Background
ART-free HIV viral control remains an unmet need for people with HIV (PWH). Trosunilimab, an anti-α4β7 integrin antibody with preserved Fc functionality, is expected to induce immune responses to control viral replication, and was evaluated in a phase 1 program in healthy volunteers (HV) and PWH.
Methods
The double-blind, placebo (PBO) controlled phase 1 studies evaluated single-ascending doses (SAD) ranging from 50 to 1800 mg IV, and 800 mg SC in healthy volunteers (Study M19-968) and 800 mg and 1600 mg IV (SAD) in viremic PWH off ART (Part A) and multiple ascending doses of 800 mg IV and SC and 1600 mg IV in aviremic PWH on ART (Part B) (Study M19-966). Safety analysis included adverse events (AEs) and lab abnormalities. Pharmacodynamic (PD) analysis included α4β7 integrin receptor target engagement. α4β7 integrin expression on HIV virion was assessed in viremic PWH.
Results
In M19-968, 55 HV received either trosunilimab or PBO. In M19-966, 9 participants received trosunilimab in Part A, and 45 received either trosunilimab or PBO in Part B. Demographics of PWH are reported in Table 1. In M19-966 Part A, no subject had significant sustained decline in HIV RNA (>0.5 Log 10) in the absence of ART. No serious AEs or drug-related AEs Grade ≥3 or leading to discontinuation of study drug occurred in either study and the frequency of drug-related AEs was low. One HV (1800 mg IV dose) had drug-related elevated transaminases which were also considered possibly related to recent passage of a gallstone. In M19-968, linear pharmacokinetics (PK) was observed from 400 to 1800 mg IV with terminal half-life ranging from approximately 12 to 25 days. The concentration required to achieve nearly complete (>90%) α4β7 receptor saturation in healthy volunteers was 3 µg/mL. Trosunilimab-mediated β7 internalization followed a U-shaped relationship with drug concentration. In M19-966 Part A, circulating HIV virions expressed α4β7 indicating potential for Fc-mediated immune responses. Expression of α4β7 on virion was found to be inversely correlated with internalization of the receptor.
Conclusions
The phase 1 studies showed that trosunilimab was well-tolerated in healthy volunteers and in PWH. The safety, PK/PD, and immunogenicity data from phase 1 studies allowed dose selection for the ongoing phase 2 study, M19-965, evaluating combinations of trosunilimab and budigalimab in PWH undergoing analytic treatment interruption.