CROI 2025 Abstract eBook

Abstract eBook

Oral Abstracts

150

Broad V2-Apex bNAb Activity in HIV-1 Through a Novel, K169 Independent bNAb Maria C. Hesselman 1 , Daniel Schmidt 1 , Peter Rusert 1 , Merle M. Schanz 1 , Nikolas Friedrich 1 , Chloé Pasin 1 , Cyrille Niklaus 1 , Tandile Hermanus 2 , Mbali Mafu 2 , Dominique L. Braun 3 , Huldrych F. Günthard 1 , Roger D. Kouyos 1 , Penny L. Moore 4 , Alexandra Trkola 1 , for the Swiss HIV Cohort Study 1 University of Zurich, Zurich, Switzerland, 2 University of the Witwatersrand, Johannesburg, South Africa, 3 University Hospital Zurich, Zurich, Switzerland, 4 National Institute for Communicable Diseases, Johannesburg, South Africa Background: Broadly neutralizing antibodies (bnAbs) targeting the V2-apex of the HIV-1 envelope glycoprotein (Env) are among the most potent, with potential utility for prevention and therapy. However, V2 bnAbs have low activity against Envs lacking K/R169, as in 88% of subtype B and 26% of recent subtype C Envs (Mkhize et al, 2023). Furthermore, subtype B infections rarely trigger prototypic V2 bnAbs (Rusert et al, 2016), suggesting K/R169 may be a key regulator of V2 bnAb induction. Increasing the coverage of resistance mutations at K169 is crucial to leverage the potential of V2 bnAbs. Methods: The bnAb SHCS-0170 was isolated from the XbnAb cohort, comprising 304 bnAb inducers from the Swiss HIV Cohort Study (SHCS) (Pasin et al, biorxiv 2024). Neutralization activities of V2 bnAbs (N=28) and XbnAb plasmas (N=304) were assessed against a multi-clade Env pseudovirus panel (N=41). Epitope mapping included binding antibody multiplex assays with 16 Env targets, Env mutant neutralization and Cryo-EM structure analysis. Results: Isolated from a subtype B donor with multispecific bnAb activity, SHCS-0170 had 80% breadth at a geometric mean IC50 0.43 µg/mL. Intriguingly, given the rarity of V2 bnAbs in subtype B, SHCS-0170 neutralization correlated strongly with V2 bnAb PGT145 (Spearman’s rho=0.72). SHCS-0170 neutralized 86% of subtype B viruses, outperforming other V2 bnAbs. Epitope mapping showed N160-dependent neutralization and binding but, consistent with its high breadth, SHCS-0170 tolerated variation at Env positions 164, 166, 167, 169 and 171. A 2.9Å structure in complex with BG505.SOSIP trimer confirmed that SHCS-0170 did not interact with K169. The long beta-hairpin CDRH3 reached an extreme trimer penetration depth of 24.6Å inserting a sulfated tyrosine residue between protomers that interacts with Env residues K121 (97% conserved across subtypes) and Q315 (Q315R/K in 84% of subtype B). Thus, SHCS-0170 reached K169-independence by targeting positive charges at positions 121 and 315. Clustering of Spearman correlations between neutralization fingerprints of XbnAb plasmas and V2 bnAbs suggested that K169-independent classes may be more commonly elicited by subtype B Envs than other prototype V2 bnAbs (mixed effects model p<0.001). Conclusions: SHCS-0170 represents a novel K169-independent V2 bnAb that may be prevalent in subtype B infection. The complementarity of its epitope, relative to other V2 bnAbs, provides opportunities for combination bnAb therapy and vaccines across subtypes. Efficacy and Safety of Lenacapavir, Teropavimab, and Zinlirvimab: Phase II Week 26 Primary Outcome Kwadwo Mponponsuo 1 , James H. McMahon 2 , Linda Gorgos 3 , Javier Morales Ramirez 4 , Kimberly Workowski 5 , Jason Brunetta 6 , Onyema Ogbuagu 7 , Sean E. Collins 1 , Laurie Vanderveen 1 , Hailin Huang 1 , Jared M. Baeten 8 , Joseph J. Eron 9 1 Gilead Sciences, Inc, Foster City, CA, USA, 2 The Alfred Hospital, Melbourne, Australia, 3 AXCES Research Group, Santa Fe, NM, USA, 4 Clinical Research Puerto Rico, San Juan, Puerto Rico, 5 Emory University, Atlanta, GA, USA, 6 Maple Leaf Medical Clinic, Toronto, ON, Canada, 7 Yale University, New Haven, CT, USA, 8 University of Washington, Seattle, WA, USA, 9 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: In a non-comparative pilot Phase 1b study (NCT04811040), the long-acting HIV-1 capsid inhibitor lenacapavir (LEN) in combination with broadly neutralizing antibodies (bNAbs) teropavimab (TAB, GS-5423) and zinlirvimab (ZAB, GS-2872) maintained virologic suppression (VS; HIV-1 RNA <50 copies/mL) for 6 months after dosing in 18/20 people with HIV-1 (PWH) highly susceptible to both bNAbs. In this Phase 2 study (NCT05729568), efficacy and safety of switching to LEN+TAB+ZAB (LTZ) every 6 months (Q6M) versus staying on stable baseline oral antiretroviral regimen (SBR) is being evaluated. Methods: This open-label study enrolled virologically suppressed PWH (≥12 months on ART) with HIV-1 highly susceptible to both bNAbs (IC 90 ≤2 µg/ mL [Monogram PhenoSense mAb DNA assay] at screening). Participants were randomized 2:1 to switch to subcutaneous (SC) LEN 927 mg Q6M (+ oral 600 mg on Days 1+2), plus intravenous (IV) TAB 2550 mg Q6M and IV ZAB 2550 mg Q6M, or SBR. Primary endpoint was the proportion of participants with HIV-1 RNA ≥50

copies/mL at Week (W) 26 per FDA snapshot algorithm. Secondary endpoints included change from baseline in CD4 cell count at W26 and adverse events (AEs). Results: Fifty-three participants received LTZ and 27 SBR. Median (range) age was 51 (20–65) years, 15% were female, 36% were Black, and mean (SD) CD4 count was 749/μL (245). At W26, 1 of 53 (2%) receiving LTZ and none in the SBR arm had HIV-1 RNA ≥50 copies/mL in the analysis window; 51 (96%) and 26 (96%) remained virologically suppressed, respectively (Table). One participant in each arm withdrew; both had HIV-1 RNA <50 copies/mL. CD4 count increased from baseline to W26; mean change (SD): +23/μL (143) with LTZ; +69/μL (203) with SBR. Treatment-emergent AEs (TEAEs) were observed in 45 (85%) and 17 (63%) of participants in the LTZ and SBR arms, respectively. The most common TEAEs in the LTZ arm were Grade 1 (mild) injection site reactions related to SC LEN. No infusion-related reactions to TAB or ZAB, study drug-related Grade ≥3 TEAEs, serious TEAEs, or TEAEs leading to study drug or study discontinuation occurred in the LTZ arm. One participant in the SBR arm discontinued the study due to a serious TEAE. Conclusions: Efficacy of Q6M LTZ was similar to that of daily oral ART through W26. LTZ was well tolerated. These results demonstrate high efficacy of LTZ through W26 and support further investigation of LTZ as the first Q6M combination treatment for PWH. Proof-of-Concept Trial of VH4524184 (VH-184), a Third-Generation Integrase Strand Transfer Inhibitor Luise Rogg 1 , Sebastián A. Núñez 2 , Maria Verónica Mingrone 3 , Pere Domingo 4 , Monica Lopez 1 , Nathan Hanan 5 , Gabriela L. Ghita 5 , Jerry L. Jeffrey 1 , Mark Underwood 1 , Jose Castillo-Mancilla 6 , Fiona Halliday 7 , Ebele Ezeadi 7 , Martin Gartland 1 1 ViiV Healthcare, Durham, NC, USA, 2 Centro Médico Maffei and Investigación Clínica Aplicada, Buenos Aires, Argentina, 3 Fundación IDEAA (Infectología de Atención Ambulatoria), Buenos Aires, Argentina, 4 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 5 GSK, Collegeville, PA, USA, 6 ViiV Healthcare, Brentford, UK, 7 GSK, London, UK Background: New long-acting antiretroviral therapy (ART) regimens are needed to expand treatment choices for people living with HIV-1. VH4524184 (VH-184) is a third-generation integrase strand transfer inhibitor (INSTI) with an enhanced in vitro resistance profile compared with second-generation INSTIs being developed as a long-acting antiretroviral agent for the treatment of HIV-1. Here, we present data for VH-184 from a proof-of-concept, phase 2a trial in people living with HIV-1. Methods: This randomized, double-blind, placebo-controlled trial evaluated oral VH-184 monotherapy in adults naive to ART with HIV-1 RNA ≥3000 c/mL. In the 10-day monotherapy period, participants received oral VH-184 10, 50, or 300 mg or placebo on Days 1 (baseline), 4, and 7. After monotherapy, participants initiated standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through Day 10. Secondary endpoints included safety, tolerability, exposure-response relationships, immunologic effects, and

Oral Abstracts

152

151

treatment-emergent resistance. Results: Of 22 participants enrolled (VH-184, n=19; placebo, n=3), 86% were assigned male at birth, 68% identified as White, and 59% identified as Hispanic or Latin American; mean age was 34.1 years. Plasma HIV-1 RNA levels declined from baseline through Day 10 with all VH-184 doses (Figure). Mean maximum

35

CROI 2025