Genentech's Risdiplam Showed Significant Improvement in Motor Function in People Aged 2-25 With Type 2 or 3 Spinal Muscular Atrophy

– First placebo-controlled trial to include adults with SMA demonstrates risdiplam improved or stabilized motor function –

– Medically-meaningful and statistically significant results in primary and key secondary endpoints –

– Pivotal SUNFISH Part 2 study population represents broad, real-world spectrum of people living with SMA –

Genentech, a member of the Roche Group (RO ROG,RHHBY, today presented 1-year data from the pivotal Part 2 of SUNFISH, a global placebo-controlled study evaluating risdiplam in people aged 2-25 years with Type 2 or 3 spinal muscular atrophy (SMA). The study showed that change from baseline in the primary endpoint of the Motor Function Measure 32 scale (MFM-32)* was significantly greater in people treated with risdiplam, compared to placebo (1.55 point mean difference; p=0.0156). The Revised Upper Limb Module (RULM),** a key secondary endpoint, also showed an improvement (1.59 point difference; p=0.0028). Safety for risdiplam in the SUNFISH study was consistent with its known safety profile. Data were presented at the 2nd International Scientific and Clinical Congress on Spinal Muscular Atrophy from February 5-7 in Evry, France.

As anticipated, exploratory subgroup analyses showed that the strongest responses in MFM-32 versus placebo were observed in the youngest age group (2-5 years) (78.1% vs. 52.9% achieving ≥3 point increase). Importantly, disease stabilization was observed in the 18-25 years age group (57.1% vs. 37.5%, with stabilization defined as a ≥0 point increase), which is the goal of treatment for those with more established disease.

"Risdiplam is the first potential treatment to have pivotal placebo-controlled data in a broad population of patients, including children, teenagers and adults," said SUNFISH principal investigator Eugenio Mercuri, M.D., Ph.D., Department of Pediatric Neurology, Catholic University, Rome, Italy. "The data suggest that risdiplam can preserve and potentially enable greater independence through improved motor function in people with Type 2 or non-ambulant Type 3 SMA."

Safety for risdiplam in the SUNFISH study was consistent with its known safety profile and no new safety signals were identified. The adverse event profile was similar to placebo. The most common adverse events were upper respiratory tract infection (31.7%), nasopharyngitis (25.8%), pyrexia (20.8%), headache (20%), diarrhea (16.7%), vomiting (14.2%) and cough (14.2%). While the rate of lower respiratory tract infections overall was similar in both treatment arms (risdiplam 19%, placebo 20%), serious lower respiratory tract infections occurred in more patients in the risdiplam group (risdiplam 10%, placebo 2%) but were reported as unrelated and resolved without change to study treatment. To date, more than 400 patients have been treated with risdiplam across all studies, with no treatment-related safety findings leading to study withdrawal in any risdiplam trial.

"We are very encouraged by the positive results in this broad group of SMA patients, many of whom are under-served and under-represented in clinical trials," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "This study has helped us understand which measurement scales are the most relevant for patients, as well as the importance of stabilization in people with more established disease."

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. Risdiplam is being studied in a broad clinical trial program in SMA, with patients ranging from birth to 60 years old, and includes patients previously treated with SMA-targeting therapies. The clinical trial population represents 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 May 24, 2020.

*MFM-32 is a validated scale used to evaluate fine and gross motor function in people with neurological disorders, including SMA. It assesses 32 different motor functions from standing and walking to the use of hands and fingers.

**RULM is a scale designed to assess upper limb movement in people with SMA. It can capture progressive muscle weakness across the spectrum of the disease, reflective of the SUNFISH Part 2 study population.

About SMA

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.

About risdiplam

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:

• SUNFISH (NCT02908685) – a two-part, double-blind, placebo-controlled pivotal study in people aged 2-25 years with Type 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 and the first two secondary endpoints. The total change from baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) was numerically greater for risdiplam but did not reach significance relative to placebo.
• 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).
• JEWELFISH (NCT03032172) – an open-label exploratory trial in people with SMA Type 1, 2 or 3 aged 6 months to 60 years who have been previously treated with SMA therapy, gene therapy or olesoxime. The study has completed recruitment.
• 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.

About Genentech

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.

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