Genentech’s Risdiplam Shows Significant Improvement in Survival and Motor Milestones in Infants With Type 1 Spinal Muscular Atrophy (SMA)
South San Francisco, CA -- April 27, 2020 -- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), 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; p<0.0001) 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%) infants 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.
“These results confirm the clinically meaningful efficacy of risdiplam in infants with an advanced and difficult-to-treat disease,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “We thank the SMA community for their partnership and especially the 62 families from around the world who participated in Parts 1 and 2 of the FIREFISH study.”
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 (in lieu of an in-person event). Genentech leads the clinical development of risdiplam, an investigational, orally administered survival motor neuron-2 (SMN-2) splicing modifier for SMA, as part of a collaboration with the SMA Foundation and PTC Therapeutics.
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.
“These results are particularly encouraging given the median age at enrollment was 5.3 months, so these infants already had progressed disease,” said Professor Laurent Servais, FIREFISH investigator and Professor of Paediatric Neuromuscular Diseases at the MDUK Oxford Neuromuscular Centre. “Maintaining the ability to swallow is particularly important as it helps infants to feed and suggests risdiplam has a major effect on bulbar function.”
Safety for risdiplam in the FIREFISH study was consistent with its previously reported safety profile and no new safety signals were identified. The most common adverse events (AE) were upper respiratory tract infection (46.3%), pneumonia (39%), pyrexia (39%), constipation (19.5%), nasopharyngitis (12.2%), rhinitis (12.2%) and diarrhea (9.8%). The most common serious adverse events were pneumonia (31.7%), bronchiolitis (4.9%), respiratory failure (4.9%) and hypotonia (4.9%).
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.
In November 2019, the U.S. Food and Drug Administration granted Priority Review for risdiplam with an expected decision on approval by August 24, 2020.
Spinal muscular atrophy (SMA) is a severe, inherited, progressive neuromuscular disease that causes devastating muscle atrophy and disease-related complications. It is the most common genetic cause of infant mortality and one of the most common rare diseases, affecting approximately one in 11,000 babies. SMA leads to the progressive loss of nerve cells in the spinal cord that control muscle movement. Depending on the type of SMA, an individual’s physical strength and their ability to walk, eat or breathe can be significantly diminished or lost.
SMA is caused by a mutation in the survival motor neuron-1 (SMN-1) gene that results in a deficiency of SMN protein. SMN protein is found throughout the body and increasing evidence suggests SMA is a multi-system disorder and the loss of SMN protein may affect many tissues and cells, which can stop the body from functioning.
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.
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.
About Genentech in neuroscience
Neuroscience is a major focus of research and development at Genentech and Roche. The company’s goal is to develop treatment options based on the biology of the nervous system to help improve the lives of people with chronic and potentially devastating diseases. Genentech and Roche have more than a dozen investigational medicines in clinical development for diseases that include multiple sclerosis, spinal muscular atrophy, neuromyelitis optica spectrum disorder, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and autism.
Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.
Posted: April 2020