CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

administered IM monthly or Q2M is approved for HIV-1 treatment. To support less frequent dosing, we evaluated safety and pharmacokinetics (PK) of the approved CAB 200 mg/mL (CAB200) formulation administered subcutaneously (SC) with recombinant human hyaluronidase PH20 (rHuPH20) and a new CAB 400 mg/mL (CAB400) formulation administered SC or IM without rHuPH20. Methods: This is an ongoing, open-label, single-dose, dose-escalation, phase I study (NCT05418868) in healthy adults with 2 sentinel participants (pts) per cohort. In part A, rHuPH20 (10,000 IU) and CAB200 (A1, 800 mg; A2, 1600 mg; A3, 3200 mg; 4 to 16 mL) were sequentially co-administered SC (abdominal). In part C, CAB400 (800 mg, 2 mL) was administered SC (abdominal; C1) or IM (gluteus medius; C2). To evaluate potential CAB400 dosing regimens, CAB PK profiles were simulated using an established CAB200 IM population PK model modified based on observed PK data in part C. Results: To date, 38 pts total received CAB (Table); 61% were male sex at birth, and 61% were non-White. Median age, weight, and BMI were 37.5 years, 74.7 kg, and 26.7 kg/m 2 , respectively. In part A, maximum observed plasma concentration (C max) and area under the plasma concentration–time curve from 0 to infinity (AUC0-∞) increased with dose proportionally and were higher than CAB200 IM, indicating potentially increased bioavailability, while t 1/2 was similar to CAB200 IM. C max in C1 was lower than in C2; both were lower than CAB200 IM. CAB t 1/2 in C1 was longer than in C2; both were longer than CAB200 IM, even though some pts have not reached terminal phase due to long t 1/2 . PK simulations predict a CAB400 SC/IM dose interval of ≥4 months achieves similar exposure to the approved CAB200 IM. Injection site reactions (ISRs) occurred in all pts dosed SC in part A (22/22) with a dose-related trend for increased ISR grades. A sentinel pt in cohort A3 experienced a drug-related serious adverse event of injection site erythema with necrosis. ISRs in C1 (8/8 pts) and C2 (3/8 pts) were grade 1 or 2. Conclusion: Safety and PK results from part A indicate low potential to achieve less frequent dosing with CAB200 and rHuPH20. The new CAB400 formulation (SC and IM) exhibits favorable safety and PK commensurate with dose intervals of ≥4 months and is in ongoing clinical development. Cabotegravir Maintains Protective Efficacy in the Setting of Bacterial STIs: HPTN 083 Meredith Clement 1 , Brett Hanscom 2 , Daniel Haines 2 , Jose A. Bazan 3 , Nuntisa Chotirosniramit 4 , Sharon Mannheimer 5 , Kenneth H. Mayer 6 , Mayara Secco Torres da Silva 7 , Lydia Soto-Torres 8 , Alex R. Rinehart 9 , James F. Rooney 10 , Marybeth McCauley 11 , Beatriz Grinsztejn 12 , Raphael J. Landovitz 13 , for the HPTN 083 Study Team 1 Louisiana State University, Baton Rouge, LA, USA, 2 Fred Hutchinson Cancer Center, Seattle, WA, USA, 3 The Ohio State University, Columbus, OH, USA, 4 Chiang Mai University, Chiang Mai, Thailand, 5 Columbia University, New York, NY, USA, 6 Fenway Health, Boston, MA, USA, 7 Instituto Nacional de Infectologia Evandro Chagas, Rio de Janeiro, Brazil, 8 National Institute of Allergy and Infectious Diseases, Rockville, MD, USA, 9 ViiV Healthcare, London, United Kingdom, 10 Gilead Sciences, Inc, Foster City, CA, USA, 11 FHI 360 , Washington, DC, USA, 12 Oswaldo Cruz Foundation - Fiocruz, Rio de Janeiro, Brazil, 13 University of California Los Angeles, Los Angeles, CA, USA Background: Bacterial sexually transmitted infections (STIs) have been shown to facilitate HIV transmission and acquisition. Long-acting cabotegravir (CAB-LA) demonstrated superiority vs daily oral tenofovir disoproxil fumarate/ emtricitabine (TDF/FTC) for HIV prevention in two large randomized controlled trials, but an assessment of efficacy in the setting of STIs has not been performed. Methods: From the blinded period of HPTN 083, we calculated incident STI events per 100 person-years (PY), including repeat events, from enrollment to last STI testing prior to May 15, 2020. We used Cox proportional hazards modeling with STI status as a time-varying covariate to look for potential interactions between STI status and the relative efficacy of CAB-LA vs. TDF/FTC. Serologic testing for syphilis and nucleic acid amplification testing for rectal and urethral gonorrhea and chlamydia were conducted every six months or when participants reported STI symptoms or exposures. Date of first HIV diagnosis

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Safety and Pharmacokinetics of MK-8527, a Novel nRTTI, in Adults Without HIV Gillian Gillespie 1 , Russ P. Carstens 1 , Xiaowei Zang 1 , Ryan Vargo 1 , Yash Kapoor 1 , Arinjita Bhattacharyya 1 , Jean-Francois Denef 2 , Tom Reynders 2 , Frédéric Vanhoutte 3 , Sylvie Rottey 4 , Randolph P. Matthews 1 , S. Aubrey 0 . Stoch 1 , Marian Iwamoto 1 1 Merck & Co, Inc, Rahway, NJ, USA, 2 MSD Belgium, Brussels, Belgium, 3 SGS Belgium NV, Antwerpen, Belgium, 4 Ghent University Hospital, Ghent, Belgium Background: MK-8527 is an oral nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development. Two phase 1 trials evaluated ascending single doses (trial A) and ascending multiple doses (trial B) of MK-8527 in adults (aged 18–55 years) without HIV. Methods: In trial A, male participants received single oral doses of MK-8527 (0.5–200 mg; fasted) or placebo; 25 mg was also assessed after a high-fat meal. In trial B, male and female participants received 3 once-weekly (QW) oral doses of MK-8527 (up to 40 mg) or placebo. In both trials, participants were randomized (3:1) to receive MK-8527 or placebo. Safety and pharmacokinetics of MK-8527 (plasma) and MK-8527-triphosphate (TP; measured in peripheral blood mononuclear cells [PBMCs]), the active form of MK-8527, were assessed. Results: In both trials, MK-8527 was generally well tolerated. In trial A, adverse events (AEs) were reported in 27 of 34 participants (79.4%); 5 (14.7%) were considered drug-related AEs. In trial B, AEs were reported in 29 of 32 participants (90.6%); 11 (34.4%) were considered drug-related AEs. In both trials, all drug-related AEs were mild or moderate, and there were no serious AEs, events of clinical interest, or deaths. After single doses, plasma exposure of MK-8527 increased in an approximately dose-proportional manner, and intracellular exposure of MK-8527-TP (PBMCs) was slightly less than dose proportional over 5–200 mg. Administration of MK-8527 with a meal resulted in a 41% decrease in plasma MK-8527 C max , with no effect on plasma MK-8527 AUC0-168, and a 22% increase in intracellular MK-8527-TP C max and 58% increase in MK-8527-TP AUC0- 168. After multiple QW doses, accumulation of plasma MK-8527 was minimal (range of C max and AUC0-168 ratios [Day 15/Day 1] was 0.9–1.4) and accumulation of intracellular MK-8527-TP was moderate (range of C max and AUC 0-168 ratios was 1.1–1.6; C168 was 1.2–2.4). Across QW doses, the range of MK-8257-TP median T max was 10–24 hours, and apparent half-life was 216–291 hours. After administration of MK-8527, the true geometric mean C168 of intracellular MK-8527-TP was above the previously identified pharmacokinetic threshold for antiviral activity against HIV-1 (≥0.2 pmol/10 6 PBMCs). Conclusion: Single (0.5–200 mg) and multiple (QW) doses (up to 40 mg) of MK-8527 administered to adults without HIV were generally well tolerated. The safety and pharmacokinetic profiles of MK-8527 support continued clinical investigation. Phase I Study of Cabotegravir Long-Acting Injectable Formulations Supports ≥4-Monthly Dose Interval Kelong Han 1 , Ronald D'Amico 2 , Jörg Sievers 3 , Darin Brimhall 4 , Brian Spears 5 , Dale Taylor 6 , David Dorey 7 , Paul Benn 3 , Lisa Morgan 1 , Randa Hareedy 8 , Gilda Bontempo 9 , Max Lataillade 9 , William Spreen 2 1 GSK, Collegeville, PA, USA, 2 ViiV Healthcare, Durham, NC, USA, 3 ViiV Healthcare, Brentford, United Kingdom, 4 Thermo Fisher Scientific, Las Vegas, NV, USA, 5 Thermo Fisher Scientific, Austin, TX, USA, 6 Thermo Fisher Scientific, Tampa, FL, USA, 7 GSK, Mississauga, ON, Canada, 8 GSK, Brentford, United Kingdom, 9 ViiV Healthcare, Branford, CT, USA Background: Long-acting cabotegravir (CAB) administered intramuscularly (IM) every 2 months (Q2M) is approved for HIV-1 prevention; CAB and rilpivirine

Oral Abstracts

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CROI 2024