CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

no relationship observed between Day 7 PBMC TFV-DP concentrations and VL reduction for either compound. No genetic resistant variants were identified. Conclusion: Single doses of MK-8504 and MK-8583 were generally well- tolerated. These TFV prodrugs were rapidly converted to the active form and maintained target concentrations in PBMCs through 7 days. Unlike other TFV prodrugs administered daily in monotherapy trials, the antiretroviral activity of MK-8504 and MK-8583 was modest and transient. The persistent adequate concentrations of TFV-DP belie the poor VL response; it is possible, though, that VL responses could improve with daily administration of MK-8504 or MK-8583. Collectively, these data raise questions about the feasibility of TFV prodrugs in extended-interval dosing regimens. 469 DOSE-RESPONSE RELATIONSHIP OF SUBCUTANEOUS LONG-ACTING HIV CAPSID INHIBITOR GS-6207 Eric Daar 1 , Cheryl McDonald 2 , Gordon Crofoot 3 , Peter Ruane 4 , Gary Sinclair 5 , Edwin DeJesus 6 , Mezgebe Berhe 7 , Moti Ramgopal 8 , Heena Patel 9 , Ya-Pei Liu 9 , Rebecca Begley 9 , Diana Brainard 9 , Robert H. Hyland 9 , Martin Rhee 9 1 Harbor–UCLA Medical Center, Torrance, CA, USA, 2 Tarrant County Infectious Disease Associates, Fort Worth, TX, USA, 3 Crofoot Research Center, Houston, TX, USA, 4 Peter J Ruane, MD Inc, Los Angeles, CA, USA, 5 AIDS Arms, Inc, Dallas, TX, USA, 6 Orlando Immunology Center, Orlando, FL, USA, 7 North Texas Infectious Diseases Consultants, Dallas, TX, USA, 8 Midway Immunology and Research Center, Fort Pierce, FL, USA, 9 Gilead Sciences, Inc, Foster City, CA, USA Background: GS-6207, a potent, selective, first-in-class, multi-stage inhibitor of HIV-1 capsid function that inhibits HIV at picomolar concentrations and is in development as a long-acting agent for treatment of HIV-1 infection. The safety, antiviral activity and pharmacokinetics (PK) of GS-6207 were evaluated in people living with HIV (PLWH) in this Phase 1b study. Methods: This is an ongoing, Phase 1b, randomized, double-blinded, placebo- controlled dose-ranging study of GS-6207 in HIV capsid-inhibitor naive PLWH who are not taking antiretroviral therapy. A single subcutaneous (SC) dose of GS-6207 (20, 50, 150, 450, or 750 mg; N=6/cohort) or placebo (N=2/cohort) was administered. The primary endpoint was maximum reduction of plasma HIV-1 RNA through post dose day 10 (D10). Safety was assessed using laboratory tests and adverse event (AE) reporting. We present antiviral activity, blinded safety, and dose-response relationship for the 20 to 450 mg dose cohorts; enrollment of the 750 mg cohort is ongoing. Results: Demographics and baseline characteristics were similar across groups (N=32, n=8 per group). All PLWH who received active drug had significantly greater reductions in HIV-1 RNA by D10 than the placebo (all p<0.0001). The 50 to 450 mg groups had a numerically greater mean reductions in HIV-1 RNA through D10 (range: 1.8 to 2.2 log 10 copies/mL) than the 20 mg group (1.4 log 10 copies/mL). At these doses, the inhibitory quotients (mean GS-6207 concentrations for each group/protein adjusted 95%maximal effective concentration in MT-4 cells for wild type HIV-1) on D10 ranged from 0.7 to 9.9. Using a maximum effect (Emax) model for GS-6207 (SC 20 to 450 mg) and antiviral activity, Emax was ~2.1 log 10 copies/mL decline in HIV-1 RNA, and a dose inhibiting viral replication by 50% (ED50) was ~10 mg. One participant experienced a serious AE (Grade 3) of atrial fibrillation after using methamphetamine; no other SAEs, Grade 3 or 4 AEs, AEs leading to discontinuation, or clinically relevant Grade 3 or 4 laboratory abnormalities were reported. The most common AEs were injection site reactions that were mostly mild and transient (50%). Conclusion: In PLWH, GS-6207 demonstrated potent antiviral activity, with up to a 2.2 log 10 copies/mL decline at Day 10, and was generally safe and well tolerated. These results support further clinical evaluation of GS-6207 as a long- acting antiretroviral agent. 470 PK, FOOD EFFECT, AND SAFETY OF ORAL GS-6207, A NOVEL HIV-1 CAPSID INHIBITOR Rebecca Begley 1 , Martin Rhee 1 , Steve K. West 1 , Angela Worth 1 , John Ling 1 , Polina German 1 1 Gilead Sciences, Inc, Foster City, CA, USA Background: GS-6207, a potent, selective, first-in-class, multi-stage inhibitor of HIV-1 capsid function is in development for treatment of HIV-1 infection as a long acting agent. In people living with HIV (PWH), GS-6207 administered subcutaneously (SC) has shown potent antiviral activity, and is generally well tolerated. In addition to GS-6207 SC formulations, an oral tablet formulation is also in development. The safety, single ascending dose (SAD) pharmacokinetics

(PK) and effect of food (FE) on GS-6207 oral tablets were evaluated in HIV negative participants. Methods: This is an ongoing, blinded, placebo-controlled Phase 1 study with staggered SAD and open label FE cohorts. In each SAD cohort subjects were randomized (4:1) to receive single doses of GS 6207 (n=8/cohort) or placebo (n=2/cohort), at 50, 300, 900 or 1800 mg. In the FE cohorts (n=8/cohort), subjects received GS-6207 300 mg following a high fat (~1000 kcal; ~50% fat) or low fat (~400 kcal; ~25% fat) meal. Intensive PK sampling will be performed for 64 days post-dose. Single dose PK parameters were estimated using noncompartmental methods using available data; dose proportionality and FE were assessed. Safety was evaluated throughout the study. Results: Interim safety and PK data are available through 35 (300 and 900 mg fasted) or 8 days post dose (50 and 1800 mg fasted, 300 mg high and low fat). 56 of 56 participants completed dosing. GS-6207 oral tablets were generally well tolerated. No serious adverse events (AEs), Grade 3 or 4 AEs, or discontinuations due to AEs were reported. The most common AEs were back pain (n=2) and headache (n=3); all Grade 1. Based on the available data, GS-6207 exposures increased in a less than dose-proportional manner over the dose range of 50 to 1800 mg. Maximal concentrations (C max ) of GS-6207 were achieved ~4 to 8 h post dose (T max ), and GS-6207 t 1/2 was ~12 days. Exposure (C max and AUC0-D8) and time to maximal exposure (T max ) were not affected by administration following a high or low fat meal, supporting dosing of GS-6207 tablets without regard to food (Table 1). Conclusion: The preliminary PK and safety data suggest GS-6207 oral tablets are well tolerated following single oral doses up to 1800 mg, and can be dosed without regards to food. These data support ongoing clinical development of oral GS-6207 for use in PWH. Jose Francis 1 , Paolo Denti 1 , Helen Mcilleron 1 , Michelle A.Kendall 2 , Xingye Wu 2 , Kelly E. Dooley 3 , Cindy Firnhaber 4 , Catherine Godfrey 5 , Susan E. Cohn 6 , Rosie Mngqibisa 7 1 University of Cape Town, Cape Town, South Africa, 2 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 3 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 University of Colorado, Aurora, CO, USA, 5 DAIDS, NIAID, Bethesda, MD, USA, 6 Northwestern University, Chicago, IL, USA, 7 Enhancing Care Foundation, Durban, South Africa Background: Depot medroxyprogesterone acetate (DMPA) is an intermediate- acting hormonal contraceptive, administered as 150-mg intramuscular injection every 3 months and is commonly used by women with HIV and TB. As MPA is a CYP3A4 substrate, drug-drug interactions (DDI) with drugs used for HIV or TB may lead to subtherapeutic MPA concentrations (<0.1 ng/mL) before the next injection, resulting in unwanted pregnancies. Methods: Pharmacokinetic data from DMPA studies ACTG A5093 (DMPA alone, or with nelfinavir, efavirenz or nevirapine), A5283 (with lopinavir/ritonavir), and A5338 (with rifampicin+efavirenz), were pooled and interpreted with a population PK model. MPA concentrations were measured at week 2, 4, 6, 8, 10 and 12 after injection. Allometric body weight was used to scale the clearance and volume of distribution parameters and the effect of DDI were investigated. Monte Carlo simulations were used to identify percentage of participants at risk of subtherapeutic MPA exposures and derive alternative dosing strategies. Results: A total of 138 women with HIV, contributing 744 MPA concentration observations were included. Median (range) weight and age were 62.5 kg (41-125) and 34 years (15-47), respectively. A one-compartment model with first-order elimination characterized DMPA disposition, while the release of MPA from the micro-crystalline suspension was characterized using two-way absorption pathway. A fraction of the dose is readily available in the systemic circulation, while the rest is released more slowly. RIF+EFV and EFV co-treatment increased clearance of MPA by 52.4% and 24.7%, respectively;

Poster Abstracts

471 ANTIRETROVIRAL & RIFAMPICIN COTREATMENT AFFECTS DMPA EXPOSURE: DOSING IMPLICATIONS

CROI 2020 165