Background:
The trispecific broadly neutralizing antibody (bNAb) SAR441236 combines the HIV-1 specificities of VRC01 (CD4 binding site), PGDM1400 (V1/V2 glycan binding), and 10E8v4 (membrane proximal external region) into one molecule with amino acid modifications (LS) in the Fc-region for half-life extension. SAR441236 provided complete protection against macaque SHIV challenge but has not been tested in people with HIV (PWH).
Methods:
ACTG A5377 was a phase I study evaluating the safety, pharmacokinetics (PK), and antiviral activity of SAR441236, a trispecific HIV-1 bNAb. Escalating intravenous (IV) or subcutaneous (SC) single doses of SAR441236 (from 0.3 – 10 mg/kg) or 4 doses at 30 mg/kg IV (every 12 weeks with 72 weeks of follow up) were assessed in ART-treated PWH with plasma viral RNA <50 copies/mL. Dose cohorts were randomized 2:1 to SAR441236 or placebo. Single open-label IV doses of 1mg/kg or 30 mg/kg were assessed in viremic participants (ART-naïve or no ART in the preceding 3 months). Primary outcomes were study treatment-related Grade ≥3 adverse events, AUC0-12wk of SAR441236, and the day 7 change in plasma HIV-1 RNA levels in viremic participants.
Results:
A total of 52 participants were enrolled and 51 received study treatment. Median age was 53 years. 10% were female, 37% were Black, and 12% were Hispanic. No events met the primary safety outcome (95% CI 0-0.09). Population PK analysis demonstrated an overall clearance (CL) of 137 ± 86 mL/d, a volume of distribution (Vds) of 6.3 ± 2.4L, population SC bioavailability of 35 ± 7%, and a half-life (t1/2β) of 38 ± 10 days. SAR441236 CL was 38% higher in viremic cohorts. For the 30 mg/kg single dose in aviremic participants, the AUC0-12wk was 22,292 ± 889 μg*d/mL (mean ± SD). Monte Carlo simulations predicted 30 mg/kg IV every 12 weeks to result in a median steady-state trough of 74 μg/mL (90% PI 25-185 μg/mL). Only 7 of 24 planned viremic participants were enrolled. The mean change to day 7 plasma HIV-1 RNA levels in the 1 mg/kg cohort (n = 5) was -0.10 log10 copies/mL and -0.38 log10 copies/mL in the 30 mg/kg cohort (n = 2).
Conclusions:
SAR441236 administration was safe and well tolerated. The PK of SAR441236 was similar to traditional HIV-1 IgG antibodies with half-life extension modifications, such as VRC07-523LS. The favorable PK and convenience of administering a single biologic with three binding specificities support the evaluation of novel trispecific or multispecific bnAbs for HIV-1 treatment or prevention.