CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: MK-8527 was discovered through a lead optimization campaign focused on identifying structurally and functionally novel NRTTIs with the potential for extended-duration dosing. The mechanism of MK-8527-TP was evaluated in primer extension and footprinting assays, and antiviral activity and persistence after washout were measured in cell-based assays. PK parameters were evaluated in rats and Rhesus monkeys. Off-target activity was assessed against human DNA polymerases and in a panel of 114 enzyme/receptor binding assays. Results: Systematic evaluation of key positions around the nucleoside core confirmed steep SAR associated with this compound class, particularly at the 2', 3', and 4' positions. Nucleobase modifications were tolerated, and a thorough evaluation of this and other positions led to the discovery of MK-8527. MK-8527-TP inhibits reverse transcriptase by immediate (translocation) and delayed chain termination. MK-8527 has comparable antiviral activity (human PBMC IC 50 = 0.21 µM) and persistence of antiviral effect after washout to ISL. The PK of MK-8527 in rats and monkeys was characterized by low to moderate clearance and volume of distribution, with good oral absorption . Following oral administration of MK-8527 to monkeys, the TP had an intracellular half-life (t 1/2 ) in PBMCs (~48 h), significantly longer than the plasma t 1/2 of the parent, MK-8527 (~7 h), as observed with other nucleos(t)ide analogs. MK-8527-TP displayed IC 50 values of ≥95 µM against the human DNA polymerases tested. Neither MK-8527 nor MK-8527-TP exhibited off-target activities at 10 μM in the panel of enzyme/receptor binding assays tested. Conclusion: The subnanomolar potency, absence of off-target activity, and suitable PK for at least once-weekly dosing make MK-8527 an attractive clinical candidate for prophylaxis of HIV-1 infection High-Dose VH3810109 (N6LS) ± Recombinant Human Hyaluronidase PH20: Phase I SPAN Study Safety Results Beta Win 1 , Peter Leone 2 , Jan Losos 2 , Paul Wannamaker 2 , Riccardo D’Agostino 1 , Michael Warwick-Sanders 1 , Gabriela L. Ghita 3 , Viviana Wilches 3 , Max Lataillade 4 1 GlaxoSmithKleine, Brentford, United Kingdom, 2 ViiV Healthcare, Durham, NC, USA, 3 GlaxoSmithKleine, Collegeville, PA, USA, 4 ViiV Healthcare, Branford, CT, USA Background: Broadly neutralizing antibodies are being developed for long acting HIV-1 therapy. VH3810109 (N6LS), a CD4-binding site antibody with broad and potent neutralization activity in vitro, demonstrated robust antiviral effect in adults with HIV-1 in the phase IIa BANNER study. Here, we report safety and tolerability for the highest subcutaneous (SC) and intravenous (IV) single N6LS doses ever administered, with and without recombinant human hyaluronidase PH20 (rHuPH20). Methods: SPAN (NCT05291520) is a phase I, open-label, 3-part study assessing safety, tolerability, and pharmacokinetics of single-dose N6LS in healthy adults. Part 1 evaluated N6LS 20 mg/kg SC + rHuPH20 2000 U/mL, part 2 N6LS 60 mg/kg IV, and part 3 N6LS 3000 mg SC + rHuPH20 2000 U/mL. Adverse events (AEs), injection site reactions (ISRs), vital signs, electrocardiograms, and clinical laboratory values were monitored for 24 weeks. Results: Eight participants were enrolled in each part to receive a single dose of N6LS. In the SC N6LS + rHuPH20 dose groups (parts 1 and 3), no relevant differences in overall AE incidences were observed (Table); across parts, no AEs led to withdrawal. In parts 1 and 3, among 32 ISRs reported by 15/16 (94%) participants, 17 were grade 3 (all injection site erythema based on size; mean duration: 2.9 days [part 1] and 5.7 days [part 3]; Table). All ISRs resolved without sequelae within ≤7 days except for 1 in part 3 that resolved after 27 days. Biphasic injection site erythema was reported in parts 1 (2/8 [25%]) and 3 (4/8 [50%]). Most participants rated local reactions and pain as acceptable and were in favor of injection treatment. No local secondary infections were reported with ISRs. In part 2 (IV), 1 participant experienced 2 grade 1 AEs; no ISRs were reported. A higher frequency of AEs was reported with SC administration compared with IV, mainly driven by ISRs. Across doses, no serious AEs or deaths occurred, and no clinically significant changes from baseline in vital signs, electrocardiograms, or laboratory values were observed. Conclusion: High-dose N6LS, when given IV or SC + rHuPH20, was generally safe and well tolerated in this study. These results support the ongoing clinical development of N6LS 3000 mg SC + rHuPH20 and N6LS 60 mg/kg IV into phase IIb.

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A Dose Escalation Study of Safety & PK of TMB-365 & TMB-380 in People With Suppressed HIV Jacob P. Lalezari 1 , Moti Ramgopal 2 , Gary Richmond 3 , Gordon Crofoot 4 , Kuei-Ling Kuo 5 , Yingan Lai 5 , Martin Markowitz 6 1 Quest Clinical Research, San Francisco, CA, USA, 2 Midway Immunology and Research Center, Fort Pierce, FL, USA, 3 CAN Community Health, Fort Lauderdale, FL, USA, 4 Crofoot Research Center, Houston, TX, USA, 5 TaiMed Biologics Inc, Taipei City, Taiwan, 6 TaiMed Biologics Inc, Irvine, CA, USA Background: TMB-365, a second generation post-attachment bNAb, binds to the second domain of CD4 and is designed to display improved PK, antiviral activity, and breadth of coverage when compared to ibalizumab. TMB-380 (aka VRC07-523LS) is a bNAb that binds to the CD4 binding site of HIV Env and has potent antiviral activity and favorable safety and PK profile. The combination is designed as a complete regimen for HIV therapy. Here we present available safety and PK results of the combination given as a single IV infusion to inform the feasibility of maintenance therapy given every 8-12 weeks in suppressed HIV-infected individuals. Methods: Three groups of 10 subjects were infused with 2400 mg (Group 1), 3200 mg (Group 2), or 4800 mg (Group 3) of each bNAb in 250 ml NS over one hour and followed for 12 to 16 weeks. Groups were dosed sequentially with dose escalation approved by an independent Data Monitoring Committee. Participants were suppressed with continuous oral cART for at least 6 months, clinically stable, without a history of severe allergies, and had no history of virologic failure on previous treatment regimens. All infusions were performed over 60 minutes in outpatient clinics with vital sign determinations every 15 minutes during and up to 3-5 hours post-infusion. A subset of participants was pre-medicated with acetaminophen 650 mg and cetirizine 10 mg at the investigator's discretion. Trough PK targets were ≥0.3 μg/ml and 65 μg/ml for TMB-365 and TMB-380, respectively in at least 80% of participants in any treatment group. Results: All 30 subjects completed the study. One Group 3 subject was erroneously dosed with 1600 mg of each antibody and is excluded from PK analysis. No SAEs, Grade 3 or 4 adverse events, or acute infusion events were observed. Treatment emergent AEs (N=32) were mild to moderate. 5 were attributed to infusions with bNAbs. 2 subjects experienced delayed onset of fatigue and chills interpreted as hypersensitivity. PK data is shown below. Duration of concentrations above trough targets is increased with increased dose. In Group 3 participants at week 8, mean TMB-365 and TMB-380 concentrations were 15.1 and 86.4 μg/ml, respectively, and approximately 80% of participants met pre-defined trough targets. Conclusion: A single infusion of TMB-365 and TMB-380 in combination up to 4800 mg each is safe. Prolonged PK duration was observed for both TMB-365 and TMB-380 and results suggest that an every 8-week infusion is feasible and will be tested in a Phase 2 clinical study.

Poster Abstracts

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CROI 2024 181