Real-world evidence in spinal muscular atrophy: addressing heterogeneity of populations and treatment comparisons

Summary

In this short correspondence, we comment the recently published article “Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study” (The Lancet–Global Health Europe, https://doi.org/10.1016/j.lanepe.2024.101092). We commend the authors for generating real-world evidence that highlights the importance of rapid access to disease modifying therapy (DMT) for newly diagnosed patients. However, we caution that confirmatory studies are required to better understand the impact of treatment sequences, particularly in the presence of prior DMT exposure. Addressing these issues will ensure that clinical decision-making is based on the most rigorous evidence available.

The study by Weiss et al. recently reported the real-world outcomes of 343 children with Spinal Muscular Atrophy (SMA) treated with gene therapy (GT) using onasemnogene abeparvovec.¹ This study provides real-world evidence on efficacy and safety of treatment for patients whose clinical characteristics extend beyond those observed in clinical trials. Indeed, the authors report the largest cohort to date published, including pre-symptomatic infants identified through newborn screening (23%) and patients with different types of SMA (1–3). However, half of patients in this heterogeneous cohort had received another disease modifying therapy (DMT) prior to GT injection, adding complexity to the analysis. While we acknowledge the authors' efforts to statistically analyse subgroups of patients, we emphasise that the heterogeneity of this population, combined with differences in treatment patterns (including switches), remains a methodological issue when considering the clinical significance in real-world studies.² This raises concerns regarding the clinical interpretation of motor and bulbar outcomes, particularly in patients who have received other DMTs prior to GT administration.

To address this challenge, direct comparisons of bulbar and respiratory effectiveness of each DMT are essential but should be conducted within well-designed comparative studies using methodologies appropriate for cohorts including both incident and prevalent users. Specifically, strategies like inception cohorts, naïve user designs, and matching designs that control for confounding -particularly confounding by indication-would enhance the robustness and validity of the results reported by Weiss et al. Addressing these issues will ensure that clinical decision-making is based on the most rigorous evidence available.

Contributors

All of the authors have contributed equally to this correspondence.

Declaration of interests

No author received financial support for the present manuscript.

JR received honoraria for presentations and/or travel support from Novartis, Roche and Biogen and participated on advisory boards for Novartis, Roche and Biogen.

SQR received honoraria for presentations and/or travel support from Novartis, Roche, Biogen and UCB and participated on advisory boards for Novartis, Roche, Biogen and UCB.

LG has no conflicts of interest to disclose.