First-in-Human Studies of a Novel VHH-Fc Antibody Construct in Healthy Subjects and Patients Hospitalized for Mild to Moderate
COVID-19
Viki Bockstal, Head of Nonclinical Development, ExeVir Bio BV
For the first time, a VHH-Fc antibody construct was evaluated in humans for safety, tolerability, pharmacokinetics (PK) and immunogenicity. XVR011 is a bivalent humanized heavy chain-only antibody, consisting of two identical VHH components targeting the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, fused to the effector-function silenced Fc fragment of a human IgG1. The SARS-CoV-2 neutralizing activity of XVR011 is explained by a dual mode of action: XVR011 binding (1) prevents the interaction of the RBD with the host ACE2 receptor through steric hinderance and (2) traps the RBD in the “up†position, destabilizing the spike. A randomized, double-blinded, single-center, placebo-controlled, Single Ascending Dose (SAD) study was performed in healthy subjects (Phase 1a, EXEVIR0102), in parallel to an open label, multi-center, SAD study in patients hospitalized for mild to moderate COVID-19 (Phase 1b, EXEVIR0101). Both studies evaluated the safety, tolerability, pharmacokinetics (PK) and immunogenicity of a single intravenous (IV) infusion in 3 dose cohorts: 250, 500 and 1000 mg. In Phase 1a, no infusion-related reactions (IRRs), serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 were observed. 53 TEAEs (49 Grade 1, 4 Grade 2) were reported in 73.3% of subjects, all unrelated to XVR011. The most common TEAE was headache, reported by 26.7% in various treatment groups. In Phase 1b, a total of 15 TEAEs were reported in 25.9% of subjects, majority (80%) being mild (Grade 1) to moderate (Grade 2), with no obvious dose response AE pattern. In both studies, a clear dose-response relationship was documented for most PK parameters. Peak exposure and systemic increased with increasing doses in a dose-proportional manner and PK profiles were characterized by a low clearance. Geometric mean half-life ranged from 15.4 to 16.96 days in Phase 1a, while individual half-life ranged from 11.4 to 15.6 days in Phase 1b. Overall, the 250, 500 and 1000 mg doses showed an acceptable safety and tolerability profile in both adult healthy volunteers and adult patients hospitalised for mild to moderate COVID-19. These data support the further development of XVR011 and pave the way for the design of VHH-Fc antibody constructs as antiviral treatments.
