Efficacy of rFVIIIFc versus Emicizumab for the Treatment of Patients with Hemophilia A without Inhibitors: Matching-Adjusted Indirect Comparison of A-LONG and HAVEN Trials

Abstract

Purpose Primary prophylaxis, using factor VIII replacement, is the recognized standard of care for severe hemophilia A. Recombinant factor VIII-Fc fusion protein (rFVIIIFc) and emicizumab, a humanized, bispecific antibody, are approved for routine prophylaxis of bleeding episodes in severe hemophilia A. These products have different mechanisms of action, methods of administration and treatment schedules. In the absence of head-to-head trials, indirect treatment comparisons can provide informative evidence on the relative efficacy of the two treatments. The aim of the study was to compare the approved dosing regimens for each product, rFVIIIFc individualized prophylaxis and emicizumab administered once every week (Q1W), every 2 weeks (Q2W) or every 4 weeks (Q4W), based on clinical trial evidence. Patients and Methods The comparison was conducted using matching-adjusted indirect comparison since clinical evidence did not form a connected network. Individual patient data for rFVIIIFc (A-LONG) were compared with data for emicizumab (HAVEN trial program) for mean annualized bleeding rate (ABR) and proportion of patients with zero bleeds. Safety data reported across the analyzed treatment arms were tabularized but not formally compared. Results After matching, no significant differences were observed between mean ABR for rFVIIIFc and emicizumab administered Q1W, Q2W or Q4W. The proportion of patients with zero bleeds was significantly higher with rFVIIIFc compared with emicizumab administered Q4W (51.2% versus 29.3%, respectively; odds ratio 2.53; 95% confidence interval 1.09–5.89); no significant differences noted when rFVIIIFc was compared with emicizumab administered Q1W or Q2W. The mean number of adverse events expressed per participant was 1.9 for individualized prophylaxis with rFVIIIFc and 3.7–4.0, 4.1 and 3.6 for emicizumab administered Q1W, Q2W or Q4W, respectively. Conclusion This indirect treatment comparison suggests that rFVIIIFc individualized prophylaxis is more efficacious than emicizumab Q4W, and at least as effective as more frequent emicizumab regimens, for the management of hemophilia A.

Expert opinion on current and future prophylaxis therapies aimed at improving protection for people with hemophilia A

“…The WFH guidelines recommend using emicizumab PPX as one possible option to prevent hemarthrosis, both spontaneous and breakthrough bleeding, in patients with severe hemophilia A without inhibitors [ 5 ]. rFVIIIFc is strongly equivalent to emicizumab in terms of mean ABR and proportion of patients with zero bleeds when considering a conservative approach to target factor levels (1–3% trough) and aiming for troughs of 3–5%; however, factor therapy offers more personalization possibilities compared with emiciaumab [ 5 , 31 ]. Moreover, serious thromboses and thrombotic microangiopathy episodes associated with the concomitant use of aPCC were observed in HAVEN-1, which led to emicizumab having a special warning regarding its concomitant use with aPCC [ 9 , 13 ].…”

Cost‐effectiveness of recombinant factor VIII Fc versus emicizumab for prophylaxis in adults and adolescents with haemophilia A without inhibitors in the UK

“…It was additionally assumed that people with haemophilia A, who receive these prophylactic treatments, have the same mortality as the general population. The ABR in the first cycle was estimated based on a previously performed MAIC analysis for each treatment option 22 . Data from the MAIC included the total study population, that is, both patients with and without bleeding events, for the calculation of ABR and the proportion of patients with no bleeding events.…”

“…Using the distribution of patients in the first cycle and the transition probabilities between cycles, the proportion of patients in each state per cycle was estimated in the rFVIIIFc arm. ORs for the proportion of patients with no bleeding events for emicizumab were obtained from the previously performed MAIC analysis, which compared rFVIIIFc versus emicizumab 22 . The ABRs for both rFVIIIFc and emicizumab were obtained from the MAIC analysis, 22 and these ABRs were used to calculate the costs and quality‐adjusted life years (QALYs) in the ‘any bleeds’ state.…”

“…There are currently no direct comparisons, in terms of efficacy or cost, between rFVIIIFc and emicizumab. A matching‐adjusted indirect comparison (MAIC) demonstrated similar efficacy for the mean ABR with rFVIIIFc individualised prophylaxis compared with emicizumab administered Q1W, Q2W and Q4W, with trends in favour of rFVIIIFc 22 . The objective of this analysis was to evaluate the cost‐effectiveness of prophylaxis with rFVIIIFc versus emicizumab in patients with haemophilia A without inhibitors in the UK.…”

Is there any place for replacement therapy of hemophilia A in children in present and future?

“…Интересно, что это было достигнуто без потери эффективности: медиана частоты спонтанных кровотечений в большинстве исследований составила менее 1 [14,16,17]. Применение концентратов с увеличенным периодом полувыведения позволяет достичь столь же эффективного и более безопасного контроля проявлений геморрагического синдрома по сравнению с применением эмицизумаба [18]. Большого интереса заслуживает и новый концентрат рекомбинантного фVIII, который вводится подкожно и использует сразу несколько технологий увеличения периода полувыведения и снижения иммуногенности, позволяющий увеличить период полувыведения до 49,4 ч, что потенциально позволит использовать его 1 раз неделю и даже реже [19].…”