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

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.

Graphical abstract

Figure 1.

Study design for the phase 2 concizumab trials. (A) explorer4 (HAwI/HBwI). (B) explorer5 (HA). As shown in panel A, patients were randomized 2:1 to receive either prophylaxis with concizumab or on-demand treatment with rFVIIa for 24 weeks (main part). Patients who received rFVIIa during the main part were switched to concizumab prophylaxis during the extension part (56-94 weeks). As shown in panel B, all patients received concizumab prophylaxis during the main part (24 weeks) and extension part (52-102 weeks). Dose escalation criteria throughout both trials were ≥3 treatment-requiring spontaneous bleeding episodes within the 12 weeks before concizumab treatment during both the main and extension parts.

Figure 2.

Patient disposition in the phase 2 concizumab trials. (A) explorer4 (HAwI, HBwI). (B) explorer5 (HA). *One patient withdrew consent after randomization. **Three patients withdrew in the extension phase (one due to lack of efficacy, one because of suspicion of no therapeutic effect due to normal TFPI level with ADA, and one withdrawal of consent). ***Four patients withdrew before the end of the main part. ^†Two patients discontinued due to lack of efficacy. ^‡One patient withdrew consent in the extension part.

Figure 3.

ABRs (treated bleeding episodes on the last concizumab dose level) during the main + extension parts of the phase 2 concizumab trials explorer4 (HAwI, HBwI) and explorer5 (HA) by hemophilia subtype; full analysis set. Least-squares mean estimates of ABR (95% CI) are shown. The ABR estimate was based on a negative binomial regression with log of exposure time as offset and hemophilia type as factor (explorer4).

Figure 4.

Plots by hemophilia subtype of (A) concizumab plasma concentration (geometric mean) vs time; (B) free TFPI plasma concentration (mean) vs time; (C) prothrombin fragments 1 + 2 vs concizumab plasma concentration; and (D) D-dimers vs concizumab plasma concentration in the main + extension parts of the phase 2 concizumab trials explorer4 (HAwI, HBwI) and explorer5 (HA). All data from visit 16 were allocated to 118 weeks (HAwI and HBwI) or 126 weeks (HA) after first concizumab dose (panels A and B). Data below the lower limit of quantification (LLOQ) were included as LLOQ/2 in the calculations. Horizontal dashed lines in panel A indicate a concizumab exposure level between 200 and 4000 ng/mL. Baseline values for panels C and D were assigned to Visit 9 (last treatment during main part) for the on-demand treatment arm in explorer4. BC, baseline concizumab; FEU, fibrinogen-equivalent units; LLN, lower limit of normal; ULN, upper limit of normal.