16 October 2023
Lenacapavir is a capsid inhibitor with a novel mechanism of action, distinguishable from other currently approved classes of antiviral agents, as it inhibits HIV at multiple stages of its lifecycle and has no known cross resistance exhibited in vitro to other existing drug classes. Lenacapavir has received regulatory approvals in Europe and 10 high-income countries as a treatment for adults with multi-drug resistant HIV, intended for use in combination with other antiretroviral medications. It is also awaiting approval for use in the context of HIV prevention.
Lenacapavir primary patents have been filed or granted in several LMICs and are expected to expire between 2034 and 2037. Gilead also holds secondary patents that may provide exclusivity until 2038 in many LMICs. Gilead has signed bilateral voluntary licence agreements with six generic manufacturers, allowing for sales of lenacapavir for HIV prevention and treatment of heavily treatment-experienced adults with multi-drug-resistant HIV in 120 countries. LMICs beyond the licence territory will not have access to the generic products via these agreements.
An approved long-acting companion medicine allowing for a fully long-acting lenacapavir-based treatment regimen is still missing, and lenacapavir is being evaluated as a long-acting option in multiple ongoing and planned early and late-stage clinical studies of potential fully long-acting HIV treatment regimens. Of notice, the current voluntary licence does not cover a broad treatment indication. Given the prominent role such regimens could play in the future, and remaining uncertainties surrounding lenacapavir’s future accessibility and affordability in LMICs for both treatment and prevention indications, including the possibility of expanding the geographical scope and indication of the licensing agreements, lenacapavir remains a priority for MPP.
Two potential HIV treatment regimens currently stand out as priorities for MPP licensing: lenacapavir with either cabotegravir or islatravir, based on relevant data as it is being generated. The possibility of the addition of a regional manufacturer for lenacapavir in countries with high HIV prevalence in sub-Saharan Africa would also be worth exploring.
Lenacapavir is a candidate for long-acting pre-exposure prophylaxis (PrEP) through a twice-yearly subcutaneous injection, following an initial oral loading phase. Gilead has submitted marketing authorisation applications to EMA (for both EU MAA and EU-M4all) and to the FDA. Results from the PURPOSE 1 and PURPOSE 2 phase III trials have demonstrated high effectiveness in preventing HIV, with mostly mild injection site reactions such as pain, nodules, and indurations . Additionally, recent data confirm lenacapavir’s safety and efficacy in adolescents, broadening its potential impact on containing the HIV epidemic if rolled out extensively.
At CROI 2025, groundbreaking findings on new intramuscular formulations of lenacapavir were presented, featuring two single-dose injections designed for annual administration. These formulations were safe and tolerable in the study participants, and maintained plasma drug concentrations above the 95% effective threshold for at least 56 weeks, highlighting the feasibility of extending dosing intervals even further. If successful in follow-up trials, adjusted yearly injections could represent a significant shift in HIV prevention strategies. If affordable and accessible, this candidate could represent a very powerful tool to contain the global HIV epidemic. It is not known whether this formulation is captured under the Gilead voluntary licence for lenacapavir.
Lenacapavir is currently approved by several stringent regulatory authorities for the treatment of HIV-1 infection in heavily treatment-experienced adults whose current antiretroviral regimen is failing due to resistance, intolerance, or safety concerns. Lenacapavir’s low administration frequency and long-acting nature could offer a paradigm shift also in treatment.
A phase II clinical study investigated the efficacy of a weekly oral combination of lenacapavir and islatravir. The study demonstrated strong virologic suppression without negatively affecting lymphocyte counts. These results have prompted the initiation of two phase III trials , which are evaluating a weekly oral fixed dose combination of islatravir and lenacapavir in virologically suppressed persons living with HIV. The research supports broader efforts to develop more convenient, decentralized HIV treatment options that could improve access while supporting increased adherence.
Lenacapavir is also under investigation in combination with cabotegravir (with or without rilpivirine) for individuals with NNRTI resistance. A small case-series showed high rates of virologic suppression in people with HIV on a LEN+CAB regimen, highlighting its potential as a long-acting injectable option for people with limited treatment choices. However, additional research is needed to confirm safety, efficacy, durability, and resistance barriers. A multicentric clinical trial assessing the use of LEN+CAB for HIV treatment in comparison to standard of care is in planning stages.
Additionally, lenacapavir is being explored in combination with once-daily bictegravir as a possible simplified regimen for people with HIV who require complex treatment due to previous resistance or treatment failures.
However, accessibility remains a challenge—lenacapavir is not yet registered for the treatment indication in LMICs, limiting its availability to those who may benefit most from this alternative in a treatment regimen.
Patent & licence data for lenacapavir in LMICs
Lenacapavir entry in LAPaL
Acronyms & abbreviations list