Introduction Concizumab, a humanized recombinant monoclonal antibody directed against the tissue factor pathway inhibitor, is under investigation as a subcutaneous prophylactic treatment for patients with hemophilia A or B (HA/HB) with and without inhibitors. In the concizumab phase 2 trials, treatment was well tolerated and a favorable safety profile was shown, with no deaths or thromboembolic events and no adverse events (AEs) leading to withdrawal. We describe the non-fatal thrombotic serious AEs (SAEs) that occurred during the pivotal phase 3 explorer7 (NCT04083781) and explorer8 (NCT04082429) concizumab trials and the risk mitigations incorporated in the explorer clinical trials.
Methods The explorer7 and explorer8 trials were initiated in late 2019 to evaluate the efficacy and safety of concizumab prophylaxis in HA/HB patients with/without inhibitors, respectively. Concizumab was administered subcutaneously with a 1.0 mg/kg loading dose (concizumab-naïve patients only) and a maintenance dose of 0.25 mg/kg daily from the second day onwards.
Results In March 2020, explorer7 and explorer8 were paused due to the occurrence of two arterial and three venous thrombotic SAEs in three patients with HA or HB with inhibitors. All three patients had thrombotic risk factors present at baseline and had used concomitant hemostatic medication on the day of, and in two cases in the days up to, event onset. Two of the patients were among those with the highest concizumab exposure measured during phase 3. Laboratory parameters in all three patients were as expected. Based on these analyses, risk mitigation plans were developed, including guidelines for the concomitant use of hemostatic agents in the management of bleeding episodes while on concizumab prophylaxis and updates to the concizumab dosing regimen.
Conclusion Novo Nordisk has assessed all available data and defined risk mitigation strategies and changes to the explorer trial protocols.
Seremetis:Novo Nordisk Ins: Current Employment, Current equity holder in private company. Cepo:Novo Nordisk: Current Employment. Skovgaard Rasmussen:Novo Nordisk: Current Employment. Høyer Rose:Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Tamer:Novo Nordisk: Current Employment, Current equity holder in private company, Divested equity in a private or publicly-traded company in the past 24 months. Porstmann:Novo Nordisk Health Care A/G: Current Employment. Haaning:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company.
Asterisk with author names denotes non-ASH members.