Efficacy and safety of lenacapavir, teropavimab, and zinlirvimab: week-26 primary outcome results from a multicentre, open-label, randomised, active-controlled, phase 2 study

  • Lancet Microbe. 2026 Mar;7(3):101283. doi: 10.1016/j.lanmic.2025.101283.
Onyema Ogbuagu  1 ,  Aditya Gaur  2 ,  James H McMahon  3 ,  Linda Gorgos  4 ,  Javier O Morales-Ramirez  5 ,  Kimberly Workowski  6 ,  Jason Brunetta  7 ,  Kwad Mponponsuo  8 ,  Sean E Collins  8 ,  Laurie A VanderVeen  8 ,  Nan Zhang  8 ,  Hailin Huang  8 ,  Jared M Baeten  8 ,  Joseph Eron  9
Affiliations
  • 1. Yale School of Medicine, Yale University, New Haven, CT, USA. Electronic address: [email protected].
  • 2. St Jude Children's Research Hospital, Memphis, TN, USA.
  • 3. Department of Infectious Diseases, Alfred Hospital and School of Translational Medicine, Monash University, Melbourne, VIC, Australia.
  • 4. AXCES Research Group, Santa Fe, NM, USA.
  • 5. Clinical Research Puerto Rico, San Juan, Puerto Rico.
  • 6. Department of Medicine, Emory University, Atlanta, GA, USA.
  • 7. Maple Leaf Medical Clinic, Toronto, ON, Canada.
  • 8. Gilead Sciences, Foster City, CA, USA.
  • 9. University of North Carolina, Chapel Hill, NC, USA.
PMID: 41720146 DOI: 10.1016/j.lanmic.2025.101283
Abstract

Background: In a phase 1b study (NCT04811040), lenacapavir combined with the broadly neutralising antibodies (bNAbs) teropavimab and zinlirvimab maintained virological suppression (HIV-1 RNA <50 copies per mL) for 6 months in people with HIV-1 highly susceptible to both bNAbs. This phase 2 study evaluated the efficacy and safety of switching to twice-yearly lenacapavir, teropavimab, and zinlirvimab versus continuing an oral stable baseline regimen (SBR) of antiretroviral therapy (ART). Here, we report the week-26 primary efficacy endpoint results.

Methods: This randomised, open-label, phase 2 study was conducted at 34 clinical sites across Australia, Canada, and the USA. People with HIV-1 RNA who had less than 50 copies per mL on oral ART with HIV-1 highly susceptible to bNAbs teropavimab and zinlirvimab (90% inhibitory concentration ≤2 μg/mL) were randomly assigned (2:1) to receive subcutaneous lenacapavir 927 mg (plus oral loading) combined with intravenous teropavimab 2550 mg and zinlirvimab 2550 mg twice-yearly (combined treatment group), or to continue an oral SBR (SBR group). Efficacy and safety analyses included participants who received at least one complete dose of the lenacapavir, teropavimab, and zinlirvimab or SBR. The primary endpoint was the proportion of participants with HIV-1 RNA concentration of 50 copies per mL or higher at week 26. Secondary endpoints included week-26 change from baseline in CD4 cell count and safety. This study is registered with ClinicalTrials.gov, NCT05729568, and is ongoing.

Findings: Between May 15, 2023, and Jan 2, 2024, of 241 participants screened, 80 were enrolled. At week 26, one (1·9%; 95% CI 0·0-10·1) of 53 participants receiving twice-yearly lenacapavir, teropavimab, and zinlirvimab and zero (95% CI 0·0-12·8) of 27 participants continuing SBR had HIV-1 RNA concentration of 50 copies per mL or higher; one participant per group had no virological data (US Food and Drug Administration Snapshot Algorithm). Excluding subcutaneous lenacapavir-related injection site reactions (n=33, predominantly grade 1), treatment-emergent adverse events occurred in 36 (68%) and 17 (63%) participants in the lenacapavir, teropavimab, and zinlirvimab group and SBR group, respectively. No infusion-related reactions to bNAbs, study drug-related grade 3 or worse adverse events, serious adverse events, deaths, or adverse events leading to discontinuation occurred in the lenacapavir, teropavimab, and zinlirvimab group.

Interpretation: A single administration of lenacapavir, teropavimab, and zinlirvimab in the study population demonstrated similar efficacy to daily oral ART through to week 26. This regimen was well tolerated, with no serious adverse events, supporting its potential as the first complete twice-yearly, long-acting, injectable HIV-1 treatment.

Funding: Gilead Sciences.

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