CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

found for TFV and EFV (up to 1.7 mm from HEME). The degree of colocalization between ARVs and vRNA varied (Fig B. TFV: 1-9%; ATZ: 4-16%; MVC: 54-68%; EFV: 89-99%). Yet NNS analysis indicated that >95% of all vRNA was ≤0.1 mm of a detectable ARV response in each cohort (Fig C). However, proximity of vRNA to ARV concentrations >in vitro IC50 values was farther (vRNA≤0.3 mm: FTER=0- 60%; FTMA=88-97%). Similar results were observed for NNS analysis of CD4+ T cells (Fig D. CD4≤0.3 mm: FTER=0-94%; FTMA=96-99%). Conclusion: A quantitative approach has been developed for analysis of spatial relationships between drug and targets such as blood, virus, and T cells. ARV coverage extends to >73% of the LN, better for CD4 (>64%) than vRNA (>58%), but may not be adequate everywhere relative to known inhibitory concentrations. The flexibility of this framework allows ARVs to be evaluated individually or in aggregate, and offers a tool help optimize pharmacokinetics and pharmacodynamics to ARV treatment.

with agents from each of 4 marketed ARV classes. Finally, GS-6207 retains full potency against a broad range of HIV-1 mutants resistant to other ARV classes, including those with naturally occurring Gag polymorphisms conferring resistance to maturation inhibitors. Conclusion: GS-6207 is a novel HIV capsid inhibitor with picomolar potency and a unique resistance and pharmacokinetic (PK) profile that make it a suitable candidate for a low-dose long-acting subcutaneous administration to treat HIV-1 infection, including variants resistant to current ARV therapies. The safety and PK of GS-6207 is now being evaluated in healthy human subjects. 481 MK-8591 POTENCY AND PK PROVIDE HIGH INHIBITORY QUOTIENTS AT LOW DOSES QD AND QW Jay Grobler 1 , Kerry Fillgrove 1 , Daria Hazuda 1 , Qian Huang 1 , Ming-Tain Lai 1 , Randolph P. Matthews 2 , Deanne J. Rudd 1 , Ryan Vargo 1 1 Merck & Co, Inc, West Point, PA, USA, 2 Merck & Co, Inc, Upper Gwynedd, PA, USA Background: MK-8591, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), has demonstrated HIV-1 suppression for ≥ 7 days with single doses as low as 0.5 mg. It is currently in a Phase 2 clinical trial (NCT03272347) for the treatment of HIV-1 infection with once daily (qd) administration of 0.25 mg, 0.75 mg, or 2.25 mg in combination with doravirine. Inhibitory quotients (IQ) for nucleoside inhibitors, based on the ratio of intracellular phosphorylated drug concentrations at trough (C trough,IC ) and the intracellular concentrations required for efficacy (IC 50,IC ), predict virologic response. We evaluated the IQ of MK-8591- triphosphate (MK-8591-TP) in relation to other NRTIs for WT and NRTI-resistant HIV-1 to assess the likelihood of virologic response and barrier to resistance at clinically relevant doses. Methods: MK-8591-TP, TFV-DP, 3TC-TP, and FTC-TP IC 50,IC levels were determined in activated, uninfected human peripheral blood mononuclear cells (hPBMCs) after 24 hr incubation with varying concentrations of MK-8591, TDF, 3TC, or FTC followed by lysis and analysis by LC-MS/MS. MK-8591 IQs for wild-type (wt) HIV-1 were calculated as the ratio of steady state C trough,IC , as observed with qd or weekly (qw) dosing in Phase 1 clinical studies,to the IC 50,IC in hPBMCs. TDF, TAF, 3TC, and FTC IQs were calculating using their corresponding C trough,IC s, as determined after dosing in humans at clinical dose levels, and hPBMC IC 50,IC s . IQs for NRTI-resistant HIV-1 were calculated using fold-shifts for NRTI-resistant clinical isolates. Results: The MK-8591-TP IC 50,IC for wt HIV-1 is >4-fold lower than any marketed NRTI. MK-8591 IQs at steady state with 0.25 mg qd and 10 mg qw dosing are 85.3 and 101, respectively, and proportionately greater for higher dose levels. Common NRTI mutations, including M184I/V, thymidine analog mutations, K65R, and K70E, confer low fold-shifts in antiviral potency, and MK-8591 retains greater IQs against these NRTI-resistant viruses than those of TDF, TAF and 3TC with wt virus. Conclusion: The IQs of MK-8591 for both wt and NRTI-resistant HIV-1 at low qd and qw doses are substantially higher than those of any NRTIs approved for HIV treatment. Coupled with the long intracellular half-life of the MK-8591-TP, these IQs suggest the opportunity for multiple low dosing options with the potential for a high barrier to the development of resistance.

Poster Abstracts

480 GS-6207, A POTENT AND SELECTIVE FIRST-IN-CLASS LONG-ACTING HIV-1 CAPSID INHIBITOR Stephen R. Yant , Andrew Mulato, George Stepan, Armando G. Villasenor, Debi Jin, Nicolas A. Margot, Shekeba Ahmadyar, Renee R. Ram, John R. Somoza 1 , Eric Singer, Melanie Wong, Yili Xu, John O. Link, Tomas Cihlar, Winston C. Tse Gilead Sciences, Inc, Foster City, CA, USA Background: We describe the in vitro pharmacological profile of GS-6207, a first-in-class HIV capsid (CA) inhibitor optimized for long-acting antiretroviral (ARV) treatment administered monthly or less frequently. Methods: GS-6207 binding to HIV-1 CA hexamer was evaluated by surface plasmon resonance and x-ray crystallography. Antiviral potency and cytotoxicity were assessed in human T-cell lines and primary cells. HIV-1 and -2 laboratory strains and clinical isolates as well as HIV-1 recombinant mutants resistant to other ARV drug classes were used for antiviral profiling. Effect of the multiplicity of infection (MOI) on antiviral potency was tested using a reporter HIV-1. Cytotoxicity was profiled in 4 non-target human cell lines and primary hepatocytes. GS-6207 activity was evaluated in combination with marketed classes of ARVs. Results: GS-6207 binds with high affinity to CA hexamers (K D = 0.2 nM) at the interface between two adjacent CA monomers. GS-6207 displays potent and selective antiviral activity in MT-4 cells (EC 50 = 0.1 nM, CC 50 = 27 µM) and exhibits a mean EC 50 of 0.05 nM (0.02 - 0.16 nM) in human PBMCs against 23 HIV-1 clinical isolates spanning all major subtypes. The human serum protein- adjusted EC 95 for GS-6207 (4 nM) is >10-fold lower than that of efavirenz (EFV), rilpivirine, dolutegravir (DTG) and atazanavir (ATV). In primary human CD4+ T-cells and macrophages, GS-6207 is >10-fold more potent and >22-fold more selective than EFV, DTG and ATV. GS-6207 also suppresses HIV-2 replication. As with other ARVs, GS-6207 antiviral activity decreases with increasing MOI but remains 5- to >100-fold more potent than 4 commonly used ARVs. GS-6207 exhibits low cytotoxicity in 4 human cell lines and primary hepatocytes (CC 50 > 44 µM) and shows synergistic antiviral activity when combined pairwise

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