CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

117

VH3810109 (N6LS) in Adults With HIV-1 Who Are ART-Naive: Phase IIa BANNER Efficacy Data Peter Leone 1 , Alejandro Ferro 2 , Sergio Lupo 3 , Joseph McGowan 4 , Paul Benson 5 , Marisa Sanchez 6 , Stefan Schneider 7 , Paul Wannamaker 1 , Beta Win 8 , Judah Abberbock 9 , Viviana Wilches 9 , Margaret Gartland 1 , Max Lataillade 10 , Jan Losos 1 1 ViiV Healthcare, Durham, NC, USA, 2 Centro de Investigaciones Medicas, Mar del Plata, Argentina, 3 Instituto Caici, Rosario, Argentina, 4 Northwell Health, New York, NY, USA, 5 Be Well Medical Center, Berkley, MI, USA, 6 Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, 7 Long Beach Education and Research Consultants, Long Beach, CA, USA, 8 GlaxoSmithKline, Brentford, United Kingdom, 9 GlaxoSmithKline, Collegeville, PA, USA, 10 ViiV Healthcare, Branford, CT, USA Background: The broadly neutralizing antibody (bNAb) VH3810109 (N6LS), a CD4-binding site antibody with broad and potent neutralizing activity in vitro, demonstrated robust antiviral effect (median viral load [VL] decline of 1.72 log 10 c/mL and maximum viral nadir from baseline [BL] of −2.60 log 10 c/mL) when given at 40 mg/kg intravenously (IV) in people with HIV-1 in part 1 of the proof-of-concept BANNER study and a good safety profile in parts 1 and 2. We report efficacy data for N6LS administered IV or subcutaneously (SC) in parts 1 and 2 of BANNER. Methods: BANNER is a randomized, open-label, 2-part, multicenter study assessing safety, pharmacokinetics, and antiviral activity of N6LS in treatment naive adults with VL ≥5000 c/mL. N6LS was evaluated during monotherapy after a single IV infusion or SC injection, followed by 48 weeks of standard-of care antiretroviral therapy. Monotherapy duration was determined by virologic non-response (VL <0.5 log 10 by Day 11) or rebound (VL ≥1.0 log 10 over nadir or <0.5 log 10 from BL). Results: Of 62 participants, 8 received 40 mg/kg IV and 6 received 280 mg IV in part 1; 16 received 700 mg IV, 16 received 70 mg IV, and 16 received 700 mg SC in part 2. Most participants were male (94%), White (61%), and Hispanic (82%). Median (range) age was 29 (18-61) years. At BL, median VL ranged from 4.1 to 4.5 log 10 c/mL across dose groups. Median (range) maximum VL decline ranged from −0.43 (−1.29 to −0.12; 70 mg IV group) log 10 c/mL to −1.72 (−2.60 to −0.60; 40 mg/kg IV group) log 10 c/mL and was reached in a median of 9 days (Figure). Among responders, median (range) time to rebound ranged from 13 (10-22; 70 mg IV group) days to 35 (12-78; 40 mg/kg IV group) days. Across dose groups, there was a weak-to-moderate correlation between BL viral sensitivity and maximum VL decline. N6LS was well tolerated when given IV or SC, with few drug-related adverse events (AEs) and no serious AEs. Conclusion: Robust antiviral activity was observed after IV and SC administration of N6LS; response was correlated with N6LS exposure. Response with SC vs IV dosing was lower and likely due to differences in BL susceptibility, serum antibody levels, and slower time to reach C max . Overall, N6LS led to dose dependent declines in VL consistent with antiviral activity reported for other bNAbs. Results support the ongoing development of N6LS into phase IIb.

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A First-in-Human Study of the Trispecific HIV-1 Broadly Neutralizing Antibody, SAR441236 Athe Tsibris 1 , Yu E. Zheng 2 , Edmund Capparelli 3 , Katherine Rodriguez 2 , Randall Tressler 4 , Antoine Deslandes 5 , Katherine Shin 4 , Philip Marzinek 6 , Lucio Gama 7 , Baiba Berzins 8 , Chanelle Wimbish 9 , Chih-Jen Wei 10 , Gary Nabel 10 , Daniel R. Kuritzkes 1 , Pablo Tebas 11 1 Brigham and Women's Hospital, Boston, MA, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 University of California San Diego, La Jolla, CA, USA, 4 National Institute of Allergy and Infectious Diseases, Rockville, MD, USA, 5 Sanofi, Vitry-sur-Seine, France, 6 Frontier Science & Technology Research Foundation, Inc, Amherst, NT, USA, 7 National Institutes of Health, Bethesda, MD, USA, 8 Northwestern University, Chicago, IL, USA, 9 Social & Scientific Systems, Inc, Silver Spring, MD, USA, 10 ModeX Therapeutics, Inc, Natick, MA, USA, 11 University of Pennsylvania, Philadelphia, PA, USA Background: The trispecific broadly neutralizing antibody (bNAb) SAR441236 combines the HIV-1 specificities of VRC01 (CD4 binding site), PGDM1400 (V1/ V2 glycan binding), and 10E8v4 (membrane proximal external region) into one molecule with amino acid modifications (LS) in the Fc-region for half-life extension. SAR441236 provided complete protection against macaque SHIV challenge but has not been tested in people with HIV (PWH). Methods: ACTG A5377 was a phase I study evaluating the safety, pharmacokinetics (PK), and antiviral activity of SAR441236, a trispecific HIV-1 bNAb. Escalating intravenous (IV) or subcutaneous (SC) single doses of SAR441236 (from 0.3 – 10 mg/kg) or 4 doses at 30 mg/kg IV (every 12 weeks with 72 weeks of follow up) were assessed in ART-treated PWH with plasma viral RNA <50 copies/mL. Dose cohorts were randomized 2:1 to SAR441236 or placebo. Single open-label IV doses of 1 mg/kg or 30 mg/kg were assessed in viremic participants (ART-naïve or no ART in the preceding 3 months). Primary outcomes were study treatment-related Grade ≥3 adverse events, AUC 0-12 wk of SAR441236, and the day 7 change in plasma HIV-1 RNA levels in viremic participants. Results: A total of 52 participants were enrolled and 51 received study treatment. Median age was 53 years. 10% were female, 37% were Black, and 12% were Hispanic. No events met the primary safety outcome (95% CI 0-0.09). Population PK analysis demonstrated an overall clearance (CL) of 137 ± 86 mL/d, a volume of distribution (Vds) of 6.3 ± 2.4 L, population SC bioavailability of 35 ± 7%, and a half-life (t 1/2 β) of 38 ± 10 days. SAR441236 CL was 38% higher in viremic cohorts. For the 30 mg/kg single dose in aviremic participants, the AUC0-12wk was 22,292 ± 889 μg*d/mL (mean ± SD). Monte Carlo simulations predicted 30 mg/kg IV every 12 weeks to result in a median steady-state trough of 74 μg/mL (90% PI 25-185 μg/mL). Only 7 of 24 planned viremic participants were enrolled. The mean change to day 7 plasma HIV-1 RNA levels in the 1 mg/ kg cohort (n = 5) was -0.10 log 10 copies/mL and -0.38 log 10 copies/mL in the 30 mg/kg cohort (n = 2). Conclusion: SAR441236 administration was safe and well tolerated. The PK of SAR441236 was similar to traditional HIV-1 IgG antibodies with half life extension modifications, such as VRC07-523LS. The favorable PK and convenience of administering a single biologic with three binding specificities support the evaluation of novel trispecific or multispecific bnAbs for HIV-1 treatment or prevention. Safety and Efficacy of VRC07-523LS Plus Long-Acting Cabotegravir in the Phase II ACTG A5357 Trial Babafemi Taiwo 1 , Yu E. Zheng 2 , Katherine Rodriguez 2 , Leah Burke 3 , Jackie Reeves 4 , Paul Wannamaker 5 , Lucio Gama 6 , Christos Petropoulos 4 , Kimberly K. Scarsi 7 , Pablo Belaunzaran-Zamudio 8 , Ronald D'Amico 5 , Katharine J. Bar 9 , Pablo Tebas 9 , for the ACTG A5357 Team 1 Northwestern University, Chicago, IL, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 Weill Cornell Medicine, New York, NY, USA, 4 Monogram BioSciences, San Francisco, CA, USA, 5 ViiV Healthcare, Research Triangle Park, NC, USA, 6 National Institutes of Health, Bethesda, MD, USA, 7 University of Nebraska Medical Center, Omaha, NE, USA, 8 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 9 University of Pennsylvania, Philadelphia, PA, USA Background: Background: Broadly neutralizing antibodies (bNAbs) hold promise for antiretroviral therapy (ART). ACTG A5357 is a phase II, single-arm clinical trial, investigating the combination of VRC07-523LS, a bNAb targeting the HIV-1 CD4-binding site, and long-acting cabotegravir (LA CAB) for maintenance ART Methods: Participants are adults with HIV, virally suppressed for >2 years, a current CD4 count ≥350 cells/mm 3 , and susceptibility to VRC07-523LS (IC 50 0.25 μg/mL and a Maximum Percent Inhibition (MPI) >98% on the Monogram PhenoSense mAb Assay using screening PBMCs). In Step 1, participants received 4 or 5 weeks of oral CAB and two NRTIs. Those still suppressed entered Step 2

Oral Abstracts

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CROI 2024