The PURPOSE-2 Trial: Exploring Lenacapavir as an HIV PrEP Treatment Option
Tanmaya Phanda, PharmD
5-min
The PURPOSE-2 Trial: Exploring Lenacapavir as an HIV PrEP Treatment Option
By: Tanmaya Phanda, PharmD, InpharmD Team
This blog will provide a background of HIV, summarize findings from the PURPOSE-2 trial, and discuss the clinical impact of lenacapavir on HIV infection prevention.
Background
Human immunodeficiency virus (HIV) is a retrovirus that attacks CD4 T lymphocytes, resulting in a weakened immune system. Early stages of HIV infection consist of flu-like symptoms such as fever, swollen lymph nodes, and sore throat. If untreated or poorly managed, the condition can progress to stage 4, also known as acquired immune deficiency syndrome (AIDS), increasing the risk for severe opportunistic infections and malignancies. As of 2022, there were 1.2 million people with HIV in the United States, with approximately 13% unaware of their HIV status.
Pre-exposure prophylaxis (PrEP) is an effective approach for preventing HIV infection, reducing the risk of HIV from sex by about 99% and from injection drug use by at least 74%, according to the CDC. Currently, there are two daily oral FDA-approved PrEP treatments: Truvada® (emtricitabine/tenofovir disoproxil fumarate) and Descovy® (emtricitabine/tenofovir alafenamide). Also, Apretude® (cabotegravir) is a long-acting injectable given every two months in patients with high-risk HIV.
PrEP has significantly contributed to the decline in newly diagnosed HIV infections by 35% globally since 2010. However, new diagnoses have increased among cisgender gay, bisexual, and other men who have sex with men and among transgender women. In 2022, 67% of the new HIV diagnoses were among cisgender gay men in the United States. In addition, due to adherence concerns, global PrEP usage remains at only 16.5% of the Joint United Nations Program on HIV/AIDS goal of 21.2 million users by 2025, underlining the importance of additional PrEP treatment options.
To address this unmet need, lenacapavir, a first-in-class, multistage, highly-potent HIV- capsid inhibitor, has emerged as a potential subcutaneous injectable PrEP with twice yearly administration. Currently, lenacapavir (Sunlenca®) is FDA-approved for multidrug-resistant HIV but has also demonstrated effectiveness in PrEP in cisgender women (PURPOSE-1; NCT04994509). However, its efficacy for HIV prevention in other gender-diverse populations must be further assessed.
Trial Introduction
PURPOSE-2, a phase 3, double-blind, randomized, active-controlled trial, evaluated the safety and efficacy of lenacapavir for PrEP in cisgender men, transgender women, transgender men, and gender-nonbinary individuals.
Methods
The study was done on cisgender gay, bisexual, and other men, transgender women, transgender men, and gender nonbinary individuals ≥16 years of age who had:
- Unprotected receptive anal sex with partners assigned as males at birth
- Unknown HIV status
- No HIV testing or PrEP use in the 3 months before screening.
During the screening phase, participants were tested for HIV, individuals with negative results proceeded to the randomization phase, and positive tests were used to measure background HIV incidence. A total of 3271 participants were randomized 2:1 to receive either 463.5 subcutaneous lenacapavir subcutaneous every 26 weeks (N =2183) and daily oral 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate (F/TDF) (N = 1080). In the lenacapavir group, participants received oral loading doses of two 300-mg tablets of lenacapavir each on days 1 and 2. Participants in both groups also received a matching dosing placebo. Follow-ups, alongside HIV prevention and drug adherence counseling, were made at weeks 4, 8, and 13, and every 13 weeks thereafter.
The demographics and baseline characteristics were similar in both treatment groups—Table 1.
Table 1. Patient Baseline Characteristics
|
Characteristic
|
Lenacapavir (N = 2183)
|
F/TDF (N=1080)
|
|
Median age (range) — years
|
28 (17-74)
|
29 (17-73)
|
|
Cisgender men — no. (%)
|
1697 (77.7)
|
846 (77.8)
|
|
Transgender women — no. (%)
|
315 (14.4)
|
161 (14.8)
|
|
Transgender men — no. (%)
|
29 (1.3)
|
14 (1.3)
|
|
Gender nonbinary — no. (%)
|
136 (6.2)
|
63 (5.8)
|
|
Straight/heterosexual — no. (%)
|
148 (6.8)
|
66 (6.1)
|
|
Gay — no. (%)
|
1634 (75.4)
|
806 (74.7)
|
|
Bisexual — no. (%)
|
322 (14.9)
|
166 (15.4)
|
|
Any previous use of PrEP — no. (%)
|
515 (23.6)
|
249 (22.9)
|
Outcomes
The primary outcome of the study was to compare the HIV infection incidence in the lenacapavir group with the background HIV incidence in the screened population. The secondary outcome was to compare the HIV infection incidence rate ratios between the lenacapavir and F/TDF groups. Safety was analyzed by adverse event occurrences in participants who had received at least one dose of either treatment group.
Results
Compared to the background HIV incidence of 2.37 per 100 person-years (95% confidence interval [CI], 1.65 to 3.42), lenacapavir and F/TDF had two and nine HIV infections with incidence rates of 0.10 per 100 person-years (95% CI, 0.01 to 0.37) and 0.93 (95% CI, 0.43 to 1.77), respectively—Figure 1. The lenacapavir group had a significantly lower HIV incidence compared to the F/TDF group (Incidence rate ratio [IRR] 0.11; 95% CI, 0.02 to 0.51; P=0.002) and the background incidence (IRR 0.04; 95% CI, 0.01 to 0.18; P<0.001.
Safety
|
Event
|
Lenacapavir (N = 2183)
|
F/TDF (N=1080)
|
|
Adverse event (%)
|
1607 (73.6)
|
803 (73.8)
|
|
Serious adverse events
|
71 (3.3)
|
43 (4.0)
|
|
Discontinuations due to adverse events
|
7 (0.3)
|
7 (0.6)
|
|
Injection-site reaction (%)
|
1816 (83.2)
|
756 (69.5)
|
|
Deaths
|
4 (0.2)
|
4 (0.2)
|
The incidence of adverse events was similar between the groups, with rectal chlamydia, oropharyngeal gonococcal, and rectal gonococcal infections as the three most common adverse events. Most injection-site reactions were mild (grade 1) or moderate (grade 2 ) in severity. However, injection-site reactions led to discontinuation in 26 of 2,183 participants (1.2%) in the lenacapavir group and 3 of 1,088 participants (0.3%) in the F/TDF group.
Study Conclusions
Twice-yearly subcutaneous lenacapavir demonstrated greater effectiveness in preventing HIV infection in comparison to F/TDF and background incidence. In addition, lenacapavir maintained tolerability and presented with no safety concerns.
Clinical Impact
Lenacapavir’s twice-yearly dose frequency addresses adherence concerns that arise from current FDA-approved PrEP options (Truvada®, Descovy®, and Apretude®). In the PURPOSE-2 trial, the adherence rate for lenacapavir was 91%, whereas, the adherence rates for F/TDF declined throughout the study: 82% of the participants at week 8, 67% at week 26, and 62% at week 52. A separate retrospective cohort study among 23,258 oral PrEP users demonstrated adherence patterns of minimal use (10.5% of the cohort), rapidly declining (25.4%), and gradually declining (24.3%), further highlighting the added benefit of twice-yearly dosing. However, lenacapavir’s convenient twice-yearly dosing may be costly, with its prices at $44,819 per person per year for HIV treatment. Generic versions of lenacapavir may also be available at lower prices to increase accessibility and provide patients with a suitable and effective PrEP option.
Studies have shown that more than 70% of the new diagnoses were among Black, Hispanic, or Latino persons. In particular, Black people make up 48% of new HIV diagnoses, but only 12% of PrEP users. As a result, alongside PURPOSE-2’s high diversity inclusivity, the trial also included a geographically diverse range of participants with 37.7% identified as Black and 62.8% as Hispanic or Latino. Lenacapavir’s high efficacy and minimal dose frequency present a promising solution to increase PrEP uptake in marginalized populations.
After the treatment phase of the PURPOSE-2 trial, participants were offered open-label lenacapavir to continue to monitor for new HIV infections, including for potential delays in HIV diagnosis or development of resistance. As a result of the positive readouts, Gilead Sciences filed a new drug application (NDA) for FDA approval in December 2024. PURPOSE-2 is part of Gilead’s PURPOSE clinical trial program which evaluates the safety and efficacy of lenacapavir for PrEP in different populations (PURPOSE-3 through PURPOSE-5 currently in clinical trials. Lenacapavir’s FDA approval can pave the way for an effective treatment option for HIV infection prevention, increasing PrEP uptake and adherence.
References:
- Kelley CF, Acevedo-Quiñones M, Agwu AL, et al. Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons. N Engl J Med. 10.1056/NEJMoa2411858
- Swinkels HM, Vaillant AAJ, Nguyen AD, et al. HIV and AIDS. In: StatPearls. Treasure Island (FL): StatPearls Published July 27, 2024. https://www.ncbi.nlm.nih.gov/books/NBK534860/
- Fast Facts: HIV in the United States. CDC. Published April 22, 2024. https://www.cdc.gov/hiv/data-research/facts-stats/index.html
- Joseph Lee WE, Lim SW, Choy CY, Wong CS. Pre-exposure prophylaxis for prevention of HIV infection. Singapore Med J. 2023;64(10):624-8.
- Unigwe IF, Goodin A, Lo-Ciganic WH, Cook RL, Janelle J, Park H. Trajectories of Adherence to Oral Pre-exposure Prophylaxis and Risks of HIV and Sexually Transmitted Infections. Open Forum Infect Dis. 2024;11(10):ofae569.
- Hill A, Levi J, Fairhead C, et al. Lenacapavir to prevent HIV infection: current prices versus estimated costs of production. J Antimicrob Chemother. 2024;79(11):2906-15.
- Gilead Presents Full PURPOSE 2 Data Results for Twice-Yearly Lenacapavir for HIV Prevention at HIV Glasgow. Gilead. 2024. https://www.gilead.com/news/news-details/2024/gilead-presents-full-purpose-2-data-results-for-twice-yearly-lenacapavir-for-hiv-prevention-at-hiv-glasgow
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