Efficacy and Safety of Subcutaneous Prophylaxis with Concizumab in Patients with Severe Hemophilia a without Inhibitors: Results from the Phase 2 explorer5 Trial
Authors: Eichler Hermann , Angchaisuksiri Pantep , Astermark Jan , Benson Gary , Cepo Katarina , Chowdary Pratima , Friedrich Ute , Kavakli Kaan , Wheeler Allison P , Oldenburg Johannes 
Published: November 2019

Background Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical development for the subcutaneous prophylactic treatment of hemophilia patients. We present results from the main part (at least 24 weeks) of the concizumab explorer5 phase 2 trial (NCT03196297) in hemophilia A (HA) patients without inhibitors.
Methods The primary objective was to assess the efficacy of once-daily subcutaneous concizumab in preventing bleeds in patients with severe HA without inhibitors. Safety and immunogenicity were secondary objectives. Patients were treated with 0.15 mg/kg concizumab with potential dose escalation to 0.20 and 0.25 mg/kg. Efficacy was evaluated as the number of bleeding episodes (annualized bleeding rate [ABR]) at last dose level. The number of adverse events (AEs) and the occurrence of anti-drug antibodies (ADAs), as well as coagulation-related parameters, were evaluated. Concizumab and free TFPI plasma levels were measured by ELISA, and thrombin generation (TG) potential using a standardized assay.
Results A total of 36 patients were exposed to concizumab. The last dose level in 21/36 (58.3%) patients was the initial concizumab dose; in 7/36 (19.4%), it was 0.20 mg/kg; and for 8/36 (22.2%), the last dose level was 0.25 mg/kg. All patients who completed the main 24-week part of the trial chose to continue to the extension part. The estimated ABR at the last dose level was 7.0, the median ABR was 4.5, and the estimated ABR for spontaneous bleeding episodes was 2.5. Concizumab concentration varied considerably between patients on the same dose level. Increasing concizumab dose was associated with lower free TFPI and normalized TG potential (Figure 1). No deaths, thromboembolic events or AE-related withdrawals occurred across any of the concizumab dose levels, including 0.25 mg/kg. Three patients had positive (very low-titer) ADA tests (titer range: 1 to 16), with one being neutralizing in vitro in a single but not subsequent tests, and with no apparent clinical effect. As expected, elevated prothrombin fragment 1+2 and D-dimers were observed across all concizumab dose levels, reflecting the hemostatic effect of concizumab.
Conclusions In the phase 2 explorer5 trial, concizumab was efficacious and safe as a subcutaneous prophylactic treatment for HA patients without inhibitors. The phase 2 trial results, which include the explorer4 trial in HA with inhibitors and hemophilia B with inhibitors, support further development of concizumab as a prophylactic treatment for all hemophilia patients and have guided selection of the phase 3 dosing regimen.

Disclosures
Eichler: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Astermark:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sparks: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Benson:Novo Nordisk: Honoraria, Speakers Bureau. Cepo:Novo Nordisk A/S: Employment. Chowdary:Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Freeline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Friedrich:Novo Nordisk: Employment. Kavakli:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Wheeler:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioMarin: Membership on an entity's Board of Directors or advisory committees; uniQure: Membership on an entity's Board of Directors or advisory committees. Oldenburg:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Freeline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sparks: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.