Recombinant FVIIIFc Versus BAY 94-9027 for Treatment of Patients with Haemophilia A: Comparative Efficacy Using a Matching Adjusted Indirect Comparison

Abstract

Introduction Prophylaxis with recombinant factor VIII (rFVIII) is the current standard of care for haemophilia A. Several approaches have been used to extend the half-life of rFVIII to improve prophylaxis outcomes. An indirect comparison of pivotal clinical trial data was performed to evaluate the relative efficacy of two extended half-life therapies approved for the prophylactic treatment of haemophilia A: recombinant FVIII–IgG 1 Fc domain fusion protein (rFVIIIFc) and pegylated rFVIII (BAY 94-9027). Methods Matching-adjusted indirect comparison (MAIC) was conducted to compare the rFVIIIFc individualised prophylaxis arm of the A-LONG phase III clinical trial ( n = 117) and the BAY 94-9027 approved dosing regimens of the PROTECT VIII phase II/III study ( n = 110). Following matching for baseline characteristics, mean annualised bleeding rate (ABR) and the proportion of patients with zero bleeds were compared for rFVIIIFc and BAY 94-9027. Additional supportive analyses comparing rFVIIIFc individualised prophylaxis and the individual prophylaxis regimens included in the PROTECT VIII group (twice weekly, and every 5 and 7 days [Q5D and Q7D]) were conducted. Results Mean ABR was lower in the rFVIIIFc individualised prophylaxis group versus the BAY 94-9027 pooled prophylaxis population (3.0 versus 4.9), providing a clinically relevant and statistically significant difference (mean difference [MD] − 1.9; 95% confidence interval [CI] − 3.5 to − 0.4). A statistically significant difference in ABR was also observed for rFVIIIFc compared with BAY 94-9027 Q7D (3.2 versus 6.4; MD − 3.3; 95% CI − 6.4 to − 0.2). The difference in the proportion of patients with zero bleeds between rFVIIIFc (46.5%) and BAY 94-9027 pooled prophylaxis population (38.2%) was not statistically significant (odds ratio 1.4; 95% CI 0.8 to 2.5). Conclusions This indirect treatment comparison indicates a statistically significant and clinically relevant difference in ABR favouring individualised prophylaxis with rFVIIIFc versus BAY 94-9027 prophylaxis. The proportion of patients with zero bleeds was numerically greater with rFVIIIFc treatment but did not achieve statistical significance.

Matching-Adjusted Indirect Comparison of Efficacy and Consumption of rVIII-SingleChain Versus Two Recombinant FVIII Products Used for Prophylactic Treatment of Adults/Adolescents with Severe Haemophilia A

“…Limitations of our study are in line with those reported in comparable studies to inform real-world clinical decision-making on prophylactic treatment with other rFVIII in severe haemophilia A, using MAIC as the preferred population-adjusted method to generate comparative evidence [33][34][35][36]. While through the MAIC approach potential confounding due to imbalance in published and available baseline characteristics can be corrected for, residual confounding might still exist in baseline characteristics unavailable either for the rVIII-Sin-gleChain prophylaxis arm and/or the prophylaxis arms of the comparator trials (e.g.…”

Indirect Treatment Comparison of Damoctocog Alfa Pegol versus Turoctocog Alfa Pegol as Prophylactic Treatment in Patients with Hemophilia A

“…(Appendix Table 1). A recent MAIC with rFVIIIFc 17 suggested no difference in the proportion of patients with zero bleeds between individualized rFVIIIFc and BAY 94-9027 pooled prophylaxis arms, but a significantly lower mean ABR in the rFVIIIFc individualized prophylaxis group versus the BAY 94-9027 pooled prophylaxis population (mean difference [MD] − 1.9; 95% confidence interval [CI] − 3.5 to − 0.4). In the publication by Batt et al, 9 the mean ABR after weighting for difference in baseline characteristics was similar between BAY 94-9027 and individualized rFVIIIFc: 4.25 vs 2.91 (P > 0.05).…”

“…The publication of Hakimi et al 17 has a relatively high effective sample size, which helps reaching statistical significance, but this was associated with the use of fewer adjustment factors. There was no adjustment on prior use of prophylaxis.…”

“…Additionally, the population was selected to be specific to only one of the treatment arms studied for rFVIIIFc compared to a pooled analysis of all treatment arms from the PROTECT VIII trial. Furthermore, the recent publication 17 was based on a comparison of arithmetic means of ABR, while that of Batt et al 9 compared mean ABRs based on a negative binomial model. ABR was highly skewed in the PROTECT VIII trial, therefore means based on a negative binomial model would be a better summary here than arithmetic means.…”

Efmoroctocog Alfa: A Review in Haemophilia A

“…Current guidelines do not recommend any one EHL or SHL FVIII preparation over another [3,67]. In the absence of direct randomized, head-to-head trials, indirect comparisons based on published clinical trials (typically pivotal studies) suggest that prophylaxis with efmoroctocog alfa requires fewer injections and less weekly FVIII consumption to achieve similar or improved ABRs relative to conventional rFVIII products (octocog alfa, moroctocog alfa, simoctocog alfa and turoctocog alfa) [68], and has comparable [69] (or improved [70]) efficacy and FVIII consumption relative to other EHL rFVIII preparations (i.e. lonoctocog alfa [69], damoctocog alfa pegol [69,70], rurioctocog alfa pegol [69] and turoctocog alfa pegol [69]).…”