Characterization of the VHH-Fc construct rimteravimab in healthy adults and patients hospitalized for mild-to-moderate COVID-19: Two Phase 1 randomized clinical trials
by Ellen Jansen, Viki Bockstal, Florence Herschke, Per Olsson Gisleskog, Manuela Rinaldi, Angélique Boerboom, Salah Hadi, Natalia Gaibu, Michel Moutschen, Dominique Tersago Background Variable Heavy domain of Heavy chains (VHH) are innovative tools to target unique epitopes, yet few have been developed as heavy chain-only antibodies for clinical use. Rimteravimab (referred to here as XVR011) is a humanized antibody developed for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19), consisting of two identical VHHs targeting the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, with a human immunoglobulin (Ig) G1 fragment constant of antibody (Fc), silenced for Fc effector functions. We conducted two Phase 1 studies in healthy volunteers or hospitalized COVID-19 patients to evaluate its safety, tolerability, pharmacokinetics and immunogenicity. Methods and findings A randomized, double-blinded, single-center, placebo-controlled, single ascending dose study was performed in healthy volunteers (Phase 1a, EXEVIR0102, EudraCT 2021-003707-17), in parallel to an open-label, multi-center, single ascending dose study in patients hospitalized for mild to moderate COVID-19 (Phase 1b, EXEVIR0101, EudraCT 2020-005299-36, NCT04884295). Participants received a single intravenous infusion of 250, 500 or 1,000 mg of XVR011. The primary objective for both trials was the safety and tolerability of XVR011. Pharmacokinetics were evaluated as a secondary objective in Phase 1a and as an exploratory objective in Phase 1b. Efficacy (evaluated as respiratory parameters and COVID-19 clinical status) and antiviral activity in patients were evaluated as a secondary objective in Phase 1b. Immunogenicity was evaluated as an exploratory objective. Part 2 of the EXEVIR0101 study (initially a phase 1b/2 study) was not conducted due to the loss of XVR011 potency against SARS-CoV-2 Omicron BA.2. Demographics, safety, efficacy, and immunogenicity were analyzed using descriptive statistics, while pharmacokinetics were analyzed with noncompartmental pharmacokinetics (PK) modeling.In the Phase 1a study, there were no infusion-related reactions, serious treatment-emergent adverse events (TEAEs) or TEAEs grade ≥3. 22/30 volunteers (73.3%) reported 53 TEAEs (49 Grade 1, 4 Grade 2) with none being related to XVR011. The most common TEAE was headache (n = 8, 26.7%) in various treatment groups. In the Phase 1b study, 27 hospitalized patients were enrolled, and followed up to 30 days. Seven patients (25.9%) reported a total of 15 TEAEs, the majority (80%) being mild to moderate (Grade 1–2). There were no treatment-related serious TEAEs. All TEAEs resolved by the end of the study. Peak exposure (maximal concentration, Cmax) and systemic exposure (area under the curve, AUC0-t, and AUC0-inf) for XVR011 increased dose-proportionally. Geomean half-life ranged from 15.4 to 17.0 days in Phase 1a, while individual half-life ranged from 11.4 to 15.6 days in Phase 1b. SARS-CoV-2 viral load, as detected in nasopharyngeal samples by reverse transcription and quantitative polymerase chain reaction (RT-qPCR), decreased similarly in all cohorts compared to baseline. No treatment-induced anti-drug antibodies (ADA) were detected in Phase 1a. In Phase 1b, higher XVR011 concentrations increased the likelihood of ADA formation, without impacting pharmacokinetics and pharmacodynamics. No obvious dose-response in COVID-19 clinical status or respiratory parameters was observed.Technological limitations included study size, absence of placebo for the Phase 1b, absence of repeated dosing, evolving SARS-CoV-2 variants and standard-of-care. Conclusions XVR011 displayed a favourable safety, tolerability, pharmacokinetics, and immunogenicity profile, both in healthy volunteers and in patients hospitalized for mild to moderate COVID-19. These data pave the way for the design and clinical development of VHH-Fc constructs.