WASHINGTON – Since 2012, Americans at risk of HIV-1 infection from sex have had just a single option for reducing their odds of acquiring it: a daily dose of Gilead Sciences Inc.'s Truvada (emtricitabine and tenofovir disoproxil fumarate). Now, about a year before Truvada goes generic, at least some of them have a second option in Gilead's Descovy (emtricitabine and tenofovir alafenamide). On Thursday, the FDA approved Descovy for HIV-1 pre-exposure prophylaxis, or PrEP, to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex.

First approved in 2016 in combination with other antiretroviral drugs to treat HIV-1 infection, Descovy was launched in May of that year and generated $1.58 billion in global 2018 sales. Sales of Truvada, which peaked at $3.68 billion in 2016, fell to about $3 billion last year.

Having more options for PrEP is valuable, Robert Grant, a University of California, San Francisco professor of medicine, who is widely regarded as the father of PrEP, told BioWorld. But at most, 8% to 20% of the people who would benefit from the prophylactic regimen in the U.S. are using it, he said. "My hope is that, as alternatives become available, more and more people will find something that appeals to them," Grant said.

What happens next, at least in the U.S., will likely be driven by a combination of economics, marketing and physician guidance. "With Descovy now approved, the focus for GILD now is on getting people to switch from Truvada to Descovy before Truvada goes generic," Jefferies analyst Michael Yee wrote, "and while the label appears narrower than we had hoped, it shouldn't hurt GILD's ability to switch patients before Truvada (old HIV prevention drug) goes generic around fall 2020, thus protecting an existing $2.5B+ franchise."

At least initially, Descovy's adoption in PrEP will also be colored in part by who can't take it: cisgender women and adolescents. Though advisors on the FDA's Antimicrobial Drug Advisory Committee were comfortable enough to support approval of Descovy as a PrEP regimen in men who have sex with men when they considered it in August, they were more divided on the drug's PrEP use in cisgender women, voting 10-8 that there weren't adequate data to support Descovy's efficacy in that population. To fill that gap, Foster City, Calif.-based Gilead has pledged to the FDA to conduct a randomized, comparative trial to evaluate the safety and efficacy of Descovy for PrEP in cisgender women and adolescent girls at risk of sexually acquired HIV-1 infection. (See BioWorld, Aug. 9, 2019.)

But what differentiates Truvada and Descovy in the PrEP realm? Less than you might think.

At least for now, the drugs are priced equally in the U.S., sharing a list price of $1,758 per month, though real-world pricing can vary significantly, as evidenced by selling for as little as €10 (US$11) per month in France, according to Grant. So, Gilead appears to be differentiating the products primarily on safety, touting evidence of advantages in certain key markers of bone density and renal function for people taking Descovy instead of Truvada. Those data, based on two subanalyses from the phase III Discover trial and presented at the Infectious Disease Society of America's IDWeek, showed that among 465 participants who switched from Truvada for PrEP to Descovy for PrEP after enrolling in the trial, there were significant improvements in key lab measures of kidney function, including urine protein-to-creatinine ratio, estimated glomerular filtration rate and markers of proximal tubular function. A second presentation found that a subset of individuals who were randomized to switch to Descovy experienced statistically significant improvements in bone mineral density of the hip and spine compared with those randomized to continue on Truvada.

Still, those differences are likely to matter to only a few individuals, including those have abnormal kidney function or baseline osteoporosis from the beginning, said Grant, who served as a site investigator for the Discover trial and helped lead earlier research that provided the first estimate of the drug concentration levels needed for Truvada to prevent the spread of HIV. "The current version of PrEP, using Truvada, is very safe for both kidneys and the bone," he said, noting that while tenofovir, which is in both medicines, can have a small effects on bone, it's not sufficient to lead to bone fractures. The same is true for kidney function, he said.

Another difference between Truvada- and Descovy-based PrEP regimens is that the former has been used to support a 2-1-1, or on-demand, dosing regimen to dramatically reduce HIV risk while Descovy has not.

A recent blog posting from the Global Advocacy for HIV Prevention drove home the point about what patients and their advocates are seeking: "We don't want Gilead or anyone else to argue that [Descovy] is 'better' or 'safer" PrEP unless the data clearly show that," the group wrote.

Much of the future for both products is likely to be tied to Teva Pharmaceutical Industries Ltd.'s launch of a generic version of Truvada in September 2020. Significantly lower pricing of a proven generic PrEP regimen, paired to community outreach and support, might substantially change the access equation for PrEP, bringing it to new beneficiaries.

Further change yet could come from the readouts of two large phase III studies sponsored by London-based Viiv Healthcare Ltd. and the HIV Prevention Trials Network. Those large-scale studies are evaluating Viiv's long-acting injectable cabotegravir for PrEP vs. Truvada in HIV-uninfected cisgender men and transgender women who have sex with men and in women alone.

Harmony Garges, head of global medical affairs at Viiv, told BioWorld that her team is especially enthusiastic about the women's study because efficacy rates for oral PrEP in women tend to be not as strong as they are in men, possibly due to adherence issues. "We're really excited about that trial, because if we can demonstrate that this long-acting injectable works, it might even work better" than daily oral options, she said.

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