Ethanol

Gilead Sciences plans to start a phase 3 program for once-yearly lenacapavir in the second half of this year, with the potential for regulatory filings in 2027, Jared Baeten, M.D., Ph.D., the company’s vice president of HIV clinical development, said. After Gilead Sciences' lenacapavir made waves with stellar clinical results as a twice-yearly HIV prevention candidate, the drug has shown promise being dosed even further apart at only once a year.Two different once-yearly formulations of lenacapavir achieved blood concentrations that exceeded those associated with the strong HIV prevention efficacy that twice-yearly lenacapavir showed in phase 3 preexposure prophylaxis (PrEP) studies.The pharmacokinetic results came from a small phase 1 trial presented at the Conference on Retroviruses and Opportunistic Infections and simultaneously published in The Lancet.Based on the early-stage data, Gilead plans to start a phase 3 program for once-yearly lenacapavir in the second half of this year, with the potential for regulatory filings in 2027, Jared Baeten, M.D., Ph.D., Gilead’s vice president of HIV clinical development, told Fierce Pharma.Gilead’s application for twice-yearly lenacapavir as a PrEP option is currently under FDA priority review with a decision expected by June 19. The drug is already approved under the brand name Sunlenca for use alongside other antivirals to treat multidrug-resistant HIV infection.Twice-yearly lenacapavir comes as subcutaneous injections of 927 mg of the drug administered every half a year. For the once-yearly study, researchers at Gilead examined two intramuscular presentations of lenacapavir given in a 5-g dose, formulated with either 5% or 10% of ethanol, which lowers the thickness of the injection.“We’ve talked with the scientific community and with people affected by HIV about where the unmet need is, and people said ‘longer’ [dosing intervals],” Baeten said in an interview with Fierce.Gilead picked the intramuscular route because of the amount of drug needed to be delivered and a better pharmacology profile compared with a subcutaneous injection, according to Baeten. In the phase 1 study, the two once-yearly formulations were given to 20 individuals each. At the end of the one-year mark, median concentration of lenacapavir in the blood was 57 ng/mL and 65.5 ng/mL, respectively. Both exceeded the 23.4 ng/mL recorded by twice-yearly subcutaneous lenacapavir at the end of 26 weeks, according to analyses of samples collected from the phase 3 Purpose 1 and Purpose 2 studies. Peak concentrations for lenacapavir were reached after a median of about 12 weeks or 10 weeks for the two formulations, respectively. Their levels then dropped slowly—generally in a stable way—and remained above that of subcutaneous lenacapavir for the rest of the study.It wasn’t just the median number. For all participants, intramuscular lenacapavir’s blood concentration at the end of 12 months was “similar to or higher than” that for twice-yearly subcutaneous drug at the half-year mark, Gilead’s researchers pointed out in the Lancet article.In terms of safety, both formulations were well tolerated, with no grade 4 treatment-emergent adverse events recorded. There were some grade 3 lab abnormalities, but they were deemed unlikely to be related to lenacapavir.The most common grade 3 adverse event was elevated low-density lipoprotein (LDL) cholesterol level, which happened in four individuals across the two formulations. However, all four participants had abnormal LDL at baseline and their grade 3 elevation didn’t match lenacapavir exposure.Injection-site pain was common but generally mild and was substantially reduced by pretreatment with ice at the sites of injection, according to the researchers. The positive phase 1 trial leaves Gilead with a couple of key considerations as the company finalizes a phase 3 design.First, because the intramuscular formulation’s Ctrough—the measurement of a drug’s blood concentration before the next dose—is notably higher than expected, the optimal clinical dose for future development is likely to be lower than 5g, the Gilead researchers noted in the study. Gilead won’t launch another study but will instead rely on the “extensive pharmacology data” to choose what lenacapavir dose to bring into phase 3 testing, Baeten said.Second, for the subcutaneous formulation, the two Purpose trials used a loading dose of oral lenacapavir at the time of the first injection to get the drug’s blood concentration to the desirable level faster. For the intramuscular formulation, the increase in initial lenacapavir plasma concentration was faster but still not at a desirable speed, suggesting that oral loading may also be needed here, study researchers pointed out.Finally, like many other trials of a new formulation of an existing drug, the upcoming phase 3 program may be able to adopt a pharmacological endpoint rather than a hard efficacy endpoint like infection rates used in the Purpose trials.Baeten wouldn’t confirm what the primary endpoint would be. But he said that, “this is the same drug, so the safety and target blood concentration targets needed for efficacy are well-established by the Purpose program.”