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Exploratory analysis of intrinsic pathway-triggered thrombin generation inhibition in healthy volunteers and patients post-total knee arthroplasty who received REGN9933A2 and REGN7508CAT Karoline A.Meagher, Kusha Mohammadi, Dateng Li, Ethan Marin, Aaron Kithcart, Meagan P.O’Brien, Selin Somersan-Karakaya, KehDih Lai, Dan Chalothorn, Robert J.Durso, Michael E.Burczynski, Poulabi Banerjee, David E.Gutstein. Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA

Abstract

Background: REGN9933^A2 and REGN7508^CAT are fully human monoclonal antibodies that bind to distinct domains of factor XI (FXI) and have demonstrated antithrombotic activity in patients undergoing total knee arthroplasty (TKA). Thrombin generation assays (TGAs) characterize thrombin generation through the intrinsic and extrinsic pathways, but lack of an automated, standardized assay leads to variability among users. Objectives: To explore parameters of FXI inhibition with REGN9933^A2 and REGN7508^CAT versus placebo in healthy adults, and versus enoxaparin and apixaban in patients post-TKA using a validated, exploratory, ellagic acid-triggered modified TGA. Methods: First-in-human (FIH) studies evaluated REGN9933^A2 (NCT05102136; intravenous [IV]: 3 mg, 10 mg, 30 mg, 100 mg, 300 mg; subcutaneous [SC]: 100 mg, 300 mg) and REGN7508^CAT (NCT05603195; IV: 5 mg, 15 mg, 30 mg, 60 mg, 125 mg, 250 mg; SC: 125 mg, 250 mg, 450 mg, 600 mg) in healthy adults. ROXI-VTE-I (NCT05618808) and ROXI-VTE-II (NCT06454630) were randomized, open-label Phase 2 studies in patients undergoing TKA. In ROXI-VTE-I, 373 patients were randomized to receive REGN9933^A2 300 mg (single IV dose), enoxaparin 40 mg (SC once daily), or apixaban 2.5 mg (orally twice daily). In ROXI-VTE-II, 179 patients were randomized to receive REGN7508^CAT 250 mg (single IV dose) or enoxaparin 40 mg (SC once daily). All treatments started 12–24 hours post-surgery. In platelet-poor plasma samples, thrombin activity was measured using a real-time calibrated automated thrombogram using a validated, exploratory, fit-for-purpose assay, with APTT-XL ellagic acid (Thermo Fisher Scientific) in the presence of microparticles (Stago) at MLM Medical Labs (Memphis, TN, USA). Endogenous thrombin potential (ETP) and other parameters were automatically calculated from the thrombogram. Results: Compared with placebo, REGN9933^A2 and REGN7508^CAT exposure led to dose-dependent inhibition of ETP in healthy volunteers (Figure 1). In the FIH REGN9933^A2 study, maximum suppression of the intrinsic pathway-triggered ETP was demonstrated in the 300 mg IV group and the 300 mg SC group, with an approximate change from baseline of −83% and −68%, respectively. In the FIH REGN7508^CAT study, maximum suppression of the intrinsic pathway-triggered ETP was demonstrated in the 250 mg IV group and the 600 mg SC group, with an approximate change from baseline of −100% for both. ETP decreased post-TKA in patients receiving REGN9933^A2 and REGN7508^CAT versus enoxaparin and apixaban (Figure 2). In the ROXI-VTE-I study, REGN9933^A2 demonstrated a decrease in the intrinsic pathway-triggered ETP that was sustained through Day 10 and returned to baseline by Day 75. Change from baseline in maximal suppression was approximately −84%. There was no observed impact from enoxaparin or apixaban. In the ROXI-VTE-II study, REGN7508^CAT demonstrated a decrease in the intrinsic pathway-triggered ETP that was sustained through Day 10 and returned to baseline by Day 75. Change from baseline in maximal suppression was approximately −84%. There was no observed impact from enoxaparin. Conclusions: These results indicate that global, intrinsic pathway-triggered TGA methodology is a valuable tool to assess the mechanism of action of monoclonal antibodies targeting FXI. REGN9933^A2 and REGN7508^CAT demonstrated inhibition of intrinsic pathway-triggered thrombin generation in healthy volunteers and in patients post-TKA.

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