Continued Improvements With Risdiplam Seen in 4-Year Analysis of FIREFISH


After 4 years of treatment, more than 95% of infants on risdiplam maintained the ability to swallow, an aspect of everyday life that is commonly lost within 2 years in patients with SMA.

Levi Garraway, MD, PhD, chief medical officer at Genentech and head of Global Product Development

Levi Garraway, MD, PhD

Recently announced long-term data from the pivotal FIREFISH study (NCT02913482) showed continued improvements in infants with spinal muscular atrophy (SMA) treated with risdiplam (Evrysdi; Genentech) for up to 4 years. All treated children who were alive at the time of the primary analysis were still alive after 48 months.1

Among the several ongoing trials of risdiplam, FIREFISH is unique in its 2-part design, Part 1 was a dose escalation study in 21 infants with the primary end point assessing safety and determining the dosing for Part 2. In the single-arm Part 2, 41 infants with SMA type 1, aged 1-7 months, were treated for 2 years, followed by an open-label extension (OLE).

Results of the OLE, presented at the Cure SMA Research & Clinical Care Meeting, held June 28-30, showed that after 4 years of treatment, many of the babies, now young children, continued to improve their ability to sit, stand, and walk without support. A major of the infants included in the OLE (n = 50) maintained their ability to feed by mouth and swallow up to month 48. At the same time point, treated individuals showed either maintained or improved motor function, as demonstrated through the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition and the Hammersmith Infant Neurological Examination 2 (HINE-2) assessments.

"The independence that comes with sitting, standing and walking is transformational for children with SMA, and their families, and we are very encouraged by how these skills increased over four years of Evrysdi treatment for many children in this study," Levi Garraway, MD, PhD, chief medical officer at Genentech and head of Global Product Development, said in a statement. "Nine out of 10 patients in our studies remain on Evrysdi long-term and these data underscore its importance as an option for people with SMA across a broad range of age and disease types."

Risdiplam, the first and only small molecule pre-mRNA splicing modifier that targets survival motor neuron-2 (SMN2), was originally approved in 2020, but later had its indication expanded to include presymptomatic babies under 2 months old with SMA in 2022. With that, it became the first approved treatment administered at home for this patient group. While the decision was based mainly off interim efficacy and safety data from the RAINBOWFISH study (NCT03779334), the approval was also supported by data from the OLE of FIREFISH, which had original 2-year data from Part 2 published in April 2021.2

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Among the infants treated with risdiplam across FIREFISH (n = 58), 37 were able to sit without support for at least 5 seconds at month 48, compared with 35 individuals at month 24. In addition, 36 infants were able to sit witout support for at least 30 seconds at month 48, up from 23 infants at month 24. Between the 2- and 4-year time points, 3 infants gained the ability to stand alone and 1 infant gained the ability to walk alone.

Between the first and fourth 12-month periods, the rate of adverse events (AEs) decreased by 71%, with pyrexia (62%), upper respiratory tract infection (62%), and pneumonia (48%) as the most common AEs observed. Throughout the study, no treatment-related AEs led to treatment discontinuation and the rate of hospitalizations decreased over time. In the 3-year analysis, risdiplam helped decrease the rate of hospitalizations from 1.24 per patient year over 12 months to 0.70 per patient year over 36 months.3

"Evrysdi’s oral route of administration allows the medicine to be distributed throughout the body, systemically increasing SMN protein production, the lack of which is the underlying cause of SMA,” Giovanni Baranello, clinical associate professor in pediatric neurology and neuromuscular disorders, University College London, said in a statement.1 “This has shown to help in delivering a meaningful impact on important functions of daily living including motor milestones, feeding and swallowing, which were maintained or improved in this long-term study, while also offering a tolerable safety profile."

Expanded data from FIREFISH published in August 2021 indicated that the treatment had a significant impact on the primary and secondary end points. Key secondary end points included a score of 40 or higher on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores, an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by HINE-2, and survival without permanent ventilation. These performance criteria were the upper limits of the 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. After 12 months of treatment, 56% (95% CI, 40-72; n = 23) of infants had a CHOP-INTEND score of 40 or higher, as compared with the performance criterion of 17% (<.001). Additionally, 90% (95% CI, 77-97; n = 37) of the cohort had at least a 4-point increase from baseline in such scores, as compared with the performance criterion of 17% (<.001).4

1. Four-year follow-up data for Genentech’s Evrysdi show continued increase in number of children with a severe form of spinal muscular atrophy (SMA) able to sit, stand and walk. News release. June 30, 2023. Accessed July 13, 2023.
2. FDA approves Genentech’s Evrysdi (risdiplam) for use in babies under two months with spinal muscular atrophy (SMA). News release. Genentech. May 31, 2022. Accessed July 13, 2022.
3. New three-year data for Genentech’s Evrysdi (risdiplam) show long-term improvements in survival and motor milestones in babies with type 1 spinal muscular atrophy. News release. Genentech. April 28, 2022. Accessed July 13, 2022.
4. Darras BT, Masson R, Mazurkiewicz-Beldzinska M, Rose K, et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021;385:427-435. doi: 10.1056/NEJMoa2102047
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