Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study.

Background and Purpose: At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months.
Methods: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire.
Results: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n  = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%).
Conclusion: The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings.
Competing Interests: TC is the lead principal investigator of the TOPAZ study; and a consultant and/or advisory board member for AveXis/Novartis, Biogen, Pfizer, and Roche/Genentech. JD has received consulting fees from Biogen, Cytokinetics, Ionis Pharmaceuticals, NGT, Pfizer, Roche, and Sarepta Therapeutics; license fees or royalty payments from Athena Diagnostics; and research funding from Biogen, Cytokinetics, NGT, Roche, Sanofi-Genzyme, and Sarepta Therapeutics. DV reports grants from Biogen during the conduct of the study, Department of Defense, Hope for Children Research Foundation, National Institutes of Health, and Spinal Muscular Atrophy Foundation; and personal fees from AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Roche, and Sarepta. JK was site principal investigator for clinical trials sponsored by Biohaven, Fibrogen, Novartis Gene Therapies, Inc., and Scholar Rock. EM is a primary investigator and advisory board/consultant for Biogen, Epirium, Novartis, Roche, and Scholar Rock; and has grants to the institution from Biogen, Novartis, and Roche. AN receives honoraria for counseling and invited talks from F. Hoffmann-La Roche, Ltd., Biogen, Novartis, Pfizer, PTC Therapeutics, Sarepta Therapeutics, Inc., Scholar Rock, and UCB Pharma. AP is an advisory board member and consultant for Scholar Rock and has served as an ad hoc scientific advisory board member for AveXis/Novartis Gene Therapies and Roche/Genentech. ESM has received consulting fees from Biogen, Novartis, Roche, and Scholar Rock. TD is an advisory board member for Biogen, CureSMA, Novartis, Roche, and Scholar Rock; and a consultant for Astellas, Avidity, Biohaven, Dyne, Genentech, Novartis, Roche, and Sarepta Therapeutics. GS, JM, DY, and LL are all full-time employees of Scholar Rock. SB was a full-time employee of Scholar Rock at the time of the study. BD has served as an ad hoc scientific advisory board member for AveXis/Novartis Gene Therapies, Biogen, Pfizer, Roche/Genentech, Sarepta Therapeutics, and Vertex; steering committee chair for Roche FIREFISH and MANATEE studies and DSMB member for Amicus Inc. and Lexeo Therapeutics; he has no financial interests in these companies. He has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund; received grants from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, and CS2/CS12 studies; from Biogen for CS11; and from AveXis, Fibrogen, Novartis (AveXis), PTC Therapeutics, Roche, Sarepta Pharmaceuticals, and Scholar Rock; and has received royalties for books and online publications from Elsevier and UpToDate, Inc. The authors declare that this study received funding from Scholar Rock, Inc. In collaboration with the academic authors, the funder was involved in the study design, data collection and analysis, interpretation of data, decision to publish, and the preparation of the manuscript. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Crawford, Day, De Vivo, Krueger, Mercuri, Nascimento, Pasternak, Mazzone, Duong, Song, Marantz, Baver, Yu, Liu and Darras.)