 100 person-years), Gilead said in a briefing document that the company prepared for the FDA advisory committee meeting.

Almost 5400 people have participated in the DISCOVER study, which recruited patients from the United States, Canada, and Europe. The Descovy group included 2694 persons, and the Truvada group included 2693.

Gilead officials have highlighted signals they saw in the DISCOVER study data about potential comparative advantages for Descovy. In a press release issued after the advisory committee meeting, Gilead noted that in the DISCOVER trial, "statistically significant improvements in renal and bone laboratory parameters were observed for participants receiving Descovy versus those receiving Truvada."

However, in the FDA briefing document, the agency staff noted that "use of Descovy resulted in a higher incidence of elevated fasting lipids compared to Truvada, with twice as many subjects in the Descovy arm initiating lipid‐lowering agents during the trial (although the percentage was low at 2%)."

In their deliberations on Wednesday, FDA panelists urged against attempts to "oversell" differences in data signals between the two drugs. Such promotion could result in patients switching from Truvada to Descovy for reasons not supported by current data, they said.

The FDA's briefing document for the meeting shows Gilead taking something akin to a regulatory gamble with the application. Well before the DISCOVER trial began, the FDA encouraged Gilead to include cisgender women in its study of Descovy for prevention, the agency staff said in a briefing document for the meeting.

But in subsequent discussions, Gilead referred to the challenges of creating a suitable study design or forming a relevant female cohort, the FDA said in the briefing document.

Gilead "also expressed concerns that adherence and perception of risk were highly variable in young women 15–25 years of age living in high HIV prevalence areas (a population with high unmet need) and that the majority would not take a daily oral drug for prevention," the FDA staff said. The company cited the results of the FEM-Prep and VOICE trials to illustrate its concerns about adherence.

A Guessing Game?

Without a study that includes cisgender women, the FDA and its advisers are left only to guess at how well Descovy works in this population.

Descovy and Truvada may differ in effectiveness with respect to rectal and vaginal tissues, the FDA panelists said. Thus, it might be hazardous to assume that Descovy would work as well as Truvada in cisgender women.

There are suggestions in the data that Descovy's safety profile may be superior to that of Truvada, but this must be balanced against the possibility that the efficacy of Descovy is inferior to that of Truvada, said FDA panelist Sankar Swaminathan, MD, of the University of Utah School of Medicine, Salt Lake City.

"In this situation, a relative lack of efficacy may translate into a currently incurable infection," he said.

In concluding the meeting, Baden urged Gilead to conduct a study of the use of Descovy in cisgender women as quickly as possible. He noted that this view was shared by his fellow panelists.

"I don't accept that it's too hard, too big, too difficult," Baden said. "Many of us believe that this should work and will work, but we cannot have belief guide policy."

Baden received a waiver for his participation in leading the meeting. He disclosed potential conflicts of interest related to his employment at Brigham and Women's Hospital and his work with the HIV Vaccine Trials Network.

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