Risdiplam Approved as First Oral Treatment for SMA


The agent, marketed under the brand name Evrysdi, is the first at-home therapy indicated for treatment of adults and children with SMA.

Dr Stuart Peltz

Stuart W. Peltz, PhD, chief executive officer, PTC Therapeutics

Stuart W. Peltz, PhD

PTC Therapeutics announced that its investigational agent risidiplam has received FDA approval for the treatment of spinal muscular atrophy (SMA) under the brand name Evrysdi. The agent is indicated for at-home oral administration of a liquid formulation in patients over the aged 2 months and older.1

The agency’s decision was made based on the findings of 2 clinical trials in risdiplam’s development, the FIREFISH (NCT02913482) and SUNFISH (NCT02908685) studies, both of which demonstrated the efficacy of the survival motor neuron 2 (SMN2)-directed RNA splicing modifier in this patient population. Risdiplam-treated patients achieved key motor milestones, such as the ability to sit without support, and experienced preserved vital function and improved survival without the need for permanent ventilation.

“Today marks an incredibly important moment for the broader SMA patient community that had been in dire need of safe and effective treatment options," said Stuart W. Peltz, PhD, chief executive officer, PTC Therapeutics, in a statement. "We are appreciative of the patients, physicians and others involved with its development, and our partners at the SMA Foundation and Roche. We are proud that the first oral treatment for spinal muscular atrophy patients was discovered through our splicing platform. I believe that this is one of the most innovative products in the pharmaceutical industry and we are gratified to have played a key role in its discovery and development.”

This decision was made after an April announcement pushing the PDUFA date of May 24, 2020, back to August 24, 2020. The delay was the result of Roche/Genentech submitting additional data from part 2 of the pivotal SUNFISH trial.

All told, the supportive data from FIREFISH showed that 7 of 17 (41%) infants treated with the therapeutic dose gained the ability to sit without support for at least 5 seconds as measured by the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) gross motor scale.

WATCH NOW: Considerations When Diagnosing SMA

Additionally, 19 of 21 (90%) of all infants were alive without permanent ventilation— defined as tracheostomy or ≥16 hours of non-invasive ventilation per day, or intubation for ≥21 consecutive days in the absence of, or following the resolution of, an acute reversible event—and reached 15 months of age or older. After a minimum of 23 months of treatment, 17 of 21 (81%) infants were alive and reached the age of 28 months or older (median, 32 months; range, 28—45).

Likewise, in SUNFISH, children and adults treated with the PTC Therapeutics product experienced a clinically meaningful and statistically significant improvement in motor function at 12 months, measured by a change in baseline in the Motor Function Measure-32 (MFM-32) total score (1.36 points; 95% CI, 0.61—2.11), compared to placebo (–0.19 points; 95% CI, 1.22–0.84; 1.55-point mean difference; P = .0156).

Additionally, the risdiplam group showed improved upper limb motor function compared to baseline, as measured by the Revised Upper Limb Module (RULM), for a 1.59-point difference (P = .0028).

As for safety, the most common adverse events (AEs) in later-onset SMA (≥10% of patients treated, and more frequently than control) were fever, diarrhea, and rash. The most common AEs in infantile-onset SMA were similar, with the most common adverse reactions (incidence ≥10%) were upper respiratory tract infection, pneumonia, constipation, and vomiting.

"We started looking for treatments for SMA more than a decade ago," said Loren Eng, President of the SMA Foundation, in a statement. "PTC was one of the companies that embraced and remained committed to the idea of developing a truly innovative therapeutic for this disease. We are proud to be part of the collaboration that brought the first oral SMA treatment for patients."

The agent is still being assessed in the JEWELFISH (NCT03032172), and RAINBOWFISH (NCT03779334) trials. The former is an open-label exploratory trial designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in those with SMA aged 6 months to 60 years who received other investigational or approved SMA therapies for ≥90 days prior. The latter is an open-label, single-arm, multicenter study investigating the efficacy, safety, pharmacokinetics and pharmacodynamics in infants, from birth to 6 weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. JEWELFISH’s recruitment is complete, with 174 people enrolled, while RAINBOWFISH is still recruiting with a goal enrollment of about 25 infants.

Very recently, a group of SMA experts, including Crystal Proud, MD; John Brandsema, MD; Julie Parsons, MD; and Nancy L. Kuntz, MD, discussed the currently available data from the SUNFISH and JEWELFISH trials as part of a NeurologyLive Peer Exchange. Watch that segment of the discussion below.


1. PTC Therapeutics Announces FDA Approval of Evrysdi™ (risdiplam) for the Treatment of Spinal Muscular Atrophy in Adults and Children 2 months and older [press release]. Published August 7, 2020. Accessed August 7, 2020. https://finance.yahoo.com/news/ptc-therapeutics-announces-fda-approval-175400735.html

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