Patients on failing HIV regimens achieve viral suppression with long-acting lenacapavir
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Researchers at the International AIDS Society Conference on HIV Science reported more promising data on lenacapavir, the investigational, long-acting HIV-1 capsid inhibitor that is administered subcutaneously every 6 months.
Data from an ongoing phase 2/3 study of heavily treatment-experienced people with multidrug-resistant HIV showed that 81% of participants who received lenacapavir in combination with an optimized background regimen achieved sustained virologic suppression at week 26.
Gilead Sciences submitted a new drug application to the FDA earlier this month seeking approval for lenacapavir.
“Lenacapavir emerges as a new and potent antiretroviral for the treatment of patients with multidrug-resistant viruses,” Jean-Michel Molina, MD, head of the infectious diseases department at Saint-Louis Hospital and Lariboisière Hospital in Paris, told Healio. “Its long half-life allowing one subcutaneous injection every 6 months will also improve adherence in these difficult-to-treat patients.”
For the Capella study, Molina and colleagues randomly assigned 36 participants in a 2:1 ratio to add either oral lenacapavir or placebo to their failing regimen for 14 days. They received 600 mg on days 1 and 2, and 300 mg on day 8.
On day 15, participants in the lenacapavir arm received a 927 mg subcutaneous injection of lenacapavir. Participants in the placebo arm started the oral lead-in, followed by 927 mg subcutaneous lenacapavir. All participants began an optimized background regimen on day 15 as well.
In a separate nonrandomized cohort, 36 participants began an optimized background regimen concurrent with lenacapavir. The authors reported the efficacy at week 26 of the randomized cohort, as well as safety and efficacy information from both cohorts.
Overall, 25% of participants were female, 38% were Black and the median age of participants was 52 years. Median CD4 count was 150 cells/µL among participants. Mean HIV-1 RNA was 4.17 log c/mL, and the rate of resistance to two or more antiretrovirals in each class was 99% for nucleoside reverse transcriptase inhibitors, 97% for non-nucleoside reverse transcriptase inhibitors, 81% for protease inhibitors and 69% for integrase strand transfer inhibitors.
At week 26, 81% (29 of 36) of participants in the randomized cohort had a viral load of less than 50 c/mL, according to the researchers. Among participants with data from both cohorts, through week 26, 79% (33 of 42) had a viral load of less than 50 c/mL and the median CD4 count increased by 82 cells/µL.
Four participants in the randomized cohort experienced emergent lenacapavir resistance. Three suppressed afterward, one with a changed optimized background regimen and two without, Molina and colleagues reported.
No serious adverse reactions or adverse reactions leading to discontinuations were reported. Lenacapavir-related injection site reactions occurred in 56% of participants (40 of 72) and were mostly mild or moderate (38 of 40). Common injection site reactions were swelling (26%) and erythema (24%).
Perspective
Back to TopMelanie Thompson, MD
The International AIDS Society meeting brought us several new glimpses into the performance of the first-in-class capsid inhibitor lenacapavir and a hint at a potential Achilles heel.
First, the open-label Calibrate study presented results of the comparison of lenacapavir (LEN; subcutaneous or oral) + emtricitabine/tenofovir alafenamide (FTC/TAF) vs. bictegravir/FTC/TAF (BIC/FTC/TAF) in treatment-naive individuals. At 28 weeks, the two subcutaneous LEN + FTC/TAF arms (after an oral LEN lead in) showed potent viral suppression of 94% and 92%, whereas the oral LEN+ FTC/TAF arm showed 94% suppression, and BIC/FTC/TAF hit a home run at 100% suppression. All arms showed acceptable safety and tolerable injection site reactions. Although only four patients on subcuteneous LEN had HIV RNA more than 50 c/mL, one of these demonstrated two capsid mutations (Q67H +K70R) and an M184M/I mutation to FTC at only 10 weeks of treatment and in spite of LEN concentrations described as “adequate.” These resulted in a 20-fold decrease in LEN sensitivity. Going forward, we will learn whether TAF or BIC alone will be good enough partners for LEN.
Capella, a relatively small study (36 randomized; 36 nonrandomized) of highly treatment-experienced patients, found that LEN was very potent against viruses resistant to currently available classes. An 81% rate of viral suppression and an increase of 81 CD4+ cells/µL at 26 weeks in the randomized cohort is a very respectable — and clinically significant — response. Again, the safety profile appeared quite good. In four of 11 patients meeting criteria for genotyping, however, capsid mutations were seen, with all four exhibiting the M66I mutation and one each having Q67H, K70N/R/S and N74D. This suggests that LEN does not have a high barrier to resistance and needs good support from background therapy.
It is important to recognize that these are short-term results for a long-acting therapy, really only encompassing the period after the very first subcutaneous dose. Durability will be known only as these studies progress. Taking these two studies together, we can be encouraged about the potency and safety of LEN, which may show great promise in the heavily treatment-experienced population but also as earlier treatment when given with a robust background. What we are learning is that the robust background, however, will be crucial. Ideally, an agent that matches the long half-life of LEN would protect against missed doses of oral background therapy. But these studies also suggest that the background must also have a rather robust barrier to resistance. As with cabotegravir and rilpivirine, the long pharmacokinetic (PK) tail will also require coverage, even after the drug is discontinued.
It appears that LEN is betrothed to islatravir (ISL) — an exciting nucleoside reverse transcriptase translocation inhibitor in development — through a collaboration between Gilead and Merck. Upcoming clinical trials will tell us whether LEN + ISL can be a viable two-drug regimen and in which settings. It is also important to mention that LEN is being studied as monotherapy for prevention. The issues for resistance in a prevention setting are somewhat different than for treatment, and coverage of the PK tail will be particularly important here. Still, the LEN glass is half full at this point, and our learnings from these early studies can certainly help to position LEN with its best partners to maximize its potential for a substantial contribution to HIV treatment.
References:
Gupta S, et al. Abstract 2211. Presented at: International AIDS Society Conference on HIV Science; July 18-21, 2021 (virtual meeting).
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Molina JM, et al. Abstract 2605. Presented at: International AIDS Society Conference on HIV Science; July 18-21, 2021 (virtual meeting).
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