Risk Mitigation Strategy for Concizumab Clinical Trials after Pause Due to Non-Fatal Thrombotic Events

Abstract

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. Disclosures 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.

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses

“…Treatment recommendations for bleeds mandate a cautious approach when administering additional hemostatic agents in patients on concizumab prophylaxis, using the lowest approved dose of any replacement product or bypassing agent and with the time interval between two doses, if relevant, not shorter than stated on the label. The mitigation includes closer oversight of treatment for breakthrough bleeds and potential concizumab dose adjustments to ensure that patients are exposed to enough concizumab to prevent bleeding, while avoiding unnecessary exposure beyond what is needed to saturate and inhibit endogenous TFPI 12 …”

“…The mitigation includes closer oversight of treatment for breakthrough bleeds and potential concizumab dose adjustments to ensure that patients are exposed to enough concizumab to prevent bleeding, while avoiding unnecessary exposure beyond what is needed to saturate and inhibit endogenous TFPI. 12 …”

“…The subsequent phase 3 trials, explorer7 (NCT04083781) and explorer8 (NCT04082429), as well as the extension phase of explorer5, were paused by Novo Nordisk and were subsequently temporarily placed on clinical hold by the Food and Drug Administration in March 2020 due to reports of non‐fatal, thrombotic events (TEs) in three patients. All three patients had thrombotic risk factors at baseline and had used concomitant hemostatic medication (rFVIIa or FVIII) on the day of, and, in two cases, in the days before the TE 12 . 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 TEs, which led to the clinical hold being lifted in August 2020 and the phase 3 trials resuming 13…”

“…All three patients had thrombotic risk factors at baseline and had used concomitant hemostatic medication (rFVIIa or FVIII) on the day of, and, in two cases, in the days before the TE. 12 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 TEs, which led to the clinical hold being lifted in August 2020 and the phase 3 trials resuming. 13…”

Haemophilia: factoring in new therapies

“…In a Phase II study in HA, HA with inhibitors, and HB with inhibitors, daily prophylaxis with SC concizumab showed initial efficacy in prevention of bleeds without AEs including thrombosis 50 . However, in Phase III studies (EXPLORER Trials) in PwH with (NCT04083781) and without (NCT04082429) inhibitors, non‐fatal thrombotic events occurred in three patients, leading to temporarily pausing the studies, which have reopened with a risk mitigation strategy regarding pharmacokinetic dosing and revised concomitant treatment for bleeding guidelines 51 …”