Evrysdi (risdiplam) is an oral daily therapy for patients, ages 2 months and older, with all types of spinal muscular atrophy (SMA). It is a small-molecule treatment that patients take at home as a liquid.

The U.S. Food and Drug Administration (FDA) approved it on Aug. 7, 2020, making it the third disease-modifying treatment for SMA available within four years. The National Health Surveillance Agency (ANVISA) also approved the treatment in Brazil on Oct. 21, 2020. In the U.K., Evrysdi is available before approval to select patients with SMA type 1 and type 2 through the early access to medicines scheme (EAMS).

Roche and Genentech (a member of the Roche Group) developed Evrysdi in collaboration with PTC Therapeutics and the SMA Foundation. The two companies are now marketing the treatment.

How does Evrysdi work?

Evrysdi works by addressing the underlying cause of SMA: a low amount of survival motor neuron (SMN) protein. This protein is essential to the health of motor neurons, which are the nerve cells that control muscle movement.

The brain and spinal cord relay messages to the muscles via motor neurons. The correct transmission of these messages is vital for muscle health. SMN protein deficiency leads to the death of motor neurons causing muscles to atrophy. Two genes — SMN1 and SMN2 — carry instructions necessary for cells to make SMN protein. The vast majority of functional SMN protein comes from the SMN1 gene. The protein that comes from the SMN2 gene is usually short and unstable. Mutations in SMN1 are the main cause of SMA. The number of SMN2 gene copies determines the disease’s severity. 

Messenger RNA (mRNA) is the molecule that guides protein production. Cells first transcribe the genetic information that a gene contains into mRNA. They then translate this information into a protein. There are several integral steps in the process. Problems in any of these steps can affect overall protein production. The unstable nature of the SMN protein that cells produce from the SMN2 gene is the result of such a problem.

A gene typically has several coding and non-coding regions, so-called exons and introns. When cells transcribe the gene into mRNA, both sets of codes get imprinted on the pre-mRNA (a non-mature version of mRNA). For pre-mRNA to become mature mRNA, cells edit its genetic material in a process called splicing. Here, 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. 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 from this gene. This results in a shorter, less stable, and poorly working SMN protein. By altering SMN2’s splicing, Evrysdi prevents exon 7 from being removed from its mRNA. The aim is to “restore” the production of more functional SMN protein.

Evrysdi in clinical trials

A Phase 1 study (NCT02633709) investigated the safety and tolerability of increasing doses of Evrysdi in healthy volunteers. It also evaluated the treatment’s pharmacokinetics (movement in the body) and 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. 

Another Phase 1 study (NCT03920865) examined the effects of a single dose of Evrysdi in healthy volunteers and adults, ages 18 to 70 with mild-to-moderate liver injury (chronic stable liver disease). It assessed participants’ ability to tolerate and process the treatment. It recruited 26 participants and finished in January 2020. The results are not yet available. 

Ongoing clinical trials

Four Phase 2 or Phase 3 trials of Evrysdi — FIREFISH, SUNFISH,  JEWELFISH, and RAINBOWFISH — are further testing Evrysdi’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. 

FIREFISH (NCT02913482) is evaluating the effectiveness of the treatment in infants with SMA type 1, ages 1 to 7 months. Researchers collected the open-label study’s pivotal data in its second phase, evaluating improvements in muscle function with once-daily treatment. The primary goal is the percentage of infants able to sit without support at 12 months of treatment. Secondary goals include the percentage of infants who experience adverse events (side effects). They also look at changes in blood biomarkers and assess developmental milestones that the children reach.

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

Researchers released two-year data from the trial in September 2020. These showed that the children continued to improve and reach motor milestones. Of them, 59% were able to sit without support for five seconds, 65% maintained upright head control, 29% were able to turn over, and 30% were able to stand with support or supporting weight. The percentage of patients with a CHOP-INTEND score above 40 also increased to 71%.

FIREFISH opened in December 2016 and is due 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 type 3. Both type 2 and type 3 are less severe than type 1 disease. Researchers divided patients into two groups based on their age. The first group included children ages 2 to 11 and the second had adolescents and adults ages 12 to 25. In part 1, 51 patients who could or could not walk randomly received either Evrysdi or a placebo for 12 weeks. The aim was to determine the optimal treatment dose. In its confirmatory part 2, 180 patients not able to walk are receiving Evrysdi at that optimal dose ,or a placebo, for up to two years. SUNFISH’s primary goal for both age groups is the change in total motor function — measured using the motor function measure-32 (MFM32) scale — after 12 months. Secondary goals include changes in blood biomarkers and measures of different motor functions. 

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

Top-line data from part 2 found that 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. Patients tolerated Evrysdi well and researchers observed no treatment-related safety findings leading to study withdrawal.

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 — occurred in 78.1% of children who received Evrysdi and 52.9% of those who received the placebo. Most older patients on Evrysdi (57.1%) showed stabilization in their motor abilities. This percentage was 37.5% for those in the placebo group. A treatment goal in older SMA patients is to prevent further loss of motor skills and greater disability.

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

SUNFISH is due to conclude in September 2023.

Patients taking part in SUNFISH and FIREFISH have the opportunity to enter an open-label extension study in which they 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 receiving Evrysdi once a day for 24 months. After this time, they also may enroll in the extension study. JEWELFISH’s primary goals are safety, 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 be completed in January 2025.

Researchers presented preliminary data from all three trials at the 24th International Annual Congress of the World Muscle Society in October 2019. They noted sustained increases in SMN protein levels in the blood of patients who received Evrysdi.

RAINBOWFISH (NCT03779334), the fourth study, is evaluating Evrysdi’s safety, efficacy, pharmacokinetics, and pharmacodynamics in presymptomatic newborns and babies up to 6 weeks old, who received a genetic diagnosis of SMA but no 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 goal. Secondary goals include adverse events, the number of children who go on to develop clear SMA symptoms, and the time to which they need permanent ventilation.

This study is due to conclude in March 2026.

Other information

Roche has filed applications for risdiplam, Evrysdi’s investigational compound name, in 16 international markets. These are Australia, Chile, India, Indonesia, Israel, Japan, Kuwait, Macedonia, Malaysia, Russia, Singapore, South Korea, Taiwan, Thailand, Ukraine, and the United Arab Emirates. The application is under review in Canada, China, the EU, and Switzerland

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

The FDA granted risdiplam orphan drug status in January 2017. The European Medicines Agency (EMA) designated it priority medicine (PRIME) in December 2018.   

 

Last updated: Nov. 2, 2020

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