Evrysdi (risdiplam) Showed Significant Improvement in Survival & Motor Milestones in Babies With Type 1 Spinal Muscular Atrophy (Medicine)

  • FIREFISH Part 2 study showed treatment with Evrysdi helped babies stay free of permanent ventilation, sit without support and improve across a range of motor milestones.
  • Evrysdi has proven efficacy in adults, children and babies 2 months and older with over 4,000 patients treated to date.
  • SMA is the leading genetic cause of death in infants.

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the New England Journal of Medicine (NEJM) has published data from FIREFISH Part 2, a pivotal global study evaluating the efficacy and safety of Evrysdi® (risdiplam) in babies 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 at least 5 seconds* by month 12, a milestone not seen in the natural course of the disease. Safety for Evrysdi in the FIREFISH Part 2 study was consistent with its known safety profile.

“Without treatment, babies with Type 1 SMA are unlikely to survive beyond two years of age,” said Professor Laurent Servais, M.D., Ph.D., FIREFISH investigator and Professor of Pediatric Neuromuscular Diseases at the MDUK Oxford Neuromuscular Center. “Important motor milestones, such as sitting, rolling over and swallowing, are the fundamental building blocks that can help these babies achieve optimal outcomes with Evrysdi, potentially reducing the need for ventilation and increasing the rate of survival.”

At the time of the data analysis, the median duration of treatment with Evrysdi was 15.2 months and the median age was 20.7 months. At month 12, 93% (38/41) of infants were alive and 85% (35/41) were free from permanent ventilation. Without treatment, the median age of death or permanent ventilation was 13.5 months in a natural history cohort. Ninety percent (37/41) had a CHOP-INTEND** score increase of at least 4 points, with 56% (23/41) achieving a score above 40; the median increase was 20 points.

In addition, the study met one of its secondary endpoints with 78% (32/41) of infants classified as HINE-2*** responders, which evaluated motor function through head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing and walking. Infants were classified as HINE-2 responders if more motor milestones showed improvement than worsened.

“These data published in the New England Journal of Medicine validate results from Part 1 of the FIREFISH study that showed Evrysdi can help babies with SMA reach the significant milestone of sitting without support for at least five seconds,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. “These results have been further confirmed in the recently presented 24-month data showing Evrysdi continued to improve motor function, doubling the number of babies able to sit without support from month 12. We will continue to work closely with governments and the SMA community to bring Evrysdi to as many people as possible.”

Safety for Evrysdi in the FIREFISH Part 2 study was consistent with its known safety profile. The most common adverse events were upper respiratory tract infection (68%), pneumonia (39%), pyrexia (39%), constipation (20%), diarrhea (10%) and maculopapular rash (10%). The most common serious adverse events were pneumonia (32%), bronchiolitis (5%), hypotonia (5%) and respiratory failure (5%). Three infants experienced fatal complications of their disease within the first 3 months of treatment. None of these were attributed by the investigator as related to Evrysdi.

In February 2021, 12-month results from the dose finding Part 1 of the FIREFISH study were published in NEJM.

Genentech leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics.

*As assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III)

**Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders

***Hammersmith Infant Neurological Examination 2

About Evrysdi® (risdiplam)

Evrysdi is a survival motor neuron 2 (SMN2) splicing modifier designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency. Evrysdi is administered daily at home in liquid form by mouth or by feeding tube.

Evrysdi is designed to treat SMA by increasing and sustaining the production of the SMN protein. SMN protein is found throughout the body and is critical for maintaining healthy motor neurons and movement.

Evrysdi was granted orphan designation by the European Medicines Agency (EMA) in 2019, PRIME designation by the EMA in 2018 and Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) in 2017. Evrysdi has been approved in 54 countries and submitted in a further 33 countries.

Evrysdi 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 with the primary objective of assessing the safety profile of Evrysdi in infants and determining the dose for Part 2. Part 2 is a pivotal, single-arm study of Evrysdi in 41 infants with Type 1 SMA treated for 2 years, followed by an open-label extension. Enrollment for Part 2 was completed in November 2018. The primary objective of Part 2 was to assess efficacy as measured by the proportion of infants sitting without support after 12 months of treatment, as assessed by 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). The study met its primary endpoint.
  • 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 the 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 designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in people with SMA aged 6 months to 60 years (inclusion criteria) who received other investigational or approved SMA therapies for at least 90 days prior to receiving Evrysdi. The study has completed recruitment (n=174).
  • RAINBOWFISH (NCT03779334) – an open-label, single-arm, multicenter study, investigating the efficacy, safety, PK and PD of Evrysdi 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 SMA

SMA is a severe, progressive neuromuscular disease that can be fatal. It affects approximately one in 10,000 babies and is the leading genetic cause of infant mortality. SMA is caused by a mutation of the survival motor neuron 1 (SMN1) gene, which leads to a deficiency of SMN protein. This protein is found throughout the body and is essential to the function of nerves that control muscles and movement. Without it, nerve cells cannot function correctly, leading to muscle weakness over time. 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.


Reference: Basil T. Darras, Riccardo Masson, Maria Mazurkiewicz-Bełdzińska, Kristy Rose, Hui Xiong, Edmar Zanoteli, Giovanni Baranello, Claudio Bruno, Dmitry Vlodavets, Yi Wang, Muna El-Khairi, Marianne Gerber, Ksenija Gorni, Omar Khwaja, Heidemarie Kletzl, Renata S. Scalco, Paulo Fontoura, Laurent Servais, “Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls
The New England Journal of Medicine  (IF91.245),  Pub Date : 2021-07-29, DOI: 10.1056/nejmoa2102047


Provided by Genentech

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