CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

has not been successful mainly due to their preclinical limitations. We recently discovered a highly potent and safe IN inhibitor STP0404 with outstanding antiviral efficacy and preclinical properties, which will be pursued for its clinical evaluations in early 2020. Methods: Anti-HIV activity of STP0404 was determined by tissue cultures. Electron microscopy and X-ray crystallographic methods were employed for understanding the action mechanism and binding site of STP0404. STP0404 resistance mutations were selected in tissue cultures, and their locations were confirmed by X-ray crystallography. The physicochemical properties and ADMET-related experiments were carried out by standard methods. The preclinical animal toxicity studies have been completed in rats and dogs: rats at 100, 300, and 600 mg/kg for 28 days and beagle dogs at 30, 60, and 90 mg/kg for 28 days. A nano-formulation study was conducted to confirm the possibility of long acting. Finally, testing the effect of STP0404 on HIV-1 rebound from latency infected reservoir T cells also has been completed. Results: We confirmed excellent tissue culture antiviral activities of STP0404 against both wild-type and Raltegravir-resistant HIV-1 strains with sub- nanomolar EC 50 values. The co-crystal structure confirmed its binding site to the cleft formed between two IN monomers and known to be the host LEDGF/p75 binding site, and EM study validated its activity to block HIV-1 maturation by mislocalizing HIV-1 RNA genomes outside of viral capsid. Two STP0404 resistant mutations (Y99H and A128T) were selected and co-crystal structure confirmed their locations near the STP0404 binding site. STP0404 also showed outstanding in vivo PK profiles and ADMET properties. There was no significant GLP toxicity issues observed in rodent and non-rodent species. We check the therapeutic potential of long-acting ARV due to the pmol-range potency. Finally, STP0404 displayed effective suppression of the HIV-1 rebound in lately infected T cells. Conclusion: STP0404 is a highly potent and safe ALLINI with picomolar EC 50 values in tissue culture as well as outstanding preclinical properties in animals, which will be soon pursued for its clinical evaluations for oral application as well as long-acting formulations.

vivo pharmacokinetic studies were carried out in mice. Resistance selection experiments were carried out using both subtype B and C isolates. Results: All compounds exhibit potent antiviral activity. Compound A exhibited an average IC 50 value of 7.3nM against a panel of 12 primary isolates including those with the BVM-resistant SP1 V7A genotype (n=5). Compounds B and C inhibit HIV-1 with average IC 50 values against V7 virus of 7.9 and 14.9nM and against A7 isolates of 48.2 and 138.7nM, respectively. A, B and C inhibit drug resistant virus with average IC 50 values of 3.1, 1.0 and 1.2nM, respectively (n=6). All compounds were metabolically stable in liver S9 fractions across species, demonstrated plasma protein binding of >99% and were orally bioavailable in the mouse. By using low concentrations of inhibitor, resistance-conferring mutations were identified. Conclusion: As resistance to approved HIV therapies develops new drugs will be needed. MIs employ a novel mechanism to block HIV replication and could replace drugs that are no longer effective due to resistance. Compounds A-C exhibit pre-clinical development profiles similar or superior to MI drug candidates that have advanced to the clinic. Based on these results, we plan to continue development activities for each compound. 506 PHASE II TRIAL OF VPU INHIBITOR BIT225 IN COMBINATION WITH ANTIRETROVIRAL THERAPY Anchalee Avihingsanon 1 , Carolyn A. Luscombe 2 , Gary D. Ewart 2 , Audrey S. Thomson 2 , Khuanchai Supparatpinyo 3 , Sivaporn Gatechompol 1 , Win Min Han 1 , Michelle Miller 2 , Robert Murphy 4 1 HIV–NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand, 2 Biotron Limited, North Ryde, Australia, 3 Chiang Mai University, Chiang Mai, Thailand, 4 Northwestern University, Chicago, IL, USA Background: Vpu is a HIV-1 encoded membrane protein with multiple regulatory functions that enhance HIV-1 replication fitness and promote innate immune evasion in multiple cell types including monocytes. BIT225 inhibits HIV-1 replication in myeloid cells in vitro. BIT225 has been studied in patients with chronic HIV-1 infection receiving antiretroviral therapy (ART). Methods: A randomized, placebo controlled, double-blind, Phase 2 study of BIT225 in individuals with HIV-1 commencing ART (males and females, aged 18 to 65 years, viral load >5,000 copies/mL; CD4+count >100 cells/mm 3 , ART naïve). HIV-1 infected individuals recruited from two sites in Thailand were treated with either BIT225 or placebo in addition to ART (Atripla) for 12 weeks. Individuals were randomized 2:1 (BIT225: placebo). Markers of viral replication and immune functions were investigated. Results: Thirty-six patients were enrolled. Plasma HIV-1 RNA levels declined with similar viral decay kinetics in both cohorts over the 12 week study period. In contrast, significant changes were observed for multiple immune markers between the 2 cohorts. Levels of the monocyte activation marker sCD163 showed significantly greater reduction from baseline (P<0.05, general linear model, two-way ANOVA) in the BIT225 treated cohort compared to ART alone over the 12 week treatment period. There was a statistically significant increase in activated CD8+, CD4+ cells, and NK cells in the BIT225 cohort. There was a transient statistically significant increase in plasma IL-21 production in the first 3 weeks of BIT225 therapy. There were no significant changes to plasma IL-6, TNF-alfa, and interferon-gamma in either cohort over the treatment period. Conclusion: The addition of BIT225 to ART resulted in unique stimulation of multiple arms of the innate immune system. The increased numbers of CD8+, CD4+ and NK cells are consistent with enhanced recognition of HIV-1 infected cells. Vpu has been associated with reducing cell surface expression/function of numerous cellular proteins/receptors involved in viral antigen presentation to CD4+, CD8+ T cells and NK cells. The production of IL-21 by Tfh, Th17, and/ or NK cells is a unique immunological consequence of addition of BIT225 to ART and offers the potential for treatment targeting different HIV-1 compartments during standard therapy. 507 COMPARABLE EFFICACY OF IBALIZUMAB IN COMBINATION WITH 1 OR 2 FULLY ACTIVE AGENTS Edwin DeJesus 1 , Colleen S. McGary 2 , Pedro Mesquita 2 , Steven Weinheimer 3 , Zvi Cohen 4 1 Orlando Immunology Center, Orlando, FL, USA, 2 Syneos Health, Somerset, NJ, USA, 3 TaiMed Biologics USA, Irvine, CA, USA, 4 Theratechnologies, Inc, Montreal, QC, Canada Background: Current guidelines recommend a regimen containing at least two, preferably three, fully active agents to suppress viremia in HIV treatment-

Poster Abstracts

505 PRECLINICAL DEVELOPMENT OF SECOND GENERATION HIV-1 MATURATION INHIBITORS

Sherimay Ablan 1 , KC Yuvraj 2 , Dibya Ghimire 2 , T.J. Nitz 3 , David E. Martin 3 , Ritu Gaur 2 , Eric O. Freed 1 , Carl Wild 3 1 National Cancer Institute, Frederick, MD, USA, 2 South Asian University, Chanakyapuri, New Delhi, India, 3 DFH Pharma, Inc, Gaithersburg, MD, USA Background: Maturation inhibitors (MIs) block HIV replication by disrupting conversion of CA-SP1 to mature CA, resulting in the formation of non-infectious viral particles. MIs bind inside a six-helix bundle that assembles at the junction of CA and SP1 in the immature Gag lattice. Proof-of-concept for MIs was established with bevirimat (BVM), which was found safe and effective in reducing viral load in infected individuals. However, a single amino acid polymorphism in the SP1 region of Gag (V7A) reduced susceptibility to BVM. Methods: We identified three C-28 alkyl amine BVM derivatives (compounds A-C) that exhibited potent activity against BVM-resistant polymorphs. These compounds were characterized for in vitro activity against i) a panel of primary HIV-1 clinical isolates representing subtypes A-G and ii) a set of viruses resistant to the approved classes of HIV-1 drugs. In vitro metabolic stability was characterized in human, rat, mouse, dog and monkey liver S9 fractions. Binding to human plasma proteins was determined using i) equilibrium dialysis and ii) in vitro activity assays employing human serum concentrations of 0-40%. In

CROI 2020 180