Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results

Abstract

Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. 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) explorer5 (HA without inhibitors) and (B) explorer4 (HAwI/HBwI). Dose-escalation criteria: if a patient experienced ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with concizumab, the patient could be escalated to the next dose level. In explorer4, after completion of the main part, patients in the rFVIIa arm continuing on to the extension part of the trial were switched to daily prophylactic subcutaneous treatment with concizumab 0.15 mg/kg, with potential dose escalation as appropriate. ↑, Dose escalate to the next dose level, based on the dose-escalation criteria. R, randomization.

Figure 2.

ABRs. ABRs (bleeding episodes on last dose level) during the main part in (A) explorer4 (HAwI/HBwI), (B) explorer5 (HA without inhibitors), and (C) by hemophilia type in explorer4 and explorer5 (HA, HAwI, HBwI). ABRs were calculated based on a negative binomial regression model with log of exposure time in the main part of the trials as offset and treatment arm as factor. (A) Bleed reduction for treatment with rFVIIa vs concizumab was 78%, 88%, and 79% for all treated bleeds and for spontaneous and joint bleeds, respectively; ***P < .001. (B) Observations from the 2-week run-in are not included. In explorer4, there was 1 medication error in which a patient unintentionally received 5 × 15 mg/kg concizumab.

Figure 3.

Mean plots. Mean plots of (A) concizumab plasma concentration vs time; (B) free TFPI vs time; (C) peak TG potential vs time; (D) peak TG potential vs concizumab plasma concentration; (E) PF1+2 vs concizumab plasma concentration; and (F) d-dimers vs concizumab plasma concentration by hemophilia type for patients with last dose level of concizumab 0.15 mg/kg (A-C) and for all dose levels (D-F) in the main parts of explorer4 (HAwI/HBwI) and explorer5 (HA without inhibitors). Baseline free TFPI, mean (standard deviation): 96.3 (11.1) ng/mL. Normal range of peakTG (lower; upper): 26; 147 nmol/L. BC, baseline values for concizumab arm; LLN, lower limit of normal; LLOQ, lower limit of quantification; ULN, upper limit of normal.