XTEND-Kids Trial Reinforces Safety, Efficacy of Efanesoctocog Alfa in Children

Malec Lynn, MD
Credit: Children's Wisconsin

The phase 3 XTEND-Kids trial is providing clinicians with reassuring insights into the safety and efficacy of once-weekly efanesoctocog alfa (ALTUVIIIO) among children with severe hemophilia A.

Published in the New England Journal of Medicine, results of the trial, which evidence a safety profile boasting favorable outcomes with once-weekly dosing, come more than a year after the agent received approval for adults and children with hemophilia A.^1,2

“Children represent a population for which it has been historically difficult to achieve effective bleed prevention,” said principal investigator Lynn Malec, MD, medical director of Comprehensive Center for Bleeding Disorders and associate Professor of Medicine and Paediatrics at The Medical College of Wisconsin.³ “The clearance of administered factor concentrates is greater in children than we see in adults, which leads to burdensome treatment regimens involving multiple injections per week. By providing high-sustained factor VIII activity levels consistently early in life with once-weekly dosing, [ALTUVIIIO] has the potential to improve reported outcomes for children living with haemophilia.”

Once-weekly efanesoctocog alfa made history in February 2023 as the first hemophilia A treatment offering the potential to achieve normal to near-normal factor activity levels for most of the week with once-weekly dosing. Codeveloped by Sanofi and Sobi, the companies billed efanesoctocog alfa as the first-and-only treatment to deliver normal to near-normal factor activity levels and significant reductions in bleeds with once-weekly dosing.²

At the time of approval, the XTEND-Kids study was still ongoing but 26-week interim data suggested children younger than 12 years of age experienced a mean annual bleeding rate of 0.5 (95% Confidence Interval [CI], 0.2 to 1.3) and a median rate of 0 among 23 children with available data. Now, the publication of full trial results in the New England Journal of Medicine provides insight into the 52-week data.^1,2,3

An open-label, international, single-group, phase 3 study, XTEND-Kids enrolled 74 male children younger than 12 years of age with severe hemophilia A who had received recombinant or plasma-derived factor VIII or cryoprecipitate. Of note, treatment with children aged 6 to less than 12 years needed to have at least 150 exposure days and children aged less than 6 years needed at least to have at least 50 exposure days.¹

Among the 74 patients included in the study, 38 were aged less than 6 years and 36 were 6 to less than 12 years of age. In total, 72 patients completed the study, with 1 withdrawing after a positive inhibitor test at baseline and 1 withdrawing due to extreme fear of blood draws. Investigators pointed out these occurred after 3 and 44 doses, respectively.

Patients enrolled in the study received once-weekly efanesoctocog alfa at a dose of 50 IU per kilogram of body weight for 52 weeks. Per trial protocol, bleeding episodes were treated with one dose of efanesoctocog alfa (50 IU per kilogram), with additional doses of 30 or 50 IU per kilogram every 2 or 3 days if the episode did not resolve as judged by the caregiver in consultation with the investigator. Study participants could continue routine prophylaxis after 72 hours if successfully treated with 50 IU per kilogram or without delay if successfully treated with 30 IU per kilogram.¹

Despite being a phase 3 study, XTEND-Kids leveraged a safety outcome, namely the occurrence of factor VIII inhibitors, as the primary end point of interest for the trial. The trial included multiple efficacy outcomes, including annualized rates of treated bleeding episodes and bleeding treatment, as secondary end points of interest.¹

Upon analysis, results indicated no factor VIII inhibitors were developed during the 52-week study. In total, 84% of patients had at least 1 adverse event after the start of treatment, with most events considered nonserious. Among those who experienced an adverse event, 4% had an event assessed by an investigator as being related to efanesoctocog alfa. Further analysis of safety outcomes revealed there were no serious adverse events considered to be related to efanesoctocog alfa.¹

Efficacy analyses among the 73 patients treated according to protocol revealed a median annualized rate of treated bleeding episodes of 0.00 (interquartile range, 0.00 to 1.02) and a model-based estimated mean overall annualized rate of treated bleeding episodes of 0.61 (95% CI, 0.42 to 0.90) among the entire study cohort at 52 weeks. Analysis of bleeding episodes indicated 64% had no treated bleeding episodes, 88% had no spontaneous bleeding episodes, and 82% had no episodes of bleeding into joints. Additionally, 41 of 43 bleeding episodes occurring during the trial were resolved with a single injection of efanesoctocog alfa.¹

In an editorial, Pratima Chowdary, MD, professor of Haemophilia and Haemostasis at University College London and haemophilia centre director at the Katharine Dormandy Haemophilia and Thrombosis Centre at the Royal Free Hospital, commended investigators on the trial and offered perspective on the findings, with the current management landscape as a backdrop. Later, he commented on the juxtaposition between the need to conduct pediatric trials for rare conditions such as hemophilia A against the difficulties associated with conducting such trials.⁴

“Studies involving children are crucial for understanding their needs and responses to treatments. However, conducting such studies involves ethical and practical challenges for investigators, parents, and sponsors,” Chowdary wrote.⁴ “These challenges are reflected in the choice by Malec et al. of safety, rather than efficacy, as the primary end point, unlike that in the study involving adults.”

References:

1. Malec L, Peyvandi F, Chan AKC, et al. Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A. N Engl J Med. 2024;391(3):235-246. doi:10.1056/NEJMoa2312611
2. Iapoce C. FDA approves first-in-class factor VIII therapy for hemophilia A. HCP Live. February 23, 2023. Accessed July 18, 2024. https://www.hcplive.com/view/fda-approves-first-in-class-factor-viii-therapy-hemophilia-a.
3. Sobi. NEJM publishes ALTUVOCT® Phase 3 XTEND-kids results highlighting treatment potential for children with severe haemophilia a. Sobi. July 18, 2024. Accessed July 18, 2024. https://www.sobi.com/en/press-releases/nejm-publishes-altuvoctr-phase-3-xtend-kids-results-highlighting-treatment-potential-children-severe-haemophilia-2252089.
4. Chowdary P. Bioengineered Factor VIII - More Innovation for Hemophilia A. N Engl J Med. 2024;391(3):277-282. doi:10.1056/NEJMe2313795