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Risdiplam is an orally administered small molecule which encourages the “back-up gene”, SMA 2, to produce functional SMN protein.

SMA Type 1 trial - FIREFISH

FIREFISH is a trial of risdiplam on 21 infants with Type 1 SMA, in 2 phases:

• Part 1: The aim of the first part of this study is to find the optimum dose to administer. Infants with SMA Type 1 survived and achieved key motor milestones after 1 year of treatment, beyond those expected in the natural history of the disease. The motor function of the infants were assessed: results showed that 10 out of 17 infants (58.8%) in the therapeutically dosed group achieved a CHOP-INTEND total score of 40 points or more. Median change from baseline to month 12 in CHOP-INTEND was 17.5 points. The maximum CHOP-INTEND score was 57 points after 12 months treatment, increasing from a maximum of 49 points after 8 months. Among all 21 infants enrolled in Part 1 of the FIREFISH study, the median duration of treatment is 14.8 months, with 19 infants treated for more than 12 months. Three infants experienced fatal complications of their disease after approximately 1, 8, and 13 months of treatment. None of these has been attributed by the investigator as related to risdiplam. No infant has lost the ability to swallow during the study and no infant has required tracheostomy or permanent ventilation. The event-free survival was 18 out of 21 (85.7%) overall and 15 out of 17 (88.2%) in the therapeutically dosed group. The most common adverse events included fever (pyrexia; 52.4%), upper respiratory tract infections (42.9%), diarrhea (28.6%), vomiting (23.8%), cough (23.8%) pneumonia (19.0%) and constipation (19.0%).
• Part 2: In this part of the study, the infants received the dose of risdiplam determined in part 1.

SMA Type 2 or 3 - SUNFISH

SUNFISH is a trial of risdiplam in 51 people with SMA aged from 2 to 25 years. This trial is also in 2 parts:

• Part 1: New data from this dose-finding study of SUNFISH reinforce risdiplam as a promising investigational therapy for people with SMA Type 2 or 3 and no treatment-related safety findings leading to withdrawal were seen to date. The functional status ranged from individuals unable to sit to those capable of walking. Scoliosis ranged from none to severe. As previously reported, a sustained median increase from baseline in SMN protein of greater than two-fold, as measured in blood, was seen after 12 months of treatment with risdiplam. An exploratory efficacy analysis of Part 1 (n=51) of the SUNFISH study assessed motor function. One patient withdrew from the trial during the open-label extension. Among the patients for which the motor assessments have been completed at all visits up to month 12 (n=43), 58% saw an improvement of at least 3 points on the scale from baseline, including 71% among patients 2-11 years old and 42% aged 12-25 years. While Part 1 of the SUNFISH study was not designed or powered to detect efficacy, the change from baseline in total functional score is the primary efficacy endpoint in the ongoing Part 2 (n=180) of the trial. The most common adverse events in this part 1 study were fever (pyrexia; 41%), cough (33%), vomiting (29%), upper respiratory tract infections (26%), persistent sore throat (oropharyngeal pain; 22%) and cold (nasopharyngitis; 20%). The most common serious adverse event that occurred in two of the 51 patients exposed to risdiplam was pneumonia. To date there have been no treatment-related safety findings leading to withdrawal from any study.
• Part 2: Among the infants who received the dose selected from part 1 of the study, 41.2% were able to sit without support for at least 5 seconds, assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III). In addition, 11 (64.7%) infants were able to sit (with or without support) while 9 (52.9%) achieved upright head control after 12 months of treatment as assessed by the Hammersmith Infant Neurological Examination Module 2 (HINE-2). Finally, 1 infant (5.9%) achieved the milestone of standing (supports weight) by this 12-month time point.

The confirmatory Part 2 portions of the SUNFISH and FIREFISH studies have completed enrollment and will conduct their primary efficacy analyses in Q4 2019 and Q1 2020, respectively. Roche is planning to include the new data presented at the AAN Annual Meeting in regulatory filings with the European Medicines Agency during the second half of 2019.