On Nov. 18, 2020, Gilead Sciences announced topline results from the Phase 2/3 CAPELLA trial evaluating the company’s investigational, long-acting HIV-1 capsid inhibitor, lenacapavir, in heavily treatment-experienced people with multidrug resistant HIV-1 infection.

The study found that 88% of participants receiving lenacapavir (n=21/24) experienced at least a 0.5 log10 reduction in HIV-1 viral load by the end of 14 days of functional monotherapy as compared with 17% of those receiving placebo (n=2/12).

Lenacapavir is being developed as a component of a long-acting regimen in combination with other antiretroviral agents for the treatment of HIV-1 infection. If approved, lenacapavir would be the first HIV capsid inhibitor available for the treatment of HIV-1 infection. In May 2019, the FDA granted Breakthrough Therapy Designation for the development of lenacapavir for the treatment of HIV-1 infection in heavily treatment-experienced patients with multidrug resistance in combination with other antiretroviral drugs.

In CAPELLA, 36 adults with multi-class HIV drug resistance and a detectable viral load while on a failing regimen were randomized 2:1 to receive oral lenacapavir or placebo for 14 days, in addition to continuing their failing regimen (functional monotherapy). Of the 24 people randomized to the lenacapavir group, the median baseline viral load was 4.2 log₁₀ copies/mL and 67% had a CD4 count of less than 200 cells/uL. A statistically significant greater proportion of participants receiving lenacapavir met the primary endpoint of a viral load reduction of at least 0.5 log₁₀ copies/mL from baseline compared with those receiving placebo at the end of the 14-day functional monotherapy period (88% vs. 17%, p<0.0001). Additionally, the lenacapavir group achieved a statistically significant greater mean change in viral load versus the placebo group (-1.93 log₁₀ copies/mL vs. -0.29 log₁₀ copies/mL, p<0.0001).

Lenacapavir was generally safe and well-tolerated, with no serious adverse events related to study drug observed and no study drug discontinuations for any reason through the 14-day period, including no discontinuations due to adverse events. The most common adverse events observed in this portion of the study include injection site swelling (21%) and injection site nodules (17%), the majority of which were Grade 1 or 2 in severity.

Following the 14-day functional monotherapy period of the study, all participants are offered open-label lenacapavir added to an optimized background regimen. This ongoing maintenance period of the study is evaluating the subcutaneous administration of lenacapavir every six months as well as the safety and efficacy of lenacapavir in addition to an optimized background regimen at Weeks 26 and 52.

Lenacapavir acts in a novel way compared with currently available antiretroviral agents by interrupting the activity of HIV capsid, a protein that surrounds and protects the virus’ genetic material and essential enzymes. In in vitro studies, lenacapavir interrupts multiple distinct stages of the viral lifecycle, potentially preventing the virus from becoming infectious and gaining access to uninfected cells.