Efanesoctocog alfa 4,000unit powder and solvent for solution for injection vials

The phase 3 XTEND-1 trial (NCT04161495) demonstrated that efanesoctocog alfa prophylaxis provided superior bleed protection compared with pre-trial factor VIII (FVIII) prophylaxis in patients with severe haemophilia A. The aim of this study was to indirectly compare the efficacy of efanesoctocog alfa with non-factor replacement therapy emicizumab in adolescent and adult patients with severe haemophilia A without inhibitors. A systematic literature review was conducted to identify phase 3 trials of emicizumab. Matching-adjusted indirect comparisons were used to compare annualised bleeding rates (ABRs) for any, treated, joint, and spontaneous bleeds, and joint health (measured using Hemophilia Joint Health Score [HJHS]), between efanesoctocog alfa and emicizumab. Estimated effects for different emicizumab regimens were pooled using random-effect meta-analysis to evaluate the overall difference in bleed outcomes between efanesoctocog alfa and emicizumab. One emicizumab trial was included (HAVEN 3), which investigated three dosing regimens. In meta-analyses, efanesoctocog alfa once-weekly (Q1W) was associated with significantly lower ABRs for any (incidence rate ratio [95% CI] 0.33 [0.20; 0.53]), any treated (0.49 [0.30; 0.80]) and treated joint (0.51 [0.28; 0.91]) bleeds compared with emicizumab Q1W in non-inhibitor patients with prior prophylaxis or on-demand treatment. Efanesoctocog alfa Q1W was also associated with a significantly better improvement from baseline in HJHS Joint Score (mean difference [95% CI] −2.06 [−3.97; −0.14]) and Total Score (−2.37 [−4.36; −0.39]) versus emicizumab Q1W or every 2 weeks. Efanesoctocog alfa prophylaxis was associated with significantly lower rates of any, treated, and joint bleeds and improved joint health compared with emicizumab in patients with severe haemophilia A. It is recommended that people with haemophilia A are treated prophylactically (treatment given regularly to prevent bleeding) with factor VIII (FVIII) replacement therapies or a non-factor replacement therapy called emicizumab. People with haemophilia who receive emicizumab may still have bleeds that need to be treated with additional FVIII therapy. In the XTEND-1 clinical trial, patients given efanesoctocog alfa, a new FVIII replacement therapy, had fewer bleeds than they did on the preventive therapy received before the trial. However, efanesoctocog alfa has not been compared with emicizumab. Researchers searched medical journals to identify clinical trials of emicizumab. They compared the number of bleeds and health status of joints in patients treated with efanesoctocog alfa in the XTEND-1 trial with patients treated with emicizumab in HAVEN 3, the trial found in the literature search. The results were analysed to find the overall difference between efanesoctocog alfa and emicizumab. Compared with once-weekly emicizumab, once-weekly efanesoctocog alfa reduced the number of overall bleeds, treated bleeds (additional therapy given to stop the bleeding), and treated joint bleeds. Patients who received efanesoctocog alfa also showed more joint health improvement over the treatment course than those given emicizumab either once-weekly or every 2 weeks. Efanesoctocog alfa may work better at preventing bleeds and improving joint health than the non-factor replacement therapy emicizumab. However, there were some differences between the groups of patients studied in the two trials.

Abstract licence: CC BY-NC 4.0

The therapeutic management of haemophilia A currently includes factor VIII (FVIII) replacement therapy, non-factor treatment options, and gene therapy. In this evolving landscape, specific challenges in safety monitoring may emerge for each product and mode of action. The potential development of neutralising antibodies (inhibitors) to FVIII is a well-known risk for the class of FVIII replacement therapy and information is included in the labels for all FVIII products. In this letter, we discuss the importance of, and challenges associated with post-marketing reporting of FVIII inhibitors. Currently available information from pharmacovigilance reports of inhibitors with efanesoctocog alfa is summarised. Overall, incidence rates for inhibitor development with factor replacement therapies vary not only between previously untreated patients (PUPs) and previously treated patients (PTPs), but also according to disease severity. In a paediatric cohort of 1076 PUPs with severe haemophilia A from the Paediatric Network on Haemophilia Management (PedNet) registry, the incidence of inhibitor development was approximately 31% (95% confidence interval [CI], 28.3–33.7), with development occurring mostly during the first 50 exposure days (EDs) [1]. For PTPs with severe haemophilia A and >50 EDs, data from the European Haemophilia Safety Surveillance (EUHASS) registry revealed an incidence rate of 1 per 1000 person years (95% CI, 0.80–1.30) [2]. Similarly, in a meta-analysis of PTPs with haemophilia A, FVIII activity levels < 2 IU/dL, and ≥ 50 EDs, Hassan et al. [3] calculated an overall incidence rate of 2.06 per 1000 person-years. Finally, in a recent analysis of people with non-severe haemophilia A (FVIII activity levels ≥ 1 IU/dL) from the EUHASS registry, the incidence of inhibitor development was 4.2/1000 treatment years, with 58% of inhibitors occurring within the first 50 EDs and the remainder developing after 50 EDs, thus highlighting the importance of continuous monitoring for inhibitor development in patients receiving factor replacement therapy. [4, 5] It is the role of the manufacturer to ensure continuous safety monitoring and evaluation of a product, including in the post-marketing setting. Collection of post-marketing safety information outside of a dedicated clinical trial programme is challenging in the context of reports being voluntary (i.e. non-solicited) with incomplete documentation being frequently observed. All reports made to the company, which can arise from various sources—e.g. healthcare professionals, patients, caregivers and company staff—are submitted to regulatory authorities in a timely manner, adhering to established regulatory timeframes. Despite the limitations, voluntary reporting remains an important source of information about the safety of marketed products. In addition to routine pharmacovigilance, independent international and national registries are an important source of safety information in the real-world setting. Examples include the American Thrombosis and Haemostasis Network (ATHN) dataset, the EUHASS registry, the France-Coag registry, the PedNet registry, and the United Kingdom Haemophilia Centre Doctors’ Organisation registry. As previously mentioned, the development of inhibitors to FVIII is a well-known risk for FVIII replacement therapies, including both plasma-derived and recombinant products. Many different FVIII products are currently available, each with distinct features. Efanesoctocog alfa is a high sustained FVIII replacement therapy that overcomes the von Willebrand factor-imposed half-life ceiling [6]. It was approved by the United States Food and Drug Administration in February 2023, the Japanese Pharmaceuticals and Medical Device Agency in September 2023, the European Medicines Agency in June 2024, and other regulatory agencies thereafter. Approvals were based on data from the clinical development programme including the pivotal phase 3 XTEND-1 (NCT04161495) [6] and XTEND-Kids (NCT04759131) [7] studies. A long-term extension study, XTEND-ed (NCT04644575), is currently ongoing. As of 22 February 2025, 431 participants with severe haemophilia A have been exposed to efanesoctocog alfa in interventional clinical trials and there have been no reports of inhibitors. Based on commercial distribution estimates, approximately 3500 patients worldwide have been treated with efanesoctocog alfa outside of clinical trials and, as of 1 April 2025, 11 reports of inhibitors have been received through the global post-marketing safety monitoring programme (Table 1). As reports are submitted voluntarily, the number of reported inhibitor cases may not reflect actual occurrence rates. The 11 reports received describe patients with haemophilia A of varying disease severity, although severity was unknown in 5 of the reports. A history of, or current inhibitors prior to initiation of efanesoctocog alfa was described in 4 reports and was unknown in 2. A negative inhibitor test prior to starting efanesoctocog alfa treatment was described in 5 reports, however, testing immediately before product initiation was available in only 1 report, and was negative. A second inhibitor test was described in 4 of the 11 reports confirming the presence of inhibitors. Based upon the available information, transient inhibitors could not be determined [8]. Eight reports originated from patients who had previously received other FVIII treatments prior to initiation of efanesoctocog alfa (however, numbers of EDs are not available); of these, 3 were reportedly receiving other FVIII therapies concomitantly with efanesoctocog alfa. As such, it has not been possible to determine how many of these reports represent true inhibitor development. All post-marketing safety reports were actively investigated and additional information from the reporter(s) requested. Based on the information provided, 4 reports do not appear to represent “de novo” inhibitor development to efanesoctocog alfa. In most of the remaining reports, there are clinical confounders, however a causal relationship cannot be ruled out. Important information to facilitate complete assessment of inhibitor development includes the number of EDs to previous FVIII therapies and to efanesoctocog alfa, as well as the timing and results of all inhibitor tests. Moreover, haemophilia severity, ethnicity, F8 genotype, family history of inhibitors, evidence of intense FVIII exposure, and information on haemophilia treatment history are all important for interpretation. Confounding factors, such as comorbidities and concomitant treatments, including immunomodulants and chemotherapy, are also relevant for comprehensive assessment. There are specific situations where inhibitor testing is of great importance. Per World Federation of Hemophilia guidelines, testing is recommended in the following scenarios: (1) after initial factor replacement therapy exposure, (2) within 4 weeks of intensive exposure, (3) during recurrent bleeding or target joint bleeding, (4) after failure to respond to FVIII therapy, (5) when FVIII recovery or half-life is lower than expected, (6) during suboptimal clinical or laboratory response to therapy, (7) before surgery, and (8) after a suboptimal post-operative response to therapy [4]. It is recommended that testing is performed after the last dose of the previous treatment (including both FVIII replacement and non-factor therapies) and after initiating new FVIII replacement therapy [4]. Additionally, if patients have a history of inhibitors, clinicians should be aware of the risk of inhibitor relapse/re-occurrence or anamnestic response to any FVIII replacement therapy [4]. Inhibitor testing should preferably be performed using the Nijmegen modified Bethesda assay, with a confirmatory test conducted on receipt of a positive result [9]. More frequent monitoring of inhibitors is recommended in PUPs as compared to PTPs [10]. This correspondence intends to highlight several critical aspects of post-marketing pharmacovigilance monitoring, using the recent experience with efanesoctocog alfa as an illustrative example. The reports described emphasize the importance of referring to clinical treatment guidelines, particularly with respect to safety monitoring, as well as improved reporting of safety data to ensure that all people living with haemophilia receive the best possible care. Medical writing support was provided by Barrie Anthony, PhD, on behalf of Envision 90TEN, an Envision Medical Communications agency, a part of Envision Pharma Group. The authors thank James Cobb, (Sanofi), Monique Bidell, PharmD, CMPP (Sanofi), and Nick Fulcher, PhD, CMPP (Sobi), for publication coordination. Sanofi and Sobi personnel reviewed this article. The authors had full editorial control of the article and provided their final approval of all content. Medical writing was funded by Sanofi and Sobi. All authors are employees of Sanofi or Sobi may hold shares and/or stock options in the companies. This report contains fully anonymised data with no personally identifiable information. Because the analysis was retrospective and used only anonymized data, ethics committee approval and informed consent were deemed not applicable. Data were handled in accordance with Sanofi and Sobi data ethics principles. The authors declare no conflicts of interest. Due to the nature of the reports, data are not publicly available due to patient privacy, ethical and legal restrictions.

Abstract licence: CC BY-NC 4.0