Presentation Details
| Tolerability and Pharmacodynamic Effect of REGN9933, a Monoclonal Antibody Directed Against the Factor XI Apple 2 Domain: Results from a First-in-Human Study Ethan Marin1, Guixian Lin1, Hisham Abdallah1, David Gutstein1, Andrew Kordahi2, Karoline Meagher1, Frederic Cauwberghs3. 1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.2Regeneron Pharmaceuticals, Inc.(at time of study), Tarrytown, NY, USA.3SGS (at time of study), Antwerp, Belgium |
Abstract
Background: Venous and arterial thromboembolic diseases are a leading cause of death worldwide. Current standard-of-care anticoagulants, although effective for the prevention and treatment of these diseases, are associated with an increased bleeding risk. REGN9933 is a monoclonal antibody that binds to the factor XI (FXI) apple 2 domain, thereby selectively blocking activation of FXI by activated FXII – an initial step in the intrinsic coagulation pathway. However, this mechanism may not interfere with FXI autoactivation, or activation by thrombin downstream of the extrinsic coagulation pathway, so REGN9933 may prevent thrombosis without increasing bleeding risk. Here, we report results from a first-in-human study (NCT05102136) of REGN9933 in healthy volunteers. Objectives: To evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of REGN9933 in healthy volunteers. Methods: This was a Phase 1, randomized, double-blind, placebo-controlled, single-center study. Healthy volunteers received a single dose of REGN9933 (or placebo), with intravenous (IV) doses ranging from 3 mg to 300 mg, and subcutaneous (SC) doses of 100 mg and 300 mg. The primary endpoint was the incidence and severity of treatment‑emergent adverse events (TEAEs). Secondary/exploratory endpoints included the effect of REGN9933 on the coagulation cascade using intrinsic pathway-triggered (activated partial thromboplastin time [aPTT]) and extrinsic pathway-triggered (prothrombin time [PT]) coagulation assays, and FXI activity. Results: In this Phase 1 study, 56 participants received REGN9933 or placebo (IV REGN9933, n=30; SC REGN9933, n=12; placebo, n=14). In the REGN9933 and placebo cohorts, the median age was 49.5 years and 45.5 years, and 69% and 86% were male, respectively. In the REGN9933 cohorts, 42.9% of participants experienced ≥1 TEAE, compared with 21.4% in the placebo cohorts. The most common TEAEs (≥5% of patients) across the REGN9933 cohorts were headache (12%) and oropharyngeal pain (5%). One participant experienced a TEAE related to REGN9933 (Grade 1 fatigue). No serious or severe TEAEs, or TEAEs of special interest (including moderate/severe bleeding), were reported. REGN9933 resulted in a dose‑dependent prolongation of aPTT (Figure 1). The maximum aPTT mean fold-change from baseline was 2.7 (8 hours post administration of IV REGN9933 300 mg), and this approximate level of aPTT prolongation was maintained for ~22 days. No meaningful changes in aPTT were observed with placebo. There was no detectable effect of REGN9933 on PT, and no clinically meaningful effect on bleeding time. REGN9933 suppressed FXI activity in a dose‑dependent manner; maximal suppression to approximately the lower limit of quantitation of the assay (5% activity) was achieved at IV REGN9933 ≥30 mg, and robust suppression was maintained to approximately Day 43 with IV REGN9933 300 mg (Figure 2). Changes in FXI activity were minimal in the placebo cohorts. REGN9933 displayed nonlinear pharmacokinetics across the dose ranges studied for the IV and SC cohorts. Conclusions: These first-in-human data suggest that REGN9933 has a dose-dependent inhibitory effect on the intrinsic coagulation pathway without affecting extrinsic pathway activity. These findings, allied with the tolerability profile of REGN9933, support its continued development as an anticoagulant that may carry less risk of bleeding than existing therapies.
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