The Evolution of Lenacapavir in HIV Treatment
The antiviral began its development as a multidrug-resistant therapy for people with HIV, and has since been studied as PrEP intervention, with many now calling for it to be made widely available for mass distribution.
HIV-1 Virus Particles Transmission electron micrograph of HIV-1 virus particles (colorized red) replicating from an HIV-infected H9 T-cell (blue).
Image credit: NIDID
Updated, July 25:
Gilead released a statement yesterday afternoon to clarify some of the ongoing events at the International AIDS Society 2024 conference and the calls to make lenacapavir widely available at a discounted price.
In its statement, the company started by saying lenacapavir is not available anywhere in the world. However, it did note in the statement that the regulatory filing for lenacapavir for HIV prevention will include the results of both the PURPOSE 1 (NCT04994509) and PURPOSE 2 (NCT04925752) trials, if positive, to ensure lenacapavir for HIV prevention can be approved for multiple populations and communities most in need of additional HIV prevention options. Gilead expects results from PURPOSE 2 in late 2024 or early 2025.
Additionally, the company did discuss pricing, noting that "the results of PURPOSE 2 are required for regulatory filing, and lenacapavir for HIV prevention remains an investigational drug until approved by regulatory authorities. While Gilead awaits the results of this Phase 3 clinical trial and the potential FDA filing, it is too early to state the price of lenacapavir for HIV prevention."
Lastly, it pointed to the distribution of the therapy, and the need for it in high-incidence, low-resource countries. "Gilead will ensure dedicated supply of lenacapavir for HIV prevention in the countries where the need is greatest until voluntary licensing partners are able to supply high-quality, low-cost versions of lenacapavir," the company stated, adding, "Gilead is developing a robust direct voluntary licensing program to expedite access to those versions of lenacapavir in high-incidence, resource-limited countries. We are moving with urgency to negotiate these contracts." 1
Original article, July 24:
In the last few years, Gilead’s lenacapavir (Sunlenca) has seen a lot of movement through the clinical pipeline that includes a complete response letter (CRL), an FDA approval, a potentially new indication in HIV prevention, and even a call for it to be mass produced for countries with high incidences rates and less resources.
Multidrug-Resistant Therapy
Lenacapavir was initially developed as therapy for adult patients living with HIV whose infections could not be successfully treated with other available treatments because of resistance, intolerance, or safety considerations. Multidrug resistance is an ongoing clinical management challenge, and in this space, there are limited options.
In March of 2022, Gilead received a CRL from the FDA. The letter cited Chemistry Manufacturing and Controls (CMC) issues relating to the compatibility of lenacapavir with the proposed container vial as the reason for their action. The CRL was not reflective of the therapy itself.
“Gilead intends to provide [the] FDA with a comprehensive plan and corresponding data to use a different vial type. We look forward to discussing this further with [the] FDA over the coming months so that we can make this investigational new therapy available to people living with multidrug-resistant HIV as soon as possible,” Gilead Chief Medical Officer Merdad Parsey, MD, PhD, said in a statement at the time.2
Gilead worked with the FDA to provide the federal agency with the information and compliance that was needed, and when it was FDA-approved in December 2022, it was a welcome addition for patients and clinicians.
“Today’s approval ushers in a new class of antiretroviral drugs that may help patients with HIV who have run out of treatment options,” Debra Birnkrant, MD, director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said in a statement when it was approved.2
Lenacapavir is the first of a new class of therapies called capsid inhibitors to be FDA-approved for treating HIV. This antiretroviral works by blocking the HIV-1 virus’ protein shell (the capsid), thereby interfering with multiple essential steps of the viral lifecycle. The approval was based on the data of the CAPELLA study (NCT04150068), which was a double-blinded, placebo-controlled global multicenter trial designed to evaluate lenacapavir when administered every 6 months as a subcutaneous injection in heavily treatment-experienced (HTE) people with multidrug-resistant HIV infection.2
Overall, 72 participants were enrolled with 36 in each of the 2 cohorts. In terms of the makeup of the participants, 25% were female, 38% were Black, the median age was 52 years, 19% had a viral load >100k c/mL, 64% had CD4 counts of <200 cells/μL, 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI), and 17% did not have any fully active agents in the optimized background regimen (OBR).2
In cohort 1 (randomized group), participants were assigned (2:1) to add oral lenacapavir or placebo to their failing regimen (600 mg on Day 1 [D1] and 2 and 300 mg on D8). At Day 15, those on oral lenacapavir received subcutaneous (SC) lenacapavir 927 mg every 6 months; those on placebo started the 2-week oral lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, OBR at D15, the investigators explained.2
In cohort 2 (unrandomized group), the participants started OBR concurrent with lenacapavir (oral lead-in to SC). The investigators reported the secondary endpoint of W52 efficacy by the FDA-snapshot algorithm in the randomized cohort and additional available efficacy and safety from both cohorts.2
Earlier this year, new data were presented at the CROI meeting that demonstrated treatment benefits over a 2-year period from the phase 2/3 CAPELLA trial evaluating the lenacapavir.3
“We found even as far out as two years or the so-called 104 [week] data, that about 82% of individuals—when we excluded those who are missing— were virologically suppressed…that's unheard of numbers for this kind of patient population,” Onyema Ogbuagu, MBBCh, FACP, FIDSA, director of HIV Clinical Trials program at Yale School of Medicine, and principal investigator on the trial said in an earlier interview with Contagion. “We have other studies with other agents that have shown lower rates of treatment success with these kinds of patients.”3
Read more: Examining a Newer Therapy for Heavily Treated HIV Patients
HIV Prevention
One of the bigger developments around the antiviral has been the recent data related to lenacapavir as a potential HIV prevention tool.
Last month, the company announced significant findings from its phase 3 PURPOSE 1 trial that showed 100% efficacy in preventing HIV infection among cisgender women. The trial included more than 5300 participants from both South Africa and Uganda.4
The second phase of the study will span from 1 to 3 years, with participant visits occurring every 4 to 13 weeks, totaling between 4 and 8 visits annually. Each participant in this phase will receive both a daily pill and a semiannual injection, with one containing the active drug and the other serving as a placebo.4
Read more: Lenacapavir's 100% Efficacy: Gilead's Step Towards HIV Prevention
Mass Distribution?
At the ongoing IAS HIV conference, a poster presented by Fortunak et al and coinvestigators offered some analysis looking at utilizing lenacapavir more widely for HIV prevention, despite it not being approved for this indication. Specifically, they wrote that it could be mass-produced under a voluntary license for approximately $40 per person-year at scale. They said lenacapavir is currently costing $40,000 per person-year in high-income countries.5
They put forth 2 hypotheses: 1. Could the lenacapavir injectable be priced at $100 person-year at a committed demand of 1 million people per year; or 2. Could the cost of goods eventually be competitive with oral PrEP?5
Lenacapavir has both oral and injectable modalities currently in use. It remains to be seen how Gilead views these hypotheses; however, its press statement, it appears the company is planning to move forward with a strategy to utilize lenacapavir as PrEP. “Gilead is building an access strategy that prioritizes speed and enables the most efficient path for the regulatory approval of twice-yearly lenacapavir for PrEP in countries that account for most of the global disease burden.”6
