CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

HIV-1 isolates with varying susceptibility to CCR5 antagonists and eCD4-Ig may help refine our understanding of the interaction between this promising novel HIV-1 entry inhibitor and the CCR5mim1 binding domain on gp120. 485 IBALIZUMAB: 96-WEEK DATA AND EFFICACY IN PATIENTS RESISTANT TO COMMON ANTIRETROVIRALS Brinda Emu 1 , Jay Lalezari 2 , Princy Kumar 3 , Steven Weinheimer 4 , Stanley Lewis 4 , Brandon Cash 5 , Zvi Cohen 6 1 Yale University, New Haven, CT, USA, 2 Quest Clinical Research, San Francisco, CA, USA, 3 Georgetown University, Washington, DC, USA, 4 TaiMed Biologics USA, Irvine, CA, USA, 5 Syneos Health, Somerset, NJ, USA, 6 Theratechnologies, Inc, Montreal, QC, Canada Background: Ibalizumab (IBA) is a CD4-directed post-attachment HIV-1 inhibitor that binds to the CD4 domain 2 and blocks viral entry into host cells without immunosuppression. Here, we report the efficacy outcomes of IBA with OBR in patients resistant and susceptible to two widely used antiretrovirals (ARV), dolutegravir (DTG) and darunavir (DRV) as well as the the long-term safety and efficacy through 96 weeks of treatment. Methods: In TMB-301, heavily treatment-experienced patients with MDR HIV-1 received an intravenous loading dose of 2000 mg followed by 800 mg doses every 2 weeks up to Week 25. An OBR with at least 1 additional sensitive agent was added 7 days after the loading dose. Following completion of the TMB-301 study, eligible patients continued to receive IBA at 800 mg every 2 weeks under TMB-311 for up to 96 weeks. Results: Among the 40 enrolled patients in TMB-301, 18 (45%) had DTG resistance, of which 11 had major DTG resistance mutations (Q148 plus additional mutations). Of 18 DTG resistant patients, 10 received DTG in their OBR while 16 of 22 DTG susceptible patients received DTG as OBR. Twenty-seven patients (68%) had DRV resistance. DRV was included as OBR in 26 patients: 18 with DRV resistant HIV and 8 with DRV susceptible HIV. Long-term results were obtained for 27 patients who continued to receive treatment in study TMB-311, of which 22 (82%) completed treatment up to 96 weeks. The reasons for 5 discontinuations were death (2 patients) consent withdrawal (2 patients) and physician decision – all 5 were non IBA-related. IBA plus OBR was well tolerated with no new safety concerns emerging between Week 25 and 96. For these 27 patients, median viral load (VL) reduction from Baseline (of TMB-301) was 2.5 log10 at Week 25 and 2.8 log10 at Week 96 in the Intent-to-Treat-Missing- Equals-Failure analysis. Of 16 patients with HIV RNA <50 copies/mL at Week 25, 14 maintained viral suppression through Week 96, with one additional patient achieving viral suppression by Week 96. Median CD4+ T cell increase was 42 cells/µl from Baseline to Week 25 (n=27), and 45 cells/µl at Week 96 among those who remained on study (n=22). Conclusion: Safety and efficacy of IBA observed at Week 25 in the Phase 3 trial were maintained through 96 weeks for patients continuing on treatment. IBA is an effective, safe and durable treatment for MDR HIV-1 infected patients.

antiretroviral (cART) therapy. Patients received weekly doses of PRO 140 on SAMT following one week of overlap of the existing cART regimen that is then discontinued. In part 1, 156 participants received 350 mg PRO 140 SC in a single-arm design. In part 2, 147 participants received 350 or 525 mg PRO 140 SC in a 1:1 ratio as randomized controlled, two-arm study. In an ongoing part 3, 47 participants are to be randomized to receive 525 or 700 mg PRO 140 SC in a 1:1 ratio. Results: Of the 327 patients enrolled, median age was 51 yrs (21-77) with the majority reported as male (79%) and 37%were non-white. On average, participants were diagnosed with HIV-1 infection for 16.8 yrs and were on cART regimen for 14.8 yrs. This abstract focuses on preliminary results from patients randomized 1:1 to 350 mg (N=73) or 525 mg (N=74) PRO 140 SC on SAMT. While the study is ongoing, a key interim finding from 147 patients (4-48 weeks on SAMT) indicate that an odds ratio of 4.43 for the virologic response rates with 525 mg compared with 350 mg PRO 140 SC. Virologic failure is defined as two consecutive plasma HIV-1 RNA levels of ≥200 c/mL. The frequency and severity of injection site reactions were comparable between the three dose groups and the incidence or severity of injection site reactions was not increased in patients receiving higher doses. Overall, PRO 140 SC was generally well tolerated at all dose levels in this study. Conclusion: Higher doses of PRO 140 SC are required to maintain virologic suppression on SAMT in the majority of patients infected exclusively with CCR5- tropic HIV-1. After testing both 350 mg and 525 mg, 700 mg of weekly PRO 140 SC is currently underway and will be presented. PRO 140 SC has the potential as a SAMT for long-term suppression of HIV-1 replication. 487 IN SILICO SIMULATION OF LONG-ACTING TENOFOVIR ALAFENAMIDE SUBCUTANEOUS IMPLANT Rajith Kumar Reddy Rajoli 1 , Zach Demkovich 2 , Ariane van der Straten 2 , Charles W. Flexner 3 , Andrew Owen 1 , Marco Siccardi 1 1 University of Liverpool, Liverpool, UK, 2 RTI International, San Francisco, CA, USA, 3 Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: Subcutaneous implants support the long-acting delivery of drugs, circumventing non-adherence issues with daily oral regimens. The aim of this study was to simulate pharmacokinetic (PK) profiles of tenofovir alafenamide (TAF) subcutaneous implants for HIV pre-exposure prophylaxis using physiologically-based pharmacokinetic (PBPK) modelling. Methods: A subcutaneous mechanistic modelling approach was integrated into a previously published whole-body PBPK model using Simbiology 2018a. The model was qualified against available PK data of oral TAF at steady state (GS-US-320-1382). The PBPK model was assumed to be qualified if the mean simulated values were within ± 50% from the mean observed values as per convention. TAF subcutaneous implants were simulated in five hundred virtual healthy women (average BMI – 29.2 kg/m 2 ) for 28 consecutive days and the area under the plasma concentration curve (AUC) and average plasma concentration (C avg ) were described. PK of plasma TAF and tenofovir, tenofovir diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs), and TFV-DP in cervical and rectal tissues were simulated considering data from clinical studies. TAF PK from the subcutaneous implant was simulated with zero-order release rates between 0.5-0.8 mg/day. TFV-DP concentrations of 48 fmol/10 6 PBMCs was considered as the target trough concentration. Results: AUC and C avg of plasma TAF/TFV and PBMC TFV-DP concentrations resulting from administration through subcutaneous implants at different zero-order release rates are shown in the table. Our simulations indicate that TAF subcutaneous implant with a minimum release of 0.6 mg/day will support sustained TFV-DP concentrations well above the target concentration of 48 fmol/10 6 cells. The TFV-DP cervical and rectal concentrations ranged between 1.47 – 2.44 fmol/10 6 cells and 0.95 – 1.57 fmol/10 6 cells, respectively between the release rates of 0.5 – 0.8 mg/day. Conclusion: These data inform the possible dosing and release rate needed for TAF such that the simulated PBMC TFV-DP concentrations remained over the target concentrations. A 2.5mm x 40mm implant rod, like that of contraceptive implants, containing 120 mg of TAF and delivering at 0.6 mg/day could provide protective levels for over 6-months. TAF subcutaneous implants may represent a valuable strategy to address issues arising from sub-optimal adherence to oral regimens, and may find application in HIV prevention.

Poster Abstracts

486 PRO 140 SC: LONG-ACTING, SINGLE-AGENT MAINTENANCE THERAPY FOR HIV-1 INFECTION Kush Dhody 1 , Kazem Kazempour 1 , Nader Pourhassan 2 , Paul J. Maddon 3 1 Amarex Clinical Research, LLC, Germantown, MD, USA, 2 CytoDyn, Inc, Vancouver, WA, USA, 3 Maddon Advisors, LLC, Scarsdale, NY, USA Background: The development of a monoclonal antibody (mAb) as a long-acting, single-agent maintenance therapy (SAMT) represents a major milestone in the treatment of HIV-1 infection. PRO 140 (humanized CCR5 mAb) demonstrates potent antiviral activity as a SAMT for >4 years as a weekly subcutaneous injection (SC) in patients infected exclusively with CCR5-tropic HIV-1 (Dhody, K. et al. (2018). HIV Clin Trials 19(3):85-93). In addition, PRO 140 presents a high genetic barrier to block HIV-1 entry, favorable tolerability, and limited drug-drug or -food interactions. Methods: PRO 140_CD03 (N=350) is a three part, phase 2 study enrolling virally suppressed HIV-1 patients with CCR5-tropic HIV-1 receiving combination

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