Combination Disease-modifying Treatment (DMT) in Spinal Muscular Atrophy (SMA): A Proposed Classification for Future Analyses


Clinical Management

Poster Number: 104


Crystal Proud, PhD, Children’s Hospital of The King’s Daughters, Eugenio Mercuri, MD, PhD, Department of Paediatric Neurology and Nemo Clinical Centre, Catholic University, Richard Finkel, MD, St. Jude Children's Research Hospital, Janbernd Kirschner, PhD, University Medical Center Freiburg, Darryl C. De Vivo, MD, Columbia University Irving Medical Center, Francesco Muntoni, MD, UCL Institute of Child Health and Great Ormond Street Hospital for Children, Kayoko Saito, MD, PhD, Institute of Medical Genetics, Tokyo Women’s Medical University, Eduardo Tizzano, MD, PhD, Hospital Vall d'Hebron, Isabelle Desguerre, MD, PhD, Hôpital Necker Enfants Malades, APHP, Susana Quijano-Roy, MD, Garches Neuromuscular Reference Center, APHP Raymond Poincare University Hospital, Nicole Gusset, MSc, PhD, SMA Schweiz; SMA Europe, Kamal Benguerba, MD, MSc, Novartis Gene Therapies Switzerland GmbH, Dheeraj Raju, PhD, Novartis Gene Therapies, Inc., Eric Faulkner, MPH, Novartis Gene Therapies, Inc., Laurent Servais, MD, MDUK, Oxford, UK

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.