Risdiplam Demonstrates 3-Year Safety, Improved Motor Function in Spinal Muscular Atrophy


Over the 36-month period of the FIREFISH study and its extension, treatment with risdiplam (Evrysdi; Genentech) resulted in decreased rate of adverse events, serious adverse events, and number of hospitalizations.

Levi Garraway, MD, PhD

Levi Garraway, MD, PhD

Treatment with risdiplam (Evrysdi; Genentech), an FDA-approved agent for spinal muscular atrophy (SMA), was found to be safe and resulted in high rates of infants remaining alive at 3 years, according to newly announced data from the pivotal FIREFISH study (NCT02913482) and its open-label extension. Infants on the study drug showed continued improvement or maintained motor functions, including the ability to swallow, sit without support, stand with support, and walk while holding on, between 2 and 3 years of treatment.1

In total, 91% of infants (n = 58) on risdiplam were alive after 3 years of treatment. Among the 48 infants who had an available motor assessment, 32 infants maintained and 4 gained the ability to sit without support for at least 5 seconds since month 24, as assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development-III (BSID-III).

"These long-term results in babies treated with Evrysdi are very encouraging, with the vast majority improving or maintaining motor functions after three years. Without treatment, they would typically not survive beyond two years of age,” Levi Garraway, MD, PhD, chief medical officer, and head, Global Product Development, Genentech, said in a statement.1 "Support for the compelling efficacy of Evrysdi continues to grow for a broad range of people, including infants with one of the most severe forms of SMA."

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 type 1 SMA were treated for 2 years, followed by an open-label extension. Original 2-year data from Part 2 were published in April 2021, with expanded results released in August 2021.

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The new results pooled participants treated with risdiplam for a minimum of 3 years. At the conclusion of the analysis, 20 infants maintained and 15 gained the ability to sit without support for at least 30 seconds. No infant who gained the ability to sit without support lost this ability after 3 years, and the majority of infants maintained the ability to feed orally and swallow up to that time point.

Using the Hammersmith Infant Neurological Examination 2 (HINE-2) scores, most risdiplam-treated infants showed the ability to improve or maintain measures between 24 and 36 months. This included being able to hold their heads upright (36 maintained, 3 gained, and none lost the ability since month 24), pivot while siting (15 maintained, 11 gained, and none lost the ability), stand with support (6 maintained, 5 gained, and 1 lost the ability), and walk while holding on (1 maintained, 2 gained, and none lost the ability).

Risdiplam, a survival motor neuron 2 splicing modifier, helped decrease the rate of hospitalizations from 1.24 per patient year over 12 months to 0.70 per patient year over 36 months. Notably, no additional deaths occurred since the primary analysis of FIREFISH, up to the data cut-off of this analysis (November 23, 2021). Pyrexia (60%), upper respiratory tract infection (57%), pneumonia (43%), constipation (26%), nasopharyngitis (24%), diarrhea (21%), rhinitis (19%), vomiting (19%), and cough (17%) were among the most common adverse events (AEs) observed. The rate of serious AEs, which was led by pneumonia (36%), respiratory distress (10%), and viral pneumonia (9%), among others, decreased by approximately 50% after each 12-month treatment period and by 78% between the first and third year of treatment.

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).2

1. 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 May 3, 2022. https://www.gene.com/media/press-releases/14950/2022-04-28/new-three-year-data-for-genentechs-evrys
2. 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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