Gilead’s lenacapavir demonstrates sustained long-acting efficacy for in heavily treated people with multi-drug resistant HIV-1 infection.

Gilead Sciences, Inc. presented additional results from the Phase II/III CAPELLA trial evaluating the company’s investigational, long-acting HIV-1 capsid inhibitor, lenacapavir, in heavily treatment-experienced people with multi-drug resistant HIV-1 infection. The data build on the positive primary endpoint results announced previously. The new interim efficacy results demonstrate that lenacapavir administered subcutaneously every six months maintained high rates of virologic suppression through 26 weeks in a difficult-to-treat patient population with limited therapy options and high unmet medical need. In this analysis of the ongoing maintenance period of CAPELLA, which evaluated lenacapavir in combination with an optimized background regimen, 73% (n=19/26) of participants who reached Week 26 since the first dose of subcutaneous lenacapavir achieved undetectable viral load (<50 copies ml). the data were presented at the 28th conference on retroviruses and opportunistic infections (virtual croi 2021). lenacapavir is being developed as the foundation of a long-acting regimen in combination with other antiretroviral agents for the treatment of hiv-1 infection. lenacapavir is a potential first-in-class capsid inhibitor that is designed to inhibit hiv replication as it interferes with the disassembly of the hiv capsid core, inhibits the role of capsid proteins during viral rna dna translocation to the nucleus, and disrupts assembly of the capsid core. 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 multi-drug resistance in combination with other antiretroviral drugs. in addition to the new interim findings from the capella trial, gilead also presented the results of a preclinical non-human primate study with gs-ca1, a close lenacapavir analog, for hiv pre-exposure prophylaxis (prep). in the study, one injection of low (150 mg kg) or high dose (300 mg kg) gs-ca1 or placebo (n="8" each) was given, followed by weekly escalating titer of rectal shiv challenges for up to 15 weeks and then monitored to week 24. overall, 8 8 animals became infected in the placebo group, whereas 2 8 and 5 8 animals remained protected in the low and high dose gs-ca1 groups, resulting in an 86% (p="0.0061)" and 96% (p="0.0002)" infection risk reduction, respectively. notably, treatment group infections occurred only after marked drug washout. these preclinical data demonstrate the potential utility of a long-acting capsid inhibitor to prevent hiv infection and may help advance clinical research evaluating lenacapavir as a potential future monotherapy option for hiv prevention. gilead previously announced plans to evaluate the use of lenacapavir as an injectable prep option administered every six months for cisgender adolescent girls and young women. an additional lenacapavir for prep study in cisgender men, persons of trans experience and gender non-binary individuals who have sex with men is planned. both trials have projected initiation dates in 2021. additional lenacapavir data presented at virtual croi 2021 provide insight into the investigational agent’s drug interaction potential, dosing response among people living with hiv with mild to moderate hepatic impairment, and resistance profile. additional data from the capella study will be presented at a future scientific conference. about capella (nct04150068) : capella is a phase ii iii randomized, double-blinded, placebo-controlled global multicenter study designed to evaluate the antiviral activity of gilead’s investigational, long-acting hiv-1 capsid inhibitor, lenacapavir, in heavily treatment-experienced people with multi-drug resistant hiv-1 infection. capella includes men and women living with hiv and is being conducted at research centers in north america, europe and asia. in capella, 36 participants with multi-class hiv drug resistance and a detectable viral load while on a failing regimen were randomized 2:1 in a blinded fashion to receive oral lenacapavir or placebo for 14 days (randomized cohort), in addition to continuing their failing regimen (functional monotherapy). an additional 36 participants were enrolled to a non-randomized cohort. the primary endpoint is the proportion of participants in the randomized cohort achieving greater than 0.5 log10 copies ml reduction from baseline in hiv-1 rna at the end of the functional monotherapy period. the study achieved its primary endpoint by demonstrating that a significantly higher proportion of participants in the randomized cohort receiving lenacapavir achieved a clinically meaningful viral load reduction of at least 0.5 log10 copies ml from baseline compared with those receiving placebo during the 14-day functional monotherapy period (88% vs. 17%, p><0.0001). specifically, those who received lenacapavir (n="24)" achieved statistically significantly greater mean decrease in viral load than those who received placebo (n="12)" during the functional monotherapy period (-1.93 log10 copies ml vs. -0.29 log10 copies ml, p><0.0001). following the 14-day functional monotherapy period, participants in the randomized cohort started open-label lenacapavir and an optimized background regimen, while those in the non-randomized cohort received open-label lenacapavir and an optimized background regimen on day 1. this ongoing maintenance period of the study is evaluating the safety and efficacy of subcutaneous lenacapavir administered every six months in combination with an optimized background regimen. lenacapavir was generally well tolerated. the most common adverse events (aes) observed to date in this study were injection site swelling (22%) and erythema (18%) and nodules (18%). importantly, there were no serious aes related to study drug and no aes leading to discontinuation. two participants experienced treatment-emergent capsid mutations and later re-suppressed while continuing lenacapavir. the safety, efficacy and dosing of lenacapavir are being evaluated in multiple ongoing clinical studies. data presented at aids 2020 from the ongoing phase 1 study support subcutaneous every six-month administration of lenacapavir for both hiv treatment and prevention studies. during idweek 2020, the company announced plans to evaluate the use of lenacapavir as an injectable prep option administered every six months among cisgender women, men who have sex with men and persons of trans experience. the trials have projected initiation dates in 2021.>