HEMATOLOGY concizumab SC

Novo Nordisk

Proposed Indications

Hemophilia A and B prophylaxis in patients with inhibitors

Clinical Overview

Concizumab, an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody, improves thrombin generation. The randomized, open-label, parallel-group, phase 3 EXPLORER 7 trial (NCT04083781) evaluated prophylactic treatment with concizumab in 132 male patients ≥ 12 years of age with hemophilia A or B with inhibitors. The study reported an estimated mean annualized bleeding rate (ABR) of 1.7 with concizumab compared to 11.8 with no prophylaxis (ABR ratio, 0.14; p<0.001). The median ABR was 0 for concizumab and 9.8 with no prophylaxis. Notably, the EXPLORER clinical program, including the EXPLORER 7 trial, was temporarily placed on hold due to reports of 3 non-fatal thrombotic events in patients who had risk factors at baseline and had used concomitant hemostatic medication (recombinant factor VIIa or VIII). The program resumed after new safety measures were adopted to mitigate this risk. No thrombotic events or other safety concerns were reported after EXPLORER 7 was restarted.

Concizumab was self-administered as a SC injection via a prefilled pen. It was administered as a loading dose of 1 mg/kg on day 1, followed by 0.2 mg/kg once daily starting on day 2. Over the next 5 to 8 weeks, the dose could be adjusted to 0.25 mg/kg or 0.15 mg/kg depending on the concizumab plasma concentrations.

Place In Therapy

Hemophilia is an X-linked congenital bleeding disorder that affects up to 33,000 males in the US. Hemophilia is characterized by chronic spontaneous bleeding into muscles and joints that can progress to debilitating arthropathy. Hemophilia A and B exhibit low or missing levels of clotting factors VIII and IX, respectively. Hemophilia A and B comprise about 80% and 20% of all cases of hemophilia, respectively. Approximately 35% of patients with hemophilia A and 3% with hemophilia B will develop neutralizing antibodies, or inhibitors, to factor products, which make the condition more difficult to treat.

The bypassing agents, recombinant factor VIIa (e.g., Novoseven RT®, Sevenfact®) and activated prothrombin complex concentrates (e.g., Feiba®), are SOC for managing hemophilia in patients with inhibitors. A hemostatic efficacy of about 80% has been reported with these agents but may vary and change over time. The first FDAapproved non-factor product, emicizumab-kxwh (Hemlibra®), mimics factor VIIIa cofactor and is indicated for routine prophylaxis for patients (newborns through adulthood) with hemophilia A with or without inhibitors. This bispecific factor IXa/X antibody is self-administered SC every 1, 2, or 4 weeks.

If approved, concizumab will be the first anti-TFPI antibody available in the US. In clinical trials, it significantly reduced ABR compared to no prophylaxis. Market uptake could be a challenge due to the need for daily SC injections and by reports of non-fatal thrombosis that led to the halting of early studies. Although, concizumab could find a niche in patients with hemophilia B – a population in which emicizumab-kxwh is not indicated. Novo Nordisk plans to submit concizumab for FDA approval for hemophilia A and B without inhibitors in 2023.

Other non-factor products in phase 3 studies for both hemophilia A and B include the anti-TFPI antibody marstacimab and the small interfering RNA fitusiran. In addition, the first gene therapy for adults with severe hemophilia A, valoctocogene roxaparvovec, is awaiting the FDA decision by June 30, 2023, as a 1-time dose.