Background: SMN-targeted DMTs are standard-of-care for patients with SMA. Despite a general paucity of supporting data, various combination treatment scenarios are observed in real-world practice. No systematic approach has been proposed to classify these various treatment scenarios to facilitate analyses that will clarify potential risk/benefit differences between treatment regimens, including DMT scenarios with lifetime durability. Relative prevalence of different regimens is also poorly understood.
Objective: We sought to devise a rational, systematic, broadly applicable approach for defining and grouping SMA treatment scenarios that will facilitate future analyses aimed at exploring potential differences in clinical outcomes
Methods: Consensus definitions were developed by a group of neuromuscular experts representing a broad geographic range and varied clinical practice settings.
Results: Our proposed treatment classification is primarily based on a two-part differentiation: initial therapy received (onasemnogene abeparvovec [OA] or SMN2 splicing modifier), and persistence or discontinuation of subsequent DMT(s). This results in six treatment categories: Add-on, Transient Add-on, Combination with OA, Switching, Bridging, and Nusinersen/Risdiplam Combinations. Because OA is a one-time therapy that provides ongoing SMN protein expression, any treatment administered after initial OA is deemed Add-on. Add-on treatment to OA that is discontinued is deemed Transient. Bridging and Switching are distinguished based on duration of therapy with initial SMN2 splicing modifier. We defined discontinuation as ≥2 consecutive missed doses based on the expected dosing schedule (nusinersen) or no doses within the last 30 days (risdiplam).
Conclusions: We propose a rational convention for defining combination DMT scenarios for patients with SMA that should be applicable to a wide range of investigations. Future analyses will explore rationales for Add-on and Combination treatment, and alignment of stated rationale with patient status at the time of Add-on/Combination initiation. We will also explore clinical outcomes for patients in the RESTORE registry according to these treatment definitions.