Real-world outcomes in patients with spinal muscular atrophy treated with onasemnogene abeparvovec monotherapy: findings from the RESTORE Registry

Abstract: Background:
Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials.

Objective:
We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting.

Methods:
RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources.

Results:
Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0–6) month and at onasemnogene abeparvovec infusion was 3 (1–10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related.

Conclusion:
These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

INTRODUCTION
Spinal muscular atrophy (SMA) is a rare, debilitating neuromuscular disease characterized by loss of motor neurons, leading to progressive weakness and atrophy of skeletal and bulbar muscles [1–8]. Although almost all cases of SMA have the same underlying genetic cause —a biallelic deletion or mutation in the survival motor neuron 1 (SMN1) gene —clinical severity is heterogeneous, with varying copy number of the SMN2 “backup” gene being strongly correlated with disease onset and severity as an important phenotypic modifier of SMA. Historically, SMA phenotype has been classified by five clinical types based on the age at onset and maximum motor function ranging from type 0 (most severe with prenatal onset) to type 4 (less severe with later onset) [3, 4, 6, 12–14]. SMA type 1 (severe with onset during the first 6 months of life) is the most common phenotype, accounting for approximately 60% of SMA cases [1, 6, 8, 9, 15, 16]. Because SMA type is based on maximum motor function achieved by untreated patients, it does not take into account the more recent changes in disease phenotype caused by administration of disease-modifying treatments (DMTs).

SMA has long been cited as the leading genetic cause of infant mortality, with natural history studies of SMA type 1 reporting nearly all patients (90%) dying or requiring permanent ventilation by 2 years of age with supportive treatment only [9, 15, 17–20]. However, prognoses have improved markedly in recent years, mainly owing to the advent of DMTs. The first of these, nusinersen, became available for the treatment of SMA in 2016. Nusinersen is an intrathecally administered antisense oligonucleotide that alters the splicing of SMN2 to increase the amount of functional SMN protein produced. An oral SMN2 splicing modifier, risdiplam, became available in 2020. In 2019, the US Food and Drug Administration approved onasemnogene abeparvovec, a one-time, intravenous, adeno-associated virus 9 (AAV9) vector-based gene replacement therapy that delivers a fully functional copy of the human SMN1 cDNA into target cells. Since then, onasemnogene abeparvovec has been approved for the treatment of SMA by the European Medicines Agency and in many other countries.

Knowledge of these new treatments for SMA has been largely based on interventional trial data, which is limited most notably by narrow eligibility criteria and limited follow-up duration. In onasemnogene abeparvovec clinical studies, which included patients with SMA type 1 who had two or three copies of SMN2, almost all of whom were younger than 6 months of age at infusion (mean age range, 0.5–7.9 months), and presymptomatic infants with either two or three copies of SMN2 at risk for developing SMA type 1 or SMA types 2 or 3, respectively, gene therapy administration resulted in longer survival (free from permanent ventilation), achievement of motor milestones, and improved motor function, especially for patients treated earlier, or in the prodromal phase of the disease [27, 31–34]. The inclusion criteria for these onasemnogene abeparvovec clinical trials were defined based on the need to produce robust evidence of clinical efficacy within the duration of the clinical trial setting; however, the real-world use of onasemnogene abeparvovec also targets patients with different criteria from those of the clinical trials [27, 31–34]. Because the approved indication for onasemnogene abeparvovec is broader than the study population upon which initial approval was based [26, 27], real-world evidence became especially important shortly after the approval of onasemnogene abeparvovec. In addition, long-term safety and durability data could not be obtained in the course of the onasemnogene abeparvovec clinical studies [27, 31–34], and long-term extension studies will fill this data gap.

Published real-world evidence to date, which mostly consists of individual case reports, small case series, and single-center experiences, has contributed a limited amount of clinical information to the body of knowledge that assists clinicians and caregivers with treatment decisions and guides therapeutic expectations for SMA patients receiving DMTs [40–46]. Therefore, additional long-term, real-world data that are more reflective of the broader SMA patient population are needed to fill this knowledge gap and characterize the effectiveness and safety of these DMTs and to guide treatment decisions.

RESTORE is an ongoing, prospective, multinational, multicenter, observational disease registry assessing real-world treatment patterns and outcomes for patients with SMA, with the goal of informing treatment decisions and improving patient outcomes [47]. The RESTORE registry was designed to augment data from existing SMA registries [38, 50–54] by providing important information about the clinical course of SMA for patients receiving DMTs that were not available as treatment options when earlier SMA patient registries were created. To enhance data from long-term extensions of completed and ongoing clinical trials and existing real-world study data, we describe patients with SMA treated with onasemnogene abeparvovec monotherapy from the RESTORE registry, including patient demographics and clinical characteristics and real-world effectiveness and safety outcomes

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Journal of neuromuscular diseases. - 11, 2 (2024) , 425-442, ISSN: 2214-3602

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2024
• Urheber: Servais, Laurent ; Day, John W. ; De Vivo, Darryl C. ; Kirschner, Janbernd ; Mercuri, Eugenio ; Muntoni, Francesco ; Proud, Crystal M. ; Shieh, Perry B. ; Tizzano, Eduardo F. ; Quijano‐Roy, Susana ; Desguerre, Isabelle ; Saito, Kayoko ; Faulkner, Eric ; Benguerba, Kamal ; Raju, Dheeraj ; LaMarca, Nicole ; Sun, Rui ; Anderson, Frederick A. ; Finkel, Richard S.

Weitere Informationen

• DOI: 10.3233/jnd-230122
• URN: urn:nbn:de:bsz:25-freidok-2440667
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 11:00 MESZ