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Genentech’s Spinal Muscular Atrophy Therapy Shows Significant Improvement in Motor Function

Risdiplam showed medically-meaningful and statistically significant results patients with type 2 and type 3 SMA.

Image: Spinal Muscular Atrophy Foundation

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a progressive genetic disease that causes devastating muscle atrophy and disease-related complications. SMA is the leading genetic cause of death in infants and toddlers, according to the Spinal Muscular Atrophy Foundation. The disease has generally been believed to be one of the most common among the “rare” diseases, affecting as many as 10,000 to 25,000 people in the US.

According to the National Human Genome Research Institute, part of the National Institutes of Health (NIH), one in 6,000 to one in 10,000 children are born with the disease. SMA is an autosomal recessive genetic disease, meaning that a person requires two copies of the defective gene to have the disease. If both parents are carriers of the defective gene, then each of their children has a 25% chance of developing SMA. One in 50 people are carriers.

The disease is caused by defects in the Survival Motor Neuron 1 (SMN1) gene that encodes the SMN protein, which is critical to the health and survival of motor neurons in the spinal cord responsible for muscle contraction.

There are several types of SMA that vary in severity and time of onset.

  • Type 0, the most severe form, which begins before birth. These newborns have little movement and have difficulties with swallowing and breathing.
  • Symptoms of type 1 SMA (Werdnig-Hoffman disease) may be present at birth or within the first few months of life. These infants usually have difficulty breathing and swallowing, and they are unable to sit without support.
  • Children with type 2 SMA usually develop muscle weakness between six and 12 months. They cannot stand or walk without help.
  • Type 3 SMA (Kugelberg-Welander disease or juvenile type) symptoms appear between early childhood (older than age 1 year) and early adulthood. Those afflicted are able to stand and walk without help, but usually lose these abilities later in life.
  • There are two other types of spinal muscular atrophy, type 4 and Finkel type that occur in adulthood, usually after age 30.

While SMA patients lack the functional SMN1 gene, they do have the SMN2 gene, or what the SMA Foundation refers to as a “backup gene.” SMN2 also encodes for SMN protein, but at greatly reduced efficiency, leading to lower than normal levels of the protein. According to the SMA Foundation, the majority of drug development efforts are focused on increasing SMN protein production from SMN2.

Genentech’s Risdiplam Shows Significant Improvement in Motor Function in People Aged 2-25 With Type 2 or 3 SMA

Genentech, a member of the Roche Group, today presented 1-year data from the pivotal 180-patient Part 2 of a global placebo-controlled study called SUNFISH, evaluating risdiplam in people aged 2-25 years with Type 2 or 3 SMA. The study showed that the 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). MFM-32 is a validated scale used to evaluate fine and gross motor function in people with neurological disorders.

The Revised Upper Limb Module (RULM), a key secondary endpoint, also showed an improvement (1.59 point difference; p=0.0028).

Data were presented at the 2nd International Scientific and Clinical Congress on Spinal Muscular Atrophy in Evry, France.

SUNFISH is the first placebo-controlled trial to include adults with SMA, and the study demonstrates that risdiplam improved or stabilized motor function in these adults.

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

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. 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.

– Levi Garraway, MD, PhD, Chief Medical Officer and Head of Global Product Development, Roche.


Roche obtained an exclusive worldwide license to PTC Therapeutics‘ SMA program in 2011. PTC had developed the program in conjunction with the SMA Foundation, which has remained active in the collaboration.

Risdiplam is designed to increase and sustain SMN protein levels both throughout the central nervous system and in peripheral tissues of the body. Genentech is evaluating risdiplam in four staged multicenter trials for its potential ability to help the SMN-2 gene produce more functional SMN protein throughout the body:

  • 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 determined the dose for the confirmatory Part 2 whose data is discussed herein.
  • FIREFISH (NCT02913482) – an open-label, two-part pivotal clinical trial in infants with type 1 SMA. Part 1 assessed safety and dosagert 2. Part 2 is a pivotal, single-arm study 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.
  • 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 of which was discontinued by Roche in 2018). JEWELFISH has completed recruitment.
  • RAINBOWFISH (NCT03779334) – an open-label, single-arm, multicenter study, investigating the efficacy, safety, pharmacokinetics and pharmacodynamics of risdiplam in babies 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.

Risdiplam is the first potential treatment to have pivotal placebo-controlled data in a broad population of patients, including children, teenagers and adults. 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.

– SUNFISH principal investigator Eugenio Mercuri, MD, PhD, Department of Pediatric Neurology, Catholic University, Rome, Italy.

FDA Priority Review

In November 2019, the FDA granted Priority Review for risdiplam, with an expected decision on approval by May 24, 2020. Today’s release of the SUNFISH data only adds to the already promising case for approval.

In January 2020, Reuters reported that Roche intends to undercut the existing SMA therapies that have been approved, Biogen’s Spinraza—priced at $750,000 for the first year and $375,000 for each successive year—and Novartis’s Zolgensma—priced at $2.1 million for what is believed to be a one-time cure.

According to Reuters, Roche CEO “Bill Anderson said the Basel-based company will price the drug much as it did its hemophilia A medicine Hemlibra in 2017, when it undercut traditional therapies made by rivals NovoNordisk and Takeda to help win patients. ‘With Hemlibra, we priced at about half of [the competition],’ Anderson said in an interview at the JP Morgan Healthcare Conference in San Francisco. ‘We aim to underwhelm with our price‘ with risdiplam.”

Reuters cited that analysts see risdiplam topping $1 billion in annual sales for Roche.


Edward Kim is Managing Editor of


Sources: Equities News

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