Shapiro A, Castaman G, Cepo K, Tønder SM, Matsushita T, Poulsen LH, Young G, Zupancic-Šalek S, Jiménez Yuste V. Safety and Longer-term Efficacy of Concizumab Prophylaxis in Patients with Hemophilia A or B with Inhibitors: Results from the Extension Part of the Phase 2 explorer4 Trial. Haemophilia. 2021;27(S2): 128. https://onlinelibrary.wiley.com/doi/pdf/10.1111/hae.14236
Introduction: The high?affinity, anti?tissue factor pathway inhibitor (TFPI) monoclonal antibody concizumab is currently in clinical trials as a once?daily subcutaneous treatment for haemophilia A and B with/without inhibitors. explorer4 (NCT03196284) was a phase 2 trial that assessed the safety and efficacy of concizumab in patients with haemophilia A or B with inhibitors (HAwI or HBwI). Results from the combined main and extension parts of explorer4 are presented.
Methods: The combined main (?24 weeks) and extension (?52 weeks) parts of explorer4 lasted ? 76 weeks. Patients were randomised 2:1 to receive daily concizumab prophylaxis or recombinant activated factor VII (rFVIIa) on?demand during the main part. If patients experienced ? 3 spontaneous bleeds within 12 weeks, concizumab dose was escalated to 0.20 and 0.25 mg/kg. During the extension, on?demand patients switched to 0.15 mg/kg concizumab prophylaxis, with the possibility to dose escalate if needed. Endpoints for the extension part included: annualized bleeding rate (ABR) after 76 weeks of treatment; concizumab and free TFPI concentration prior to last concizumab administration; number of adverse events (AEs); occurrence of anti?drug antibodies (ADAs). Least?squares means estimates based on negative binomial regression with log exposure time to concizumab were used to assess ABR.
Results: During explorer4, 15 HAwI and 10 HBwI patients were exposed to concizumab, 8 of whom received on?demand rFVIIa therapy in the main part. During the entire trial, the estimated ABR for patients treated with concizumab was 5.7 (95% CI: 4.2–7.8), with a 4.8 (95% CI: 3.2–7.2) ABR at the last dose level. Overall, 4 (16%) patients had no bleeds on their last dose level in the trial. Plasma concizumab concentrations varied throughout the extension part. ADAs developed in 6 patients. No AEs led to withdrawal, no thromboembolic events occurred, and no patients died. Some patients treated with concizumab experienced an increase in prothrombin fragment 1 + 2 and D?dimer concentrations.
Discussion/Conclusion: Results from this analysis of the combined main and extension parts of explorer4 support the clinical proof?of?concept established in the main part, and longer?term safety and efficacy of concizumab as a subcutaneous treatment for patients with HAwI and HBwI.