Seremetis S, Cepo K, Rasmussen JS, Rose TH, Søren Tamer, Porstmann T, Haaning J. Risk Mitigation Strategy for Concizumab Clinical Trials after Pause Due to Non-fatal Thrombotic Events . Haemophilia. 2021;27(S2): 124. https://onlinelibrary.wiley.com/doi/pdf/10.1111/hae.14236
Introduction: Concizumab is a humanized monoclonal anti?tissue factor pathway inhibitor (TFPI) antibody, currently under investigation for the treatment of haemophilia A and B with and without inhibitors. In the concizumab phase 2 clinical trials, investigators reported no deaths, thromboembolic events or adverse events (AEs) leading to withdrawal. During the pivotal phase 3 trials, explorer7 (NCT04083781) and explorer8 (NCT04082429), non?fatal thrombotic serious AEs (SAEs) occurred in three patients. Here, we describe those events and the risk mitigation incorporated in the explorer clinical trials.
Methods: Two phase 3 trials were initiated in late 2019 to assess the efficacy and safety of concizumab prophylaxis in patients with haemophilia A or B with (explorer7) or without inhibitors (explorer8). Concizumab?naïve patients received a subcutaneous loading dose of 1.0 mg/kg concizumab, and from the second day onwards, all patients received a daily subcutaneous maintenance dose of 0.25 mg/kg. Patients from the phase 2 trials who consented to transfer to phase 3 received concizumab 0.25 mg/kg daily (no loading dose).
Results: explorer7 and explorer8 were temporarily paused in March 2020 because three patients with haemophilia A or B with inhibitors and baseline thrombotic risk factors experienced two arterial and three venous thrombotic SAEs. All patients had received concomitant haemostatic medication on the day of the event onset. In two cases, haemostatic medication had also been administered in the days leading up to the event. Two of the patients were among those with the highest concizumab exposure in the phase 3 trials. Novo Nordisk developed a risk mitigation plan based on in?depth, cross?functional analysis of available data from phase 2 and 3 clinical trials with concizumab, including data from the three patients who experienced thrombotic events, which was approved by the relevant authorities. The risk mitigation includes guidelines for the management of bleeding episodes with concomitant haemostatic agents in patients treated with concizumab and updates to the concizumab prophylactic dosing regimen.
Discussion/Conclusion: After assessing all available data, Novo Nordisk defined strategies for risk mitigation and made amendments to the phase 3 explorer trial protocols, allowing the re?initiation of the explorer7 and explorer8 trials.