Taryn Berger,¹ Thomas O. Crawford,² Basil T. Darras,³ Laurent Servais,⁴ Jena Krueger,⁵ Heike Heike Kölbel,⁶ Andreea Seferian,⁷ Claude Cances,⁸ Nancy Kuntz,⁹ Richard S. Finkel,¹⁰ Bert Yao,¹ Jose Rossello¹, Guolin Zhao,¹ Guochen Song,¹ Jing L. Marantz,¹ Eugenio Mercuri¹¹

¹ Scholar Rock, Inc., Cambridge, MA, USA

² Department of Neurology, Johns Hopkins Medical, Baltimore, MD, USA

³ Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

⁴ Department of Pediatrics, University of Oxford, Headington, Oxford, UK

⁵ Helen DeVos Childrens Hospital Neurology-Grand Rapids, Grand Rapids, MI, USA

⁶ Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany

⁷ Institut de Myologie, I-Motion Clinical Trials Platform, Paris, France; APHP, Pediatric Neurology Department, Hôpital Armand Trousseau, Centre Référent pour les Maladies Neuromusculaires Nord/Est/Ile de France, Paris, France; APHP, Pediatric Neurology and ICU Department, Université Paris Saclay, DMU Santé de l’Enfant et de l’Adolescent, Hôpital Raymond Poincaré, Garches, France

⁸ AOC (Atlantic-Oceania-Caribbean) Reference Centre for Neuromuscular Disorders, Paediatric Clinical Research Unit/Paediatric Multi-Thematic Module CIC 1436, Neuropaediatric Department, Toulouse University Hospital, Toulouse, France

⁹ Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

¹⁰ Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA

¹¹ Centro Clinico Nemo, U.O.C. Neuropsichiatria Infantile Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Pediatric Neurology Unit, Catholic University, Rome, Italy

SAPPHIRE (NCT05156320), a double-blind, global, placebo-controlled phase 3 trial, assessed apitegromab, a muscle-targeted treatment, in patients with nonambulatory SMA receiving SMN-targeted treatment (nusinersen/risdiplam). Patients aged 2-12y were randomized 1:1:1 to receive apitegromab 20 (n=53) or 10mg/kg (n=53) or placebo (n=50) Q4W; patients aged 13-21y were randomized 2:1 to receive apitegromab 20mg/kg (n=22) or placebo (n=10). Change from baseline (CFB) in HFMSE score was the primary efficacy endpoint. Secondary endpoints included additional motor outcomes, PK/PD, and safety. Overall, 188 patients enrolled (2-12y, n=156; 13-21y, n=32). The primary endpoint was achieved; motor function outcomes were significant and clinically meaningful. At 12mo, LSM difference (SE) in HFMSE CFB was 1.8 (0.76; P=0.0192) for apitegromab (2-12y, combined dose) vs placebo. LSM (SE) difference in HFMSE CFB for apitegromab 20 and 10mg/kg vs placebo was 1.4 (0.88, P=0.1149) and 2.2 (0.87, nominal P=0.0121). Total latent myostatin levels were superimposable for each apitegromab dose, suggesting target saturation. AEs were consistent with underlying SMA and SMN treatment. No patients discontinued due to AEs. Apitegromab provided significant improvements in motor function and was well-tolerated.