RAINBOWFISH: Primary Efficacy and Safety Data in Risdiplam-treated Infants with Presymptomatic Spinal Muscular Atrophy (SMA)
Laurent Servais1, Michelle Farrar2, Richard Finkel3, Dmitry Vlodavets4, Edmar Zanoteli5, Mohammad Al-Muhaizea6, Alexandra Prufer de Queiroz Campos Araújo7, Leslie Nelson8, Birgit Jaber9, Ksenija Gorni10, Heidemarie Kletzl11, Laura Palfreeman12, Eleni Gaki12, Michael Rabbia13, Dave Summers12, Paulo Fontoura10, Enrico Bertini14
1MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, 2Sydney Children’s Hospital Network and UNSW Medicine, UNSW Sydney, 3Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, 4Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, 5Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, 6Department of Neurosciences, King Faisal Specialist Hospital & Research Center-Riyadh, 7Pediatrics Department, Faculty of Medicine, Federal University of Rio de Janeiro, 8Physical Therapy, University of Texas Southwestern Medical Center, 9Pharma Development, Safety, F. Hoffmann-La Roche Ltd, 10PDMA Neuroscience and Rare Disease, F. Hoffmann-La Roche Ltd, 11Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, 12Roche Products Ltd, 13Genentech, Inc., 14Research Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children’s Research Hospital IRCCS
Objective:

To assess the efficacy and safety of risdiplam (EVRYSDI®) in infants with presymptomatic spinal muscular atrophy (SMA).

Background:

In patients with SMA, motor neuron degeneration begins before symptom onset, due to a deficiency of survival of motor neuron (SMN) protein. Risdiplam is an oral SMN2 pre-mRNA splicing modifier that increases and sustains functional SMN protein levels.

Design/Methods:

RAINBOWFISH (NCT03779334) is an open-label, single-arm, multicenter study of risdiplam in infants with genetically diagnosed, presymptomatic SMA. The primary endpoint was the proportion of infants with two SMN2 copies and baseline ulnar CMAP amplitude ≥1.5 mV, who were able to sit without support for ≥5 seconds at Month 12 (Item 22, Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, third edition). Secondary endpoints include motor milestone achievement; motor function; nutritional status; growth measures; survival and permanent ventilation; CMAP; development of clinically manifested SMA; and safety monitoring.

Results:

The median age at first risdiplam dose was 25.0 (range 16−41) days (n=26). The primary endpoint at Month 12 was met, with 80% of infants (n=5) able to sit without support for ≥5 seconds. Additionally, 7/8 infants with two SMN2 copies were able to sit without support for ≥30 seconds, including all infants with CMAP amplitude <1.5 mV (n=3). At Month 12, all infants were alive without permanent ventilation and no adverse events (AEs) led to withdrawal or treatment discontinuation. Most AEs were not considered treatment-related and resolved over time. One infant met the criteria for development of clinically manifested SMA. At Month 12, 24/26 infants (92%) were able to sit without support, and many were able to stand (21/26 [81%]) and walk (16/26 [62%]), as assessed by the Hammersmith Infant Neurological Examination, Module 2.

Conclusions:

RAINBOWFISH is ongoing globally to provide additional data on the efficacy and safety of risdiplam in infants with presymptomatic SMA.

10.1212/WNL.0000000000205694