Genentech, a member of the Roche Group, has announced positive two-year data from the RAINBOWFISH trial, demonstrating that early intervention with Evrysdi (risdiplam) significantly improves motor milestones in infants with pre-symptomatic spinal muscular atrophy (SMA). The Phase II study assessed the efficacy and safety of Evrysdi in children treated before six weeks of age.
The Rainbowfish trial (NCT03779334) enrolled babies aged from birth to six weeks who had not yet shown symptoms of SMA. The results, presented at the World Muscle Society (WMS) Congress 2024, revealed that after two years of Evrysdi treatment, all 26 children were able to swallow and feed orally, and none required permanent ventilation. This is a stark contrast to untreated Type 1 SMA, where children typically do not reach these milestones and rarely survive past two years, according to natural history studies.
Cognitive development was also evaluated using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), and was found to be comparable to babies without SMA. Genentech noted that this is the first clinical trial in SMA to assess cognitive skills as an exploratory endpoint using a standardized scale.
Laurent Servais, M.D., Ph.D., Professor of Paediatric Neuromuscular Diseases at the MDUK Oxford Neuromuscular Centre, emphasized the importance of early intervention: “In children with SMA, motor neuron degeneration starts before the onset of symptoms, so time is of the essence if we hope to preserve muscle function. It’s heartening to see that through early intervention with Evrysdi these children have achieved important milestones like sitting, standing and walking that would typically be unattainable without treatment.”
Detailed Motor Milestone Achievements
The study further highlighted that all children with three or more SMN2 copies (n=18) achieved standing and walking (100%) milestones, as assessed by BSID-III and Hammersmith Infant Neurological Examination, Module 2 (HINE-2). Most of these children reached these milestones within the World Health Organization (WHO) windows of typical child development. Among children with two SMN2 copies (n=5), all could sit (100%), and most could stand and walk (60%) independently after two years of treatment.
Safety and Tolerability
The safety profile of Evrysdi in the Rainbowfish trial was consistent with previous studies. There were no deaths or adverse events (AEs) leading to withdrawal or treatment discontinuation. The most common AEs included teething, gastroenteritis, diarrhea, eczema, and pyrexia, which were considered more reflective of age than the underlying SMA.
Implications for SMA Treatment
Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development, commented on the broader implications of the findings: “These two-year findings confirm the potential of early intervention with Evrysdi to meaningfully improve the lives of children with SMA. Working in tandem with newborn screening programs, Evrysdi is the only non-invasive SMA treatment that can be administered during a child’s first hours of life.”
Evrysdi, an oral survival motor neuron 2 (SMN2) splicing modifier, targets mutations in chromosome 5q, which are implicated in survival motor neuron (SMN) protein deficiency. It is approved by the US Food and Drug Administration (FDA) to treat SMA in patients of all ages, including infants under two months with Type 1, Type 2, or Type 3 SMA, or those with one to four SMN2 copies. Evrysdi generated CHF 1.4bn ($1.64bn) in 2023 for Genentech, with projections estimating $2.8bn in revenue by 2030.
Competitive Landscape
Evrysdi faces competition from Biogen’s Spinraza (nusinersen) and Novartis’ gene therapy Zolgensma (onasemnogene abeparvovec). Spinraza, approved in 2016, is projected to generate $1.13bn in 2030, less than Evrysdi, due to Evrysdi's favorable oral delivery compared to Spinraza's intrathecal administration. Zolgensma, a one-time infusion gene therapy, delivers a working copy of the SMN gene but faces challenges related to its invasive nature, cost, and accessibility.
