CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

38 A RANDOMIZED TRIAL OF THE IMPACT OF 3BNC117 AND ROMIDEPSIN ON THE HIV-1 RESERVOIR Henning Gruell 1 , Yehuda Z. Cohen 2 , Jesper D. Gunst 3 , Marie H. Pahus 3 , Clara Lehmann 1 , Katrina Millard 2 , Martin Tolstrup 3 , Julio C. Lorenzi 2 , Michel Nussenzweig 2 , Gerd Fätkenheuer 1 , Florian Klein 1 , Marina Caskey 2 , Ole S. Søgaard 3 1 Cologne University Hospital, Cologne, Germany, 2 The Rockefeller University, New York, NY, USA, 3 Aarhus University Hospital, Aarhus, Denmark Background: Broadly neutralizing antibodies (bNAbs) administered prior to reversal of latency may facilitate killing of HIV-1-infected CD4+ T cells and could be a component of an HIV-1 cure strategy. To clinically assess this concept in individuals on antiretroviral therapy (ART), we evaluated the impact of the bNAb 3BNC117 followed by latency reversal with romidepsin on measures of viral transcription, reservoir size, as well as time to viral rebound during analytical treatment interruption (ATI). Methods: This randomized phase Ib/IIa trial enrolled 20 HIV-1-infected adults on long-term ART. Group A received 3BNC117 (30 mg/kg) 2 days prior to each romidepsin cycle, with romidepsin (5 mg/m 2 ) administered at weeks 0, 1, and 2 (cycle 1), and weeks 8, 9, and 10 (cycle 2). Group B received cycles 1 and 2 but no 3BNC117. This was followed by an ATI at week 24 when bNAb levels were expected to be low or undetectable. The primary endpoint was time to viral rebound (≥200 copies/mL) during ATI. Secondary endpoints were safety, changes in HIV-1 reservoir measures, as well as effects on HIV-1-specific immunity. Results: Nineteen of 20 enrolled participants (3 females, 17 males, median age 44 years, median of 645 CD4+ cells/mm 3 ) completed all treatment cycles; 11 in Group A and 8 in Group B. Two participants (one in each group) opted out of the ATI. Seven participants (Group A = 4, Group B = 3) had detectable viral blips (21-144 copies/ml) after romidepsin infusions. Unspliced HIV-1 RNA increased in most individuals after the 2nd and 3rd infusions in each romidepsin cycle. Decline in total HIV-1 DNA was 90 vs 61 copies/106 CD4+ T cells for group A vs B (p=0.79). Median time from interrupting ART to plasma HIV-1 RNA ≥200 copies/ ml during ATI was 2.5 weeks for Group A and 4.0 weeks for Group B. A total of 237 AEs were recorded (184 grade 1, 52 grade 2, and 1 grade 3), of which 64 (27.4%) were considered at least possibly related to study medications. Conclusion: This is the first reported trial of the combination of a latency- reversing agent and potent bNAb designed to target the HIV-1 reservoir. While the combination was safe, it did not reduce the combined defective and intact proviral reservoir as measured by total HIV DNA, or delay viral rebound during ATI. These results may serve as a benchmark for further optimization of HIV-1 cure strategies under ART. 39 SAFETY & PHARMACOKINETICS OF GS-9722 IN HIV-NEGATIVE PARTICIPANTS AND PEOPLE WITH HIV Peter Ruane 1 , Eric Daar 2 , Kimberly Workowski 3 , Rebecca Begley 4 , Rita Humeniuk 4 , Tariro Makadzange 4 , Steve K. West 4 , Hui Liu 4 , Yizhao Li 4 , John Ling 4 , Luisa M. Stamm 4 , Polina German 4 , Joseph J. Eron 5 , Princy N. Kumar 6 , Edwin DeJesus 7 1 Peter J Ruane, MD Inc, Los Angeles, CA, USA, 2 Harbor–UCLA Medical Center, Torrance, CA, USA, 3 Emory University, Atlanta, GA, USA, 4 Gilead Sciences, Inc, Foster City, CA, USA, 5 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 6 MedStar Health, Washington, DC, USA, 7 Orlando Immunology Center, Orlando, FL, USA Background: GS-9722 is an effector-enhanced, broadly neutralizing antibody (bNAb) targeting a V3 glycan motif of the HIV envelope protein which is being developed for use in a HIV cure regimen. GS-9722 is a derivative of the bNAb PGT121 which has demonstrated immune cell-mediated killing of HIV-infected cells in vitro and efficacy in SHIV-infected monkeys. The safety, tolerability and pharmacokinetics (PK) of GS-9722 administered intravenously (IV; 30’ infusion) were evaluated in a first-in-human study in HIV-negative participants (Study 1) and in virally suppressed people with HIV (VS-PWH; Study 2). Methods: Two randomized, blinded, placebo-controlled, staggered dose escalation studies were conducted. In Study 1, HIV-negative participants received single dose (SD; 150, 500, or 1500 mg) or multiple doses (MD; 150, 500, or 1000 mg every other week [QOW] for three doses) of GS 9722 (n=6/cohort) or placebo (n=2/cohort). In Study 2, VS-PWH received SD or MD (QOW for five doses) GS-9722 150 or 500 mg (n=6/cohort) or placebo (n=2/cohort). Study 1 has completed; Study 2 is ongoing. Safety and PK are assessed throughout each study.

Results: In Studies 1 and 2, 45 of 49 and 32 of 32 participants completed treatment, respectively. In Study 1, dose-proportional increases in GS-9722 AUC and Cmax were observed (Table). GS-9722 t 1/2 was ~26 days, supportive of at least QOW dosing. Preliminary SD PK data in VS-PWH are similar to HIV-negative participants (Table); PK analysis in MD VS-PWH cohorts is ongoing. Most AEs were grade 1 or 2. In Study 1, two participants discontinued study drug due to AEs (1000 mg; MD), both of which were considered related to study drug; one participant had a grade 3 SAE of thrombocytopenia and the other had a grade 2 AE of infusion related-reaction. In Study 2, one participant had a grade 3 unrelated SAE of small intestinal obstruction (150 mg; SD). No other SAEs or AEs leading to study drug discontinuation were reported to date. Conclusion: These studies demonstrate that GS-9722 is generally safe and well tolerated in HIV-negative participants and VS-PWH, with similar single dose PK in the two populations. These data support ongoing evaluation of GS-9722 as part of a combination therapy for HIV cure.

Oral Abstracts

40 SAFETY AND ANALYTIC TREATMENT INTERRUPTION OUTCOMES OF VESATOLIMOD IN HIV CONTROLLERS Devi SenGupta 1 , Moti Ramgopal 2 , Cynthia Brinson 3 , Edwin DeJesus 4 , Anthony Mills 5 , Peter Shalit 6 , Scott McCallister 1 , Hiba Graham 1 , Heena Patel 1 , Lijie Zhong 1 , Joseph Hesselgesser 1 , Brian Doehle 1 , Susan Guo 1 , Diana Brainard 1 , Steven G. Deeks 7 1 Gilead Sciences, Inc, Foster City, CA, USA, 2 Midway Immunology and Research Center, Fort Pierce, FL, USA, 3 Central Texas Clinical Research, Austin, TX, USA, 4 Orlando Immunology Center, Orlando, FL, USA, 5 Southern California Men's Medical Group, Los Angeles, CA, USA, 6 University of Washington, Seattle, WA, USA, 7 University of California San Francisco, San Francisco, CA, USA Background: Administration of a toll-like receptor (TLR) 7 agonist in combination with a therapeutic vaccine induces CD8+ T cell-mediated control of SIV in a non-human primate model. We hypothesized that among people living with HIV (PLH) who had evidence of a partially effective host response (viremic controllers), treatment with the investigational oral TLR7 agonist vesatolimod (VES; GS-9620) would lead to enhanced immune control post-ART. Methods: We conducted a phase 1b, randomized, double-blind, placebo- controlled study in virologically suppressed PLH with historical chronic pre-ART plasma HIV-1 RNA of 50 to ≤5,000 c/mL. Participants were randomized 2:1 to receive 10 biweekly doses of VES 4-8 mg or placebo while continuing ART, followed by carefully monitored analytical treatment interruption (ATI). Viral rebound and safety were evaluated through at least 24 weeks (w) of ATI. Results: Twenty-five participants were randomized to VES (n=17) or placebo (n=8). The median age was 45 yrs (range 27-66 yrs) and 16%were women. The median pre-ART HIV-1 RNA 3.2 log 10 c/mL (IQR 3, 3.3) and the median time on ART was 2.7 yrs (range 0.7-17.2 yrs). VES was well tolerated, with no drug-related discontinuations. Most common study-drug related AEs were lymphadenopathy, chills, and headache. Pharmacodynamic activity of VES was confirmed by increases in whole blood interferon stimulated gene mRNAs and plasma cytokine levels. During the ATI, the median (95% CI) times to viral rebound (>50 c/mL and >200 c/mL, respectively) were 4.1 w (2.9-5.9) and 5 w (3.9-6) for the VES group, and 3.9 w (2.0-4.1) and 4 w (2-4.4) for placebo (p=0.036; p=0.024; see Figure). Median (95% CI) plasma viral set-point change from pre-ART value was -0.34 (-0.60, 0.06) log 10 c/mL for VES (p=0.035) and -0.28 (-0.75, 0.32) log 10 c/mL for placebo (p=0.38). Four individuals in the VES group had no virologic rebound (>50 c/mL) for ≥6 w, with one participant rebounding at 15 w (and >200 c/mL at 31 w); this participant also had a 0.94 log 10 c/mL decrease in viral set-point and completed the study after 48 w off ART with HIV-1 RNA 164-215 c/mL. Conclusion: VES was well tolerated in HIV controllers at multiple doses up to 8 mg and was associated with a modest increase in time to viral rebound after ATI,

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CROI 2020