Evrysdi (risdiplam) is an oral daily therapy for people ages 2 months and older with all types of spinal muscular atrophy (SMA), a neurodegenerative disease characterized by progressive muscle weakness and wasting (atrophy). 

A small molecule treatment, taken as a liquid at the home, Evrysdi was approved by the U.S. Food and Drug Administration (FDA) on Aug. 7, 2020, becoming the third disease-modifying treatment for SMA available within four years. 

It is marketed by Roche and Genentech (a member of the Roche Group), which developed it in collaboration with PTC Therapeutics and the SMA Foundation.

How does Evrysdi work?

Evrysdi works by addressing  the underlying cause of SMA: a reduced amount of survival motor neuron (SMN) protein. This protein is essential to the health of motor neurons, the nerve cells that control muscle movement. The brain and spinal cord relay messages to the muscles via motor neurons, and the correct transmission of these messages is vital for muscle health because they instruct muscles to contract and move. SMN protein deficiency leads to the breakdown of nerve cells and impedes their ability to work, causing muscles to atrophy. 

Two genes — SMN1 and SMN2 — carry instructions to make SMN protein. The vast majority of functional SMN protein in the body is produced from the SMN1 gene. The protein that comes from SMN2 is usually short and unstable. 

Mutations in SMN1 are the main cause of SMA, while the number of SMN2 gene copies determines the disease’s severity because it does produce some of the working protein. 

Messenger RNA (mRNA) is the molecule that guides protein production inside cells. The genetic information contained in the DNA is first transcribed into mRNA, which is then translated into a protein. There are several integral steps in the process, and problems in any of these steps can affect overall protein production. The unstable nature of the SMN protein produced from SMN2 is caused by such a problem.

A gene typically has several coding and non-coding regions, so-called exons and introns. When the gene is transcribed into mRNA, both sets of codes get imprinted on the mRNA producing what is called pre-mRNA (a less mature version of mRNA). 

For pre-mRNA to become mature mRNA, its genetic material is edited in a process called splicing, in which the non-coding introns are removed. Splicing determines the fate of the generated protein. 

Evrysdi works by correcting an event that’s called alternative splicing, which allows for a single gene to give rise to many different proteins. Much like in a recipe, adding or removing certain key ingredients — in this case, exons — can change what results: the mature mRNA and final protein. 

In SMN2, this splicing event results in the exclusion of exon 7 from most mRNA molecules this gene produces, resulting in the shorter, less stable, and poorly working SMN protein this gene produces. By correcting SMN2’s splicing, Evrysdi prevents exon 7 from being removed from its mRNA to “restore” the production of more functional SMN protein.

Evrysdi in clinical trials

A Phase 1 study (NCT02633709) investigating the safety and tolerability of increasing doses of risdiplam in healthy volunteers finished in August 2016. That study also evaluated risdiplam’s pharmacokinetics (movement in the body), and its pharmacodynamics (effect on the body). In addition to establishing reasonable safety and tolerability, its data helped in determining an optimal therapeutic dose for future studies in SMA patients.

Four Phase 2 or Phase 3 trials of Evrysdi — FIREFISH, SUNFISH,  JEWELFISH, and RAINBOWFISH — are testing the treatment’s efficacy and safety in a wide range of SMA patients. 

Data from FIREFISH (part 1) and SUNFISH (parts 1 and 2) supported Evrysdi’s approval request, submitted by Roche and Genentech, and accepted by the FDA in November 2019. 

FIREFISH (NCT02913482) is evaluating the effectiveness of Evrysdi in infants with SMA type 1, ages 1 to 7 months. The open-label study’s pivotal data was collected in its second phase, evaluating improvements in muscle function with once daily treatment. Its primary endpoint is the percentage of infants able to sit without support at 12 months of treatment. Secondary trial goals include the percentage of infants who experience adverse events, changes in blood biomarkers, and assessments of milestones reached in the children’s development.

Top-line data, announced in April 2020, showed that 29% of the 21 treated infants were able to sit without support for five seconds, meeting the trial’s primary goal. Clinically meaningful improvements — a four-point or greater increase in the CHOP-INTEND scale — were also recorded in 90% of these type 1 patients. CHOP-INTEND scores above 40, considered close to normal, were recorded in 56% of them.  

FIREFISH opened in December 2016 and is expected to conclude in November 2023.

The two-part SUNFISH (NCT02908685) trial is assessing the safety, tolerability, and effectiveness of Evrysdi, against a placebo, in patients, ages 2 to 25, with SMA type 2 or SMA type 3. Both type 2 and type 3 are less severe than type 1disease.

Enrolled patients were divided into two groups based on their age: children ages 2 to 11, and adolescents and adults ages 12 to 25. In part 1, 51 patients who could or could not walk were randomly assigned to either Evrysdi or a placebo for 12 weeks to determine the optimal treatment dose. In its confirmatory part 2, 180 non-ambulatory patients are being treated for up to two years at that optimal dose, or given a placebo. 

SUNFISH’s primary endpoint for both age groups is the change in total motor function — measured using the Motor Function Measure-32 (MFM32) scale — after 12 months. Secondary endpoints include changes in blood biomarkers and measures of different motor functions. 

Roche and PTC Therapeutics presented preliminary results from part 1 in July 2017. It reported a 400% increase from the study’s start (baseline measures) in full-length SMN protein produced from the SMN2 gene in treated patients, indicating that Evrysdi promotes the correct splicing of the SMN2 mRNA in these people.

Top-line data from part 2 found SUNFISH met its primary goal — that of statistically significant improvements in motor function from baseline on the MFM32 scale  — after 12 months of treatment compared with a placebo. Evrysdi was well-tolerated and no treatment-related safety findings leading to study withdrawal were observed. Additional analysis of these results, released in February 2020, showed that younger patients (ages 2 to 5) responded better to therapy than older ones. Clinically meaningful improvements — a three-point or greater increase on the MFM32 scale — were seen in 78.1% of Evrysdi-treated children and 52.9% of those given a placebo. Most older patients on Evrysdi (57.1%) showed stabilization in their motor abilities, compared with 37.5% of those in the placebo group. A treatment goal in older SMA patients is to prevent further loss of motor skills and greater disability, so these findings are considered relevant.

Results also showed that revised upper limb module (RULM) scores, a secondary trial goal, were significantly higher among treated patients. 

SUNFISH is due to conclude in September 2023.

After finishing in their respective trial, SUNFISH and FIREFISH patients are offered the opportunity to enter an open-label extension study where all will receive Evrysdi. 

An open-label Phase 2 trial, called JEWELFISH (NCT03032172), is evaluating Evrysdi’s safety and tolerability in a broad range of SMA patients, ages 6 months to 60 years, all previously treated with another SMA-targeted therapy, including Spinraza and Zolgensma. The study has enrolled about 180 people with SMA types 1, 2, and 3 at sites in the U.S., the U.K., and Europe. All are being given Evrysdi once a day for 24 months, after which they may also enroll in the extension study. JEWELFISH’s primary goals are safety in these previously treated patients, measured by the percentage of adverse or serious side effects, evidence of new or worsening symptoms, and measures of blood markers including treatment concentrations. 

JEWELFISH is expected to finish in December 2024.

Preliminary data from all three trials were presented at the 24th International Annual Congress of the World Muscle Society in October 2019. Sustained increases in SMN protein levels was noted in the blood of patients given Evrysdi.

RAINBOWFISH (NCT03779334), the fourth study, is evaluating Evrysdi’s safety, efficacy, pharmacokinetics, and pharmacodynamics in presymptomatic newborns and patients up to 6 weeks old, who are genetically diagnosed with SMA but without any evident symptoms. This open-label study in up to 25 babies is still enrolling at multiple centers worldwide. The number of infants able to sit up without support after 12 months of treatment is the study’s primary endpoint. Secondary endpoints include adverse events, the number of children who go on to develop clear SMA symptoms, and time to which they need permanent ventilation.

This study is expected to conclude in October 2025.

A Phase 1 study (NCT03920865) examined the effects of a single dose of Evrysdi in 26 healthy volunteers and adults, ages 18 to 70 with mild-to-moderate liver injury (chronic stable liver disease). Particularly, it assessed participants’ ability to tolerate and process the treatment. The study recruited 26 participants and finished in January 2020. Results are awaited. 

Other information

Risdiplam, as Evrysdi is known by its investigational compound name, is currently under review by regulatory agencies in seven countries: Brazil, Chile, China, Indonesia, Russia, South Korea, and Taiwan. A filing is expected to be made shortly to the European Medicines Agency (EMA), the regulatory agency for the European Union.

Evrysdi can be directly shipped to patients’ places of residence through Accredo Health Group, an Express Scripts specialty pharmacy

Evrysdi was granted orphan drug status by the FDA in January 2017, and designated a priority medicine or PRIME by the EMA in December 2018. The purpose of both designations is to advance the development of possible treatments for people with rare diseases.   


Last updated: Aug. 7, 2020


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