HPN Symposium

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Poster · Rare Neurological Disorders

Impact of baseline characteristics on apitegromab efficacy in patients with spinal muscular atrophy

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Eugenio Mercuri1, Laurent Servais2, Sabrina W. Yum3, Heike Kölbel4, Astrid Pechmann5, Giovanni Baranello6,7, Mariacristina Scoto7, Anne-Marie Childs8, Randal Richardson9, Andrej Marich10, Tracy Copeland10, Thomas Brown10, Mouhamed Gueye10, Guolin Zhao10, Giridhar S. Tirucherai10, Jing L. Marantz10

  1. 1 Centro Clinico Nemo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Neuropsichiatria Infantile Paediatric Neurology Unit, Catholic University, Rome, Italy
  2. 2 Department of Paediatrics, MDUK Oxford Neuromuscular Centre and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; Department of Paediatrics, Neuromuscular Reference Centre, University Hospital of Liège, Liège, Belgium
  3. 3 Departments of Pediatrics and Neurology, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
  4. 4 Department of Pediatric Neurology, Centre for Neuromuscular Disorders, University Hospital Essen, Essen, Germany
  5. 5 Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  6. 6 University College London, London, UK
  7. 7 Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
  8. 8 Leeds Teaching Hospitals Trust, Leeds, UK
  9. 9 Pediatric Neurology, Gillette Children's Specialty Healthcare, St Paul, MN;
  10. 10 Scholar Rock, Cambridge, MA

Background: Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by irreversible motor neuron degeneration and progressive skeletal muscle atrophy and weakness. Many patients on survival motor neuron (SMN)-targeted treatment have significant remaining unmet needs, and due to the nature of SMA the improvement seen may attenuate over time. To address these unmet needs, muscle-targeted treatments are under development in clinical trials. Apitegromab is an investigational monoclonal antibody that selectively inhibits activation of myostatin, a negative regulator of muscle growth, leading to increased muscle mass and improved motor function. Here we present clinical evidence supporting the efficacy of apitegromab across broad populations of patients living with SMA.

Methods: Baseline concentrations of latent myostatin, the therapeutic target for apitegromab, were assessed for all study participants. Target engagement and clinical efficacy of apitegromab were analyzed across baseline characteristics, including latent myostatin concentration, motor function status as assessed by the Hammersmith Functional Motor Scale–Expanded (HFMSE) scale, and age, using data from the Phase 3 SAPPHIRE (NCT05156320) study with supportive data from the Phase 2 TOPAZ (NCT03921528) study.

Results: At baseline, latent myostatin concentrations were measurable for all patients with SMA enrolled in SAPPHIRE (N=188; non-ambulatory, aged 2-21 years), and were generally similar regardless of disease severity, as determined by HFMSE score, or age group (2-12 vs 13-21 years). To assess results across disease severity, study participants were separated into tertiles of baseline latent myostatin concentration (as latent myostatin is produced by and mainly resides in skeletal muscle, its concentration can serve as an approximation of muscle mass). Total latent myostatin, a reliable pharmacodynamic marker, increased following apitegromab administration through 52 weeks in all baseline latent myostatin tertiles, indicating effective target engagement across groups. Least squares mean (LSM) changes from baseline to week 52 in HFMSE score mirrored the pharmacodynamic effect, favoring apitegromab vs placebo regardless of baseline latent myostatin tertile, with LSM differences (95% CI) of 1.2 (-0.86, 3.20), 2.5 (-0.29, 5.21), and 1.5 (-1.01, 3.96) points. Similarly, changes from baseline in motor function favored apitegromab vs placebo across all baseline HFMSE score tertiles. Furthermore, effective target engagement was observed in ambulatory patients with SMA enrolled in TOPAZ (n=12). Over the course of 4 years, increases in total latent myostatin concentration were sustained and associated with functional stability on the Revised Hammersmith Scale, with a mean (95% CI) change from baseline of -0.2 (-4.3, 3.9) points. In SAPPHIRE, effective target engagement was also observed across age groups. Changes from baseline to week 52 in motor function as assessed by the HFMSE favored apitegromab across age groups; LSM differences (95% CI) vs placebo were 1.8 (0.3, 3.32) and 1.8 (-1.06, 4.57) points for the 2-12- and 13-21-year-old age groups, respectively.

Conclusion: Clinical studies demonstrated consistent evidence of measurable therapeutic target as well as effective target engagement and motor function benefit with apitegromab across the SMA disease spectrum. These results demonstrate that apitegromab efficacy is broadly applicable across all patients living with SMA, regardless of disease severity or age.