Genentech, a member of the Roche Group, today presented 1-year data from FIREFISH Part 2, a pivotal global study evaluating risdiplam in infants aged 1-7 months old with symptomatic Type 1 spinal muscular atrophy (SMA). The study met its primary endpoint with 29% of infants (12/41) sitting without support for 5 seconds by month 12, as assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III). No infants achieve this milestone in the natural history of Type 1 SMA. In addition, 18 (43.9%) infants were able to hold their head upright, 13 (31.7%) were able to roll to the side, and 2 (4.9%) were able to stand with support, as measured by the Hammersmith Infant Neurological Examination 2 (HINE-2). Safety for risdiplam in the FIREFISH study was consistent with its known safety profile.
The data were selected for the 72nd American Academy of Neurology (AAN) Annual Meeting and will be made available online via virtual presentation in the coming weeks. At the time of analysis, the median duration of treatment was 15.2 months and the median age was 20.7 months. 93% (38/41) of infants were alive and 85.4% (35/41) were event-free. Without treatment, the median age of death or permanent ventilation was 13.5 months in a natural history cohort. Three infants experienced fatal complications of their disease within the first three months of treatment. None of these has been attributed by the investigator as related to risdiplam. 90% (37/41) had a Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score increase of at least 4 points, with 56% (23/41) achieving a score above 40; the median increase was 20 points. Without treatment, infants with Type 1 SMA show a decrease in CHOP-INTEND scores over time.
In an exploratory endpoint, 95% of infants who were alive at 12 months (36/38) maintained the ability to swallow and 89% (34/38) were able to feed orally. In contrast, in a natural history cohort, all infants with Type 1 SMA older than 12 months required feeding support.
Risdiplam is being studied in a broad clinical trial program in SMA, with patients ranging from birth to 60 years old, and includes pre-symptomatic patients and those previously treated with other SMA-targeting therapies. The clinical trial program was designed to represent the broad, real-world spectrum of people living with this disease with the aim of ensuring access for all appropriate patients.
Risdiplam is an investigational survival motor neuron-2 (SMN-2) splicing modifier for SMA and is an orally administered liquid. It is designed to increase and sustain SMN protein levels both throughout the central nervous system and in peripheral tissues of the body. It is being evaluated for its potential ability to help the SMN-2 gene produce more functional SMN protein throughout the body. Roche and Genentech are leading the clinical development of risdiplam in collaboration with the SMA Foundation and PTC Therapeutics. Risdiplam is currently being evaluated in four multicenter trials in people with SMA:
- FIREFISH (NCT02913482) – an open-label, two-part pivotal clinical trial in infants with Type 1 SMA. Part 1 was a dose-escalation study in 21 infants. The primary objective of Part 1 was to assess the safety profile of risdiplam in infants and determine the dose for Part 2. Part 2 is a pivotal, single-arm study of risdiplam in 41 infants with Type 1 SMA treated for 24 months, followed by an open-label extension. Enrollment for Part 2 was completed in November 2018. The primary objective of Part 2 is to assess efficacy as measured by the proportion of infants sitting without support after 12 months of treatment, as assessed in the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III) (defined as sitting without support for 5 seconds).
- SUNFISH (NCT02908685) – SUNFISH is a two part, double-blind, placebo controlled pivotal study in people aged 2-25 years with Types 2 or 3 SMA. Part 1 (n=51) determined the dose for the confirmatory Part 2. Part 2 (n=180) evaluated motor function using total score of Motor Function Measure 32 (MFM-32) at 12 months. MFM-32 is a validated scale used to evaluate fine and gross motor function in people with neurological disorders, including SMA. The study met its primary endpoint.
- JEWELFISH (NCT03032172) – an open-label exploratory trial in people with SMA aged 6 months-60 years who have been previously treated with SMA-directed therapies. The study has completed recruitment (n=174).
- RAINBOWFISH (NCT03779334) – an open-label, single-arm, multicenter study, investigating the efficacy, safety, pharmacokinetics and pharmacodynamics of risdiplam in babies (~n=25), from birth to 6 weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. The study is currently recruiting.