Abstract: Tissue factor pathway inhibitor (TFPI) inhibits coagulation initiation, and TFPI inhibition enhances the activation of factor X by tissue factor. Shapiro et al report the results of a phase 2 study of prophylactic administration of the TFPI inhibitor concizumab for bleeding prevention in hemophilia, reporting efficacy in Factor VIII and IX deficiency even in patients with inhibitors to Factor VIII or IX.

Abstract: Despite current therapies, there remains an unmet need for treatment for patients with hemophilia. The main parts of two phase 2 trials established clinical proof-of-concept for once-daily, subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors (HAwI/HBwI; explorer4) and severe hemophilia A without inhibitors (HA; explorer5). Here, we present results from extension parts of these trials, included to evaluate longer term safety and efficacy. Both trials included main (≥24 weeks) and extension (52-102 weeks) parts, with patients receiving concizumab 0.15 mg/kg with potential dose escalation to concizumab 0.20 or 0.25 mg/kg if they experienced ≥3 treated spontaneous bleeding episodes within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and occurrence of antidrug antibodies. Thromboembolic events were AEs of special interest. Thirty-six patients with HA, 15 with HAwI, and 10 with HBwI were exposed to concizumab. Estimated ABRs during the main + extension parts at last dose level were 4.8 (95% confidence interval [CI], 3.2-7.2) and 6.4 (95% CI, 4.1-9.9) in explorer4 and explorer5, respectively (spontaneous ABRs were 1.8 [95% CI, 1.2-2.6] and 2.1 [95% CI, 1.3-3.3]). Most AEs were mild, with no deaths, events leading to withdrawal, or thromboembolic events. Anti-drug antibodies developed in 25% of patients and were low titer and transient, with no observed clinical effect in most cases. Results of the main + extension parts of these trials were consistent with results of the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.

Abstract: Turoctocog alfa pegol (N8‐GP) is a glycoPEGylated, extended half‐life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019,  〉  800 patients have been treated worldwide. Aim To present data from identified post‐marketing cases of less‐than‐expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8‐GP. Methods The post‐marketing safety database was searched using keywords such as ‘coagulation FVIII level decreased’. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded. Results Here we report 14 cases of less‐than‐expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post‐dose) to 51% (2 days post‐dose). Seven patients experienced bleeding episodes after switching to N8‐GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti‐PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product. Conclusion In conclusion, the 14 reported cases of less‐than‐expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti‐PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8‐GP continues.

Abstract: 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.