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.
Conclusions:
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.
