CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

by biolayer interferometry assays, antiviral potency by TZM-bl neutralization assays and plasma PK following intravenous injection in wild type Balb/c mice. Results: Engineered CD4 mimetic constructs eliminated MHC II binding without reducing binding to gp120 or loss of neutralization potency against both CCR5 and CXCR4 tropic viruses (IC 50 of 130 and 953 ng/ml, respectively). The plasma half-life (t 1/2 = 129 hours) in wild-type mice following IV injection was markedly prolonged compared to the prototypic CD4 mimetic construct, LSEVhLS-F and comparable to the long-lasting IgG1 bnAb 10-1074 (t 1/2 = 174 hours). Conclusion: We have successfully engineered CD4 mimetics to prolong their in vivo half-life without affecting antiviral potency. These new constructs are promising candidates as long-acting entry inhibitors for HIV prevention and treatment. The figure, table, or graphic for this abstract has been removed. The Preclinical Profile of Maturation Inhibitor VH3739937 Brian McAuliffe , Paul Falk, Ira Dicker, Susan Jenkins, Jean Simmermacher, Mark Krystal ViiV Healthcare, Branford, CT, USA Background: VH3739937 (VH937) is a next generation maturation inhibitor (MI) currently in clinical trials. We report here on its preclinical profile. Methods: Replication competent and single cycle inhibition assays were performed using a cohort of clinical isolates or site-directed mutant (SDM) viruses. Biochemical experiments using purified viral like particles (VLPs) were performed, while a radiolabeled surrogate compound was used to examine binding kinetics to viral-like particles (VLPs). Resistance selection was carried out using NL4-3 virus at escalating concentrations of VH937. DMPK studies were also carried out. Results: Biochemical experiments showed VH937 to be a bona fide MI. VH937 is a pan-genotypic MI that was active against all HIV-1 viruses examined. EC 50 s of 1-5 nM were obtained against 8 laboratory strains and 43 clinical isolates. VH937 was also highly potent against all SDM polymorphisms previously identified as causing reduced susceptibility to first generation MIs. VH937 was partially active against a replication competent A364V mutant, with an EC 50 of 5 nM and a maximum percent inhibition (MPI) of 95%. However, A364V could be selected under escalating VH937 conditions in cell culture, potentially explained by its weaker activity in a single cycle inhibition assay (EC 50 =32 nM; MPI=57%). Other mutations selected by VH937 included T332P, L363W or the triple mutant H144Y/V362I/R384K. However, whereas each of these mutations induced highly reduced susceptibility in a single cycle assay, incorporation of any of these mutations into a replicating virus clone did not produce functional virus. The surrogate compound bound to an NL 4-3 VLP with a binding affinity of 3.3 ± 0.8 nM and had a dissociative half-life of 4125 minutes (almost 3 days), showing the compound binds avidly and dissociates slowly. This was in agreement with SP1 cleavage data obtained with VLPs. Finally, VH937 was ~93.3% protein bound in 100% human serum and exhibited DMPK profiles suitable for clinical development. Conclusion: The pre-clinical virology profile of VH937 supported the progression of this MI into clinical development. Next-Generation Maturation Inhibitor GSK3640254 Showed Broad Spectrum Potency Without MI Resistance Jerry L Jeffrey 1 , Tom White 2 , Samit Joshi 2 , Brian Wynne 2 1 ViiV Healthcare, Research Triangle Park, NC, USA, 2 ViiV Healthcare, Brentford, United Kingdom Background: HIV-1 maturation inhibitors (MI) offer a novel mechanism of action but have suffered from gag polymorphisms and decreased antiviral potency. GSK3640254 (GSK'254) is a next-generation MI that demonstrated broad spectrum coverage of gag polymorphisms in vitro (Dicker et al. AAC 2022;66:e0187621). GSK'254 + 2 nucleoside-reverse transcriptase inhibitors (NRTIs) demonstrated comparable efficacy to DTG + 2 NRTIs with no treatment emergent resistance across all doses and a comparable safety/tolerability profile in the DOMINO Phase 2b dose-ranging study (Joshi et al. EACS 2023. Oral RA2.O1.). HIV-1 gag/protease from day 1 baseline and on-treatment samples were tested for sensitivity to GSK'254 and gag sequences generated to identify polymorphisms and/or treatment emergent resistance mutations. Methods: Plasma samples from study participants at day 1 pre-dose, week 4 on-study and any time point at protocol defined virologic failure (PDVF) were sent to Monogram Biosciences for phenotypic analysis using the Phenosense gag-pro assay. Gag genotypic data were generated using the gag next generation sequencing (NGS) assay.

suppressed at a later visit; 1 participant not suppressed at W26 developed LEN-R (M66I) but was suppressed at W52 and 104 (OBR changed at W25); and 2 participants had HIV-1 RNA ≥50 copies/mL throughout, but with a stable, low level viral load (1 with <600 copies/mL, OBR changed at W30; 1 with <3000 copies/mL despite emerging LEN-R at W4 [M66M/I]). None of the 12 participants discontinued the study drug. Conclusion: In HTE PWH with MDR on an OBR with no fully active ARVs, LEN led to sustained virologic suppression over 104 weeks for most participants. LEN is an important option for treating HTE PWH with MDR. Intramuscular Injection vs Intravenous Infusion of Ibalizumab for HTE PWH: The Results of TMB-302 Kaitlin R. Anstett 1 , R. Brandon Cash 1 , Anthony Mills 2 , Mezgebe Berhe 3 , Edwin DeJesus 4 1 Theratechnologies, Inc, Montreal, Canada, 2 Men's Health Foundation, Los Angeles, CA, USA, 3 Baylor Institute for Immunology Research, Dallas, TX, USA, 4 Orlando Immunology Center, Orlando, FL, USA Background: Ibalizumab (IBA) is a monoclonal antibody approved for the treatment of multi-drug resistant HIV-1 infection in heavily treatment experienced (HTE) people with HIV (PWH) in combination with an optimized background regimen. The efficacy of ibalizumab (IBA) in combination with an optimized background regimen has been demonstrated in clinical trials previously. IBA is currently administered every two weeks (Q2W) via intravenous infusion (IVI) over 15-30 minutes, or via undiluted intravenous push over 30 seconds. This requires a peripheral IV catheter for administration by trained staff, which can limit access. Altering the mechanism of administration of IBA will expand and simply access for HTE PWH in need of new therapies to achieve their treatment goals. Methods: TMB-302 (ClinicalTrials.gov Identifier: NCT03913195) is a phase 3 study of the safety and efficacy of IBA administered as an intramuscular (IM) injection in clinically stable HIV-1 infected IBA experienced patients and healthy HIV-uninfected volunteers. All subjects in this study received at least two IVI infusions of IBA prior to administration via IM injection for 8 weeks. The HIV treatment satisfaction questionnaire – status (HIVTSQS) and study medication satisfaction questionnaire - status (SMQs) were administered at the last IVI administration (day 29) and after 8 weeks of IM administration (day 85) and the HIV treatment satisfaction questionnaire – change (HIVTSQC) and study medication questionnaire - change (SMQc) were also administered on day 85. All study participants were also asked to answer a one-question Preference Assessment at Day 85 comparing the experience on IM injections with IV infusion. Results: Administration of IBA via both IVI and IM were well-tolerated by study participants. Although there was no statistically significant difference in either the HIVTSQS or SMQs between day 29 and 85, 83% of HIV-uninfected volunteers and 67% of HIV-infected clinical stable participants preferred administration of IBA IM compared to IVI. Importantly, no PWH lost viral suppression throughout the course of the study. No new or unexpected safety signals were identified. Conclusion: Administration of IBA via IM injection was safe, well-tolerated, did not result in the loss of viral suppression among HTE PWH, and was the preferred method of administration of all participants in the TMB-302 study. Expanding the administration options for IBA is an important step to increasing access and agency for PWH. Discovery of Next-Generation CD4 Mimetic-Based Long-Acting Entry Inhibitors Wei Li, Margaret G. Hines, Xiaojie Chu, Tianjian Liang, Cory Shetler, Kerri Penrose, Zhiwei Feng, Urvi M. Parikh, Jana L Jacobs , John W. Mellors University of Pittsburgh, Pittsburgh, PA, USA Background: CD4 mimetics have shown promise for HIV prevention and treatment because of the broadest HIV neutralization profiles and high barrier to virus escape stemming from the essential role of CD4 in HIV entry. Their development has been limited, however, by rapid in vivo clearance, possibly related to major histocompatibility complex (MHC) class II binding. An optimal CD4 mimetic construct would retain neutralization breadth and have a long in vivo half-life requiring infrequent administration. To this end, we have engineered CD4 mimetics to reduce/abrogate MHC II binding, increase neutralization potency and prolong in vivo half-life. Methods: Candidate CD4 mimetic constructs exhibiting increased stability were engineered using molecular modeling, DNA mutagenesis and phage display selection. Promising variants were assessed for MHC Class II binding

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