Abstract Background Lenacapavir (LEN), the HIV-1 capsid inhibitor, combined with the broadly neutralizing antibodies teropavimab (TAB, GS-5423) and zinlirvimab (ZAB, GS-2872), is an investigational twice-yearly (Q6M) regimen for HIV-1 treatment. In Phase 1b (NCT04811040) and Phase 2 (NCT05729568) studies, LEN, TAB, and ZAB maintained virologic suppression (HIV-1 RNA 50 copies/mL) for 6 months after one dose. We evaluated pooled Phase 1b/2 safety and tolerability of LEN, TAB, and ZAB, including the effects of anti-drug antibodies (ADAs) against TAB and ZAB on safety.Table 1.Pooled Baseline CharacteristicsLEN, lenacapavir; TAB, teropavimab; ZAB, zinlirvimab.Table 2.Pooled Safety Outcomes at Week 26a.Including ISRs, 71 participants (84.5%).b.Acute pyelonephritis, ureteritis, and nephrolithiasis in 1 participant; injection site cellulitis in 1 participant (not considered an ISR per Medical Dictionary for Regulatory Activities 26.1).c.Increased lacrimation, diarrhea, headache, nausea, abnormal dreams, insomnia, device dislocation, infusion-related reaction, injection site cellulitis (n=1 each). Including ISRs, 57 participants (67.9%).d.Injection site cellulitis.AE, adverse event; ISR, injection site reaction; LEN, lenacapavir; TAB, teropavimab; ZAB, zinlirvimab. Methods Both studies enrolled virologically suppressed adults with HIV-1. In Phase 1b, participants were randomized 1:1 across two cohorts to receive one dose of 927 mg subcutaneous (SC) LEN (+ oral loading), 30 mg/kg intravenous (IV) TAB, and either 10 mg/kg or 30 mg/kg IV ZAB. In Phase 2, participants were randomized 2:1 to switch to Q6M 927 mg SC LEN (+ oral loading), 2550 mg IV TAB and 2550 mg IV ZAB, or to continue daily oral stable baseline regimen (SBR) through Week (W)52. Safety and ADA data through W26 for those receiving LEN, TAB, and ZAB were pooled. Results The pooled analysis included 84 participants (Phase 1b, n=31; Phase 2, n=53); baseline characteristics are shown in Table 1. Excluding injection site reactions (ISRs), treatment-emergent adverse events (AEs) occurred in 56 (66.7%) participants (Table 2). ISRs related to SC LEN were reported in 55 (65.5%) participants and in most (47/55) these were Grade 1 (mild). There were no infusion-related reactions, serious AEs, or AEs leading to study drug or study discontinuation. Grade ≥3 laboratory abnormalities occurred in 5 (6.0%) participants and were judged not clinically significant by the investigator. Safety profiles for the pooled LEN, TAB, and ZAB cohort were comparable to the Phase 2 SBR cohort. ADAs against TAB were detected in 11 (13.3%) participants and against ZAB in 15 (18.1%). ADAs were generally observed at low titers and did not have an identifiable effect on safety. Conclusion LEN, TAB, and ZAB were well tolerated with a favorable safety profile up to W26 across Phase 1b and Phase 2 studies. ADAs against TAB and ZAB were low in titer and did not impact safety. The ongoing Phase 2 study will continue to evaluate LEN, TAB, and ZAB as the first complete twice-yearly regimen for HIV-1 treatment. Disclosures Kimberly Workowski, MD, Gilead Sciences, Inc.: Institutional research support Peter Ruane, MD, Gilead Sciences, Inc.: Advisor/Consultant|Merck: Advisor/Consultant|ViiV: Advisor/Consultant Olayemi O. Osiyemi, MD, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria Linda Gorgos, MD, MSc, FIDSA, Akero Therapeutics: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|Glaxo SmithKline/ViiV: Grant/Research Support|Merck Sharp and Dohme: Grant/Research Support|Moderna: Grant/Research Support|Novavax: Grant/Research Support Gordon E. Crofoot, MD, Gilead Sciences, Inc.: Grant/Research Support Moti Ramgopal, MD, AbbVie: Honoraria|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|Shionogi: Advisor/Consultant|ViiV: Advisor/Consultant|ViiV: Honoraria Cynthia C. Brinson, MD, Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Gilead Sciences, Inc.: Medical writing funds|GSK: Grant/Research Support|ViiV: Grant/Research Support Kwad Mponponsuo, MD, MSc, Gilead Sciences, Inc.: Employee and shareholder Sean E. Collins, MD, MS, Gilead Sciences, Inc: Employee Hui Liu, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Nan Zhang, PhD, Exelixis: Employee|Gilead science, inc.: Employee|Gilead science, inc.: Stocks/Bonds (Public Company) Keith Flower, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Tina Chakrabarti, MD, Gilead Sciences, Inc.: Employee Onyema Ogbuagu, MA, FACP, FIDSA, Gilead Sciences, Inc.: Advisor/Consultant|ViiV: Advisor/Consultant
Workowski et al. (Thu,) studied this question.