Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors.

Despite current treatments, there remains an unmet need 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 parts (52-102 weeks), with patients receiving 0.15 mg/kg concizumab with potential dose escalation to 0.20 or 0.25 mg/kg if they experienced ≥3 treated spontaneous bleeds within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and anti-drug antibody (ADA) occurrence. 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. ADAs 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 the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes. Trials registered at www.clinicaltrials.gov (NCT03196284; NCT03196297).