#MDA2021 – Evrysdi Leads to Longer-term Benefits for SMA Types 2, 3, Data Show

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by Marta Figueiredo PhD |

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Editor’s note: The SMA News Today team is providing in-depth coverage of the 2021 MDA Virtual Clinical and Scientific Conference, March 15–18. Go here to read the latest stories from the conference.


Evrysdi (risdiplam) continues to improve or stabilize motor function in children and young adults with spinal muscular atrophy (SMA) types 2 and 3, two-year data from the second part of the SUNFISH trial show.

“These results build on the one-year findings from the SUNFISH trial and importantly show the durability of improvement or stabilization of motor function through two years of treatment,” Eugenio Mercuri, MD, PhD, the trial’s principal investigator, said in a press release.

In addition, no new safety concerns were identified and the rate of adverse events was reduced during the second year of treatment relative to the first year, supporting “the favorable benefit-risk profile of Evrysdi over a longer period of time,” added Mercuri, a professor of pediatric neurology at the Catholic University in Rome, Italy.

Levi Garraway, MD, PhD, the chief medical officer and head of global product development at Roche, one of Evrysdi’s developers, said that these “encouraging results” further “highlight the potential longer-term benefit this first-of-its-kind medicine can have for people of varying ages and levels of SMA disease severity.”

The findings were presented by Maryam Oskoui, MD, of McGill University, in an oral presentation, titled “SUNFISH Part 2: 24-Month Efficacy and Safety of Risdiplam in Patients with Type 2 or Non-Ambulant Type 3 Spinal Muscular Atrophy (SMA),” at the 2021 MDA Virtual Clinical and Scientific Conference, held March 15–18.

Evrysdi is a small molecule that works by increasing the levels of SMN, the protein whose production is impaired in SMA patients, leading to progressive muscle weakness and wasting. A flavored liquid, it is administered daily at home by mouth or feeding tube.

In August, it became the first oral and at-home treatment for adults and children, 2 months and older, with all types of SMA in the U.S.; similar decisions soon followed in Brazil, Chile, Ukraine, South Korea, Georgia, and Russia.

Identical approval requests are currently being reviewed by health authorities in 30 countries and in the European Union, where the application is under accelerated assessment and received a positive recommendation by an arm of the European Medicines Agency.

Top-line results from the two-part, global Phase 2/3 SUNFISH clinical trial (NCT02908685) supported the therapy’s approvals and regulatory applications. The study is testing Evrysdi in children and young adults, ages 2 to 25, with SMA type 2 or 3 — the broadest population in terms of age and disease severity included in an SMA trial.

After determining Evrysdi’s optimal dose in 51 ambulatory (able to walk) and non-ambulatory patients in part 1, the trial is evaluating the safety and effectiveness of the selected, now-approved dose in 180 non-ambulatory patients in part 2.

Part 2 participants, with a median age of 9 years, were randomly assigned to receive either Evrysdi (120 patients) or a placebo (60 patients) for one year, after which all received the therapy for an additional year.

There were no major differences between the groups in terms of age, sex, and disease type, of which type 2 was the most common (70%). Notably, about one-third of patients were under 5 years of age, one-quarter were teenagers, and around 12% were young adults.

One-year data from the second part of SUNFISH highlighted that the study achieved clinically meaningful and/or statistically significant results in its main and key secondary goals, with Evrysdi-treated patients having improved or stabilized motor function, compared with those given a placebo.

Motor function was assessed with the Motor Function Measure-32 (MFM32) scale, the Revised Upper Limb Module (RULM) score, and the Hammersmith Functional Motor Scale Expanded (HFMSE). Higher scores indicate better motor function in all three measures.

Newly presented findings concerned data from the second year of treatment during part 2 and showed motor function improvements or maintenance in patients continuing Evrysdi treatment.

Specifically, MFM-32 improvements achieved during the first year were maintained in the second year, with similar proportions of patients showing stable or higher scores (about two-thirds) and achieving clinically meaningful score changes (about one-third) at one and two years.

RULM scores were continuously increased during the second year, while HFMSE scores — which were not distinct between the groups at one year — showed “an upward trend” in those consistently on Evrysdi, which was considered clinically meaningful since the study’s start, Oskoui said.

Researchers also evaluated the therapy’s impact on patients’ daily life through the caregiver- and patient-reported SMA Independence Scale (SMAIS), which looks at the “level of help that the patients need to perform activities of daily living,” such as chores, dressing, hand dexterity, and eating, Oskoui said.

Results showed that caregivers continued to report gains in patients’ independence during the second year of Evrysdi treatment, while patients 12 and older reported SMAIS score stabilization during that period.

In addition, participants switching from placebo to Evrysdi after one year showed stabilization or slight improvements in motor function, without “further deterioration,” and in daily independence.

The therapy’s safety profile continued to be “quite favorable,” Oskoui said, with no new safety concerns identified, and no Evrysdi-related adverse events leading to withdrawal or treatment discontinuation.

Notably, there was an overall decrease in the rates of adverse events during the second year relative to the first year in both groups.

During the second year, the most commonly reported adverse events included common cold (21.7% in the Evrysdi group vs. 16.7% in the placebo-to-Evrysdi group), upper respiratory tract infection (15.8% vs. 10%), and fever (13.3% vs. 10%).

The most common serious adverse events were pneumonia (6.7%) and influenza (0.8%), exclusively occurring in the group of patients given Evrysdi since the beginning of the study.

Importantly, ophthalmological monitoring, which initially had shown some retinal findings in preclinical studies with monkeys, did not show any evidence of eye damage throughout the two years of the study.

“SUNFISH Part 2 is ongoing and will provide further long-term efficacy and safety data of risdiplam in a broad population of children, teenagers and adults,” the researchers wrote in the abstract.

These findings support “the strong U.S. launch and the need for an at-home oral treatment option for the SMA community,” Stuart W. Peltz, PhD, co-founder and CEO of PTC Therapeutics — also instrumental in developing Evrysdi — said in a separate press release.

At two years, SUNFISH participants were given the opportunity to enter the trial’s open-label extension phase, in which all will continue treatment for a longer period.

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