Lenacapavir (LEN) is a novel investigational long-acting injectable ARV that is administered every 6 months by subcutaneous (SC) injection. It is an HIV-1 capsid inhibitor that acts at several points in the HIV life cycle. As a novel class, has full activity against viruses with resistance to the NRTI, NNRTI, PI, or INSTI classes.
Recent conferences gave us the chance to see early results from two small studies evaluating the efficacy and safety of LEN – one in highly treatment-experienced persons (CAPELLA) and the other in treatment-naïve persons (CALIBRATE).
The CAPELLA Study, presented at IAS 2021, is a Phase 2/3 double-blind evaluation of LEN in persons meeting the following criteria:
- On failing ART regimens (HIV RNA >400 copies/mL)
- HIV resistance to at least 2 agents from at least 3 of the main ART classes (NRTI, NNRTI, INSTI, PI)
- 2 or fewer remaining active ARV agents from these classes
The study design is somewhat complex and involves both a randomized and a nonrandomized arm; the present analysis comprises interim week 26 results of the randomized arm. In this arm, 36 patients were assigned 2:1 to: (A) add daily oral LEN to their baseline (failing) ART regimen for 14 days (i.e. to take LEN functional monotherapy for 14 days), then switch to SC LEN + an optimized background regimen (OBR), or (B) take placebo + their baseline regimen for 14 days, then switch to LEN (oral lead-in followed by SC LEN) + OBR. At baseline, the cohort had a median HIV RNA of >4 log10 copies/mL and had been on a median of 9 previous ART regimens; resistance to ≥2 ARVs in the NRTI and NNRTI classes was present in nearly 100%, and resistance to ≥2 INSTIs and PIs was found in >85%.
At day 14 (as previously reported) there was a median drop in HIV RNA of 1.9 log10 copies/mL in the LEN functional monotherapy group compared to a drop of 0.3 log10 copies/mL in the placebo group. At week 26 (after 24-26 weeks of LEN + OBR for each group), 81% of patients had HIV RNA <50 copies/mL, and 89% had HIV RNA <200 copies/mL. HIV RNA was <50 copies/mL in 67% (4/6) of subjects with 0 fully active ARVs in their background regimen, in 86% of those with 1 active ARV, and 81% of those with 2 or more active ARVs in the optimized regimen. Lenacapavir resistance was found in 4/11 participants with virologic failure; 3 of these later achieved viral suppression with continuation of LEN (1 had a change of the background regimen). No serious adverse events related to LEN were reported. Injection site reactions occurred in 56% of subjects; most were mild, and all participants elected to receive their second LEN injection at the 6-month timepoint.
The CALIBRATE Study, whose early results were presented at IAS 2021 and at IDWeek, is a small Phase 2 open-label study in treatment-naïve individuals, with several treatment arms involving both randomized and open-label components. The current analyses presented week 28 data for persons who received SC LEN (following a 2-week oral lead in) + daily oral tenofovir alafenamide (TAF)/emtricitabine (FTC) (n=105), daily oral LEN + TAF/FTC (n=52), or daily oral bictegravir (BIC)/TAF/FTC (n=25).
At baseline, median HIV RNA was 4.37 log10 copies/mL. At week 28, by intent-to-treat analysis, viral suppression to <50 copies/mL was seen in 92-94% of both the SC LEN and the oral LEN groups and in 100% of the BIC/TAF/FTC group. Two of the 105 persons in the SC LEN groups had HIV RNA >50 copies/mL at week 28; one of these had emergence of FTC resistance mutations (M184I/V) followed by LEN resistance mutations (Q67H, K70R). As in the CAPELLA study, no serious adverse reactions related to LEN were reported. 39% of SC LEN recipients reported injection site reactions, 83% of these were grade 1.
Clinical Bottom Line
These studies, particularly the CAPELLA study in people whose HIV had extensive ARV resistance, provide exciting early data on the efficacy of LEN. The manufacturer has applied for FDA approval of LEN for use in treatment-experienced persons with multidrug-resistant HIV. It also is sponsoring studies of LEN (administered as an SC injection every 6 months) for the prevention of HIV in cisgender men and transgender and nonbinary persons who have sex with men, and in cisgender women and adolescent girls.
These studies also are another exciting presage of a near (we hope) future when multiple long-acting ARV agents may be available for both treatment and prevention. Long-acting injectable cabotegravir + rilpivirine is approved for HIV treatment in appropriate persons, long-acting cabotegravir has been shown to be highly effective as PrEP and may gain FDA approval in the next year, and studies of multiple other long-acting agents (both injectable and oral) are underway.
- Molina J-M, Segal-Maurer S, Stellbrink H-J, et al. Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (Capella study). 11th IAS Conference on HIV Science, July 18-21, 2021. Abstract OALX01LB02.
- Gupta S, Berhe M, Crofoot G, et al. Long-acting subcutaneous lenacapavir dosed every 6 months as part of a combination regimen in treatment-naïve people with HIV: interim 16-week results of a randomized, open-label, phase 2 induction-maintenance study (CALIBRATE). 11th IAS Conference on HIV Science, July 18-21, 2021. Abstract OALB0302.
- Segal-Maurer, S Castagna A, Berhe M, et al. Potent antiviral activity of lenacapavir in phase 2/3 in heavily ART-experienced PWH. 28th Conference on Retroviruses and Opportunistic Infections (CROI), March 6-10, 2021. Abstract 127.
- Laurie VanderVeen, Nicolas Margot, Vidula Naik, et al. Interim Resistance Analysis of Long-Acting Lenacapavir in Treatment-Naïve People with HIV at 28 Weeks (CALIBRATE). IDWeek 2021 Virtual Conference, Sep 29-Oct 3, 2021. Abstract 73.