RAINBOWFISH: A Study of Risdiplam in Newborns with Presymptomatic Spinal Muscular Atrophy (SMA) (4281)

Objective: To determine the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics of risdiplam in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA). Background: SMA is a severe, progressive, genetic neuromuscular disease caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations of the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein. Risdiplam is a centrally and peripherally distributed oral SMN2 pre-mRNA splicing modifier that increases the levels of functional SMN protein. Risdiplam (EVRYSDI™) has been approved by the FDA for the treatment of patients with SMA, aged 2 months and older. Design/Methods: RAINBOWFISH (NCT03779334) is an open-label, single-arm, multicenter, global clinical study enrolling infants aged from birth–6 weeks of age (at first dose), regardless of SMN2 copy number. Infants will receive risdiplam for 24 months, followed by a 36-month extension. Primary analysis will be conducted at 12 months of treatment in infants with two SMN2 copies and compound muscle action potential (CMAP) amplitude ≥1.5mV at baseline. Results: The primary endpoint is the proportion of infants sitting without support for at least 5 seconds after 12 months of treatment (assessed by the Bayley Scales of Infant and Toddler Development, Third Edition). Secondary endpoints include the development of clinically manifested SMA, survival and permanent ventilation, achievement of motor milestones, motor function, growth measures, nutritional status, CMAP, PK, safety monitoring, and other clinical parameters. The median age at first dose (range) for the first seven enrolled infants was 35 (16–40) days. We will report updated baseline demographics and baseline SMN protein data in enrolled infants with presymptomatic SMA. Additional preliminary data will also be presented. Conclusions: RAINBOWFISH will provide valuable information about the effects of risdiplam treatment at the presymptomatic stage in young infants with SMA. Recruitment for the study is ongoing worldwide. Disclosure: Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AveXis. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Catabasis. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Capricor. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ReveraGen. Dr. Finkel has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Finkel has received research support from AveXis. The institution of Dr. Finkel has received research support from Biogen. The institution of Dr. Finkel has received research support from Capricor. The institution of Dr. Finkel has received research support from Catabasis. The institution of Dr. Finkel has received research support from ReveraGen. The institution of Dr. Finkel has received research support from Roche. The institution of Dr. Finkel has received research support from Scholar Rock. Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. Dr. Finkel has a non-compensated relationship as a advisor with n-Lorem Foundation that is relevant to AAN interests or activities. Dr. Finkel has a non-compensated relationship as a Board Member with Every Life Foundation that is relevant to AAN interests or activities. Dr. Al-Muhaizea has nothing to disclose. Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Michelle Farrar has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Leslie Nelson, PT, MPT, OCS has received personal compensation for serving as an employee of UT Southwestern Medical Center. Leslie Nelson, PT, MPT, OCS has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Leslie Nelson, PT, MPT, OCS has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avexis. Leslie Nelson, PT, MPT, OCS has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Audentes. Leslie Nelson, PT, MPT, OCS has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen, Inc. Leslie Nelson, PT, MPT, OCS has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Manickvasagam Janarthanam has nothing to disclose. Yi Wang has nothing to disclose. Edmar Zanoteli has nothing to disclose. Laura Palfreeman has received personal compensation for serving as an employee of Roche. Muna El-Khairi has received personal compensation for serving as an employee of Roche Products Limited. Dr. Gorni has received personal compensation for serving as an employee of Hoffman La Roche. Heidemarie Kletzl has received personal compensation for serving as an employee of Hoffmann-La Roche. Marianne Gerber has received personal compensation for serving as an employee of Roche. Marianne Gerber has received stock or an ownership interest from F Hoffmann La Roche . Dr. Bertini has nothing to disclose.