Background Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody indicated for hemophilia A/B with/without inhibitors, approved in US, Europe and other countries for once-daily, subcutaneous prophylaxis in hemophilia A/B with inhibitors. During the prospective, multicenter, open-label, phase 3 explorer8 study (NCT04082429), superiority was confirmed for concizumab compared with on-demand treatment in patients with hemophilia A/B without inhibitors (HA/HB). Furthermore, a subset of patients was included in an intra-patient comparison of concizumab to previous prophylaxis. The estimated annualized bleeding rate (ABR) ratio between concizumab and previous prophylaxis was 1.39 (95% confidence interval [CI]: 0.73; 2.63) for HA and 1.75 (0.81; 3.78) for HB. The upper limit of the 95% CI was above 2 (pre-defined non-inferiority margin), meaning that non-inferiority of concizumab to previous prophylaxis was not confirmed. The median ABRs for the intra-patient analysis group were numerically similar for HA (concizumab: 2.3 [interquartile range, IQR: 0.0–4.7]; previous prophylaxis: 2.2 [0.8–6.2]) and decreased in HB with concizumab (concizumab: 1.4 [0.0–8.1]; previous prophylaxis: 2.1 [0.9–4.2]). A review of the data showed that extreme ABRs in three patients (HA n=2; HB n=1) influenced the mean ABR. However, no common risk factors or characteristics were identified and neutralizing anti-concizumab antibodies were not reported.

Aim The impact of the extreme ABRs on the intra-patient comparison of concizumab to previous prophylaxis was investigated with a post-hoc sensitivity analysis.

Methods Male patients (≥12 years) were assigned to one of four arms in explorer8. A subset of patients receiving concizumab in a non-randomized arm were included in the intra-patient analysis. Patients received a 1.0 mg/kg concizumab loading dose (Day 1), followed by 0.20 mg/kg daily starting from Day 2+, with potential dose adjustment (5–8 weeks) to 0.15 or 0.25 mg/kg based on concizumab plasma concentration measured after week 4. Informed consent/ethics committee approval were obtained. Sensitivity analyses using imputation were performed to investigate the impact of the extreme ABRs at the 32-week cut-off (defined as when patients receiving concizumab prophylaxis had completed the visit after 32 weeks, or permanently discontinued treatment). Here, treated spontaneous and traumatic bleeding episodes for the three patients with extreme ABRs were replaced by imputed values computed from the remaining patients with HA/HB. The sensitivity analyses were conducted using parametric (negative binomial regression models) and non-parametric (Wilcoxon signed-rank test) approaches.

Results The sensitivity analyses included all patients in the intra-patient analysis set (HA n=29; HB n=22). Among these patients, 38 (74.5%) were White, 12 (23.5%) were Asian, and 1 (2.0%) was Black/African American. For HA, the post-hoc sensitivity analysis using imputed values for the three patients with extreme ABRs showed that the estimated mean ABR (95% CI) for concizumab decreased from 5.1 (2.71; 9.65) to 2.8 (1.76;4.57) upon analysis after imputation using the negative binomial regression. The ABR ratio (95% CI) of concizumab vs previous prophylaxis reduced from 1.39 (0.73; 2.63) to 0.75 (0.40; 1.42). For HB, the estimated mean ABR for concizumab decreased from 5.4 (2.27; 12.91) to 3.1 (1.80; 5.37) and the ABR ratio (95% CI) of concizumab vs previous prophylaxis reduced from 1.75 (0.81; 3.78) to 1.00 (0.58; 1.73). For both HA/HB, the upper limits of the 95% CIs were below the non-inferiority margin of 2.0. Wilcoxon signed-rank tests showed that 'no difference’ could not be rejected between median ABRs for concizumab and previous prophylaxis with imputed data for both HA/HB.

Conclusion Post-hoc sensitivity analyses using imputed data for the three patients in the explorer8 intra-patient comparison subset who had extreme ABRs showed that the upper limit of the 95% CI of the ABR ratios decreased below the non-inferiority margin of 2.0 when comparing concizumab to previous prophylaxis. This indicates that for the majority of patients, ABRs during concizumab demonstrated non-inferiority when compared to prior prophylaxis regimens. As with any therapy, there may be some variability in individual responses to treatment. Overall, the phase 3 explorer8 study showed that once-daily, subcutaneous concizumab prophylaxis was efficacious and well-tolerated.

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2025
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