Evrysdi (risdiplam) for spinal muscular atrophy

Last updated Aug. 30, 2023, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD

What is Evrysdi for SMA?

Evrysdi (risdiplam) is a disease-modifying therapy, taken daily, that’s approved for children and adults with spinal muscular atrophy (SMA). It is the only approved SMA treatment that can be taken orally or via feeding tube, and the first that can be administered at home.

Because it targets the underlying cause of SMA, the therapy can help maintain or improve motor function in people with the genetic disease.

It was developed by Roche and its subsidiary Genentech, in collaboration with PTC Therapeutics and the SMA Foundation. Roche and Genentech market it.

Therapy Snapshot

How does Evrysdi work?

Evrysdi is a small molecule that works by addressing the underlying cause of SMA, which is a low amount of survival motor neuron protein, known as SMN. This protein is essential for the health of motor neurons, the specialized nerve cells that control voluntary movement. SMN deficiency leads to motor neuron death, ultimately causing the muscle weakness and atrophy that characterizes SMA.

SMA patients produce no to low SMN levels due to mutations in the SMN1 gene, which provides instructions for making the protein. Humans also have a gene called SMN2, which serves as a type of backup to the SMN1 gene. However, while SMN2 also provides instructions for making SMN protein, a slight difference in its DNA sequence results in an event called alternative splicing. This limits the amount of working SMN the gene produces to 10% to 15% of what’s produced by SMN1.

Alternative splicing is a natural process that 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, pieces of genetic information called exons — can change the mature messenger RNA (mRNA) and final protein. The mRNA is a molecule derived from DNA that is used as a template for protein production.

In SMN2, this splicing event results in the exclusion of exon 7 from most of its mature mRNA molecules, leading to the generation of a shorter, less stable, and poorly working SMN protein.

Evrysdi, whose small size allows it to reach the brain and spinal cord, works by binding to SMN2’s premature mRNA molecule and preventing the removal of exon 7 from the subsequent mature mRNA molecule. By correcting the gene’s splicing, the therapy has the potential to restore the production of functional SMN throughout the body.

Who can use Evrysdi?

Evrysdi was approved by the U.S. Food and Drug Administration in August 2020, making it the country’s third new disease-modifying treatment for SMA within four years.

It initially was approved for adults and children 2 months and older with all types of SMA, but that indication was extended in 2022 to include infants younger than 2 months. Evrysdi now is indicated to treat all types of SMA in children and adults of all ages in the U.S.

The therapy also is approved in Europe to treat patients of all ages with SMA, including babies from birth, and in Canada for patients ages 2 months and older.

According to Roche, Evrysdi is available in more than 100 countries, including Brazil, Chile, Egypt, Georgia, Kuwait, Japan, Russia, South Korea, the U.K., and Ukraine.

Who should not use Evrysdi?

The prescribing information for Evrysdi lists no contraindications or warnings associated with using it. However, its use in combination with some specific medications should be avoided.

How is Evrysdi administered in SMA?

Evrysdi, given as a flavored liquid, can be taken by mouth or administered via a feeding tube. It should be taken once daily after a meal, at approximately the same time each day. When administering the therapy to infants, it should not be mixed with formula or breastmilk.

Evrysdi is dosed according to age and body weight.

• For infants younger than two months, the dose is 0.15 mg/kg.
• For children ages 2 months but younger than 2 years, the dose is 0.2 mg/kg.
• For patients 2 years and older, weighing less than 20 kg (about 44 pounds), the dose is 0.25 mg/kg.
• For individuals ages 2 and older, weighing 20 kg or more, the dose is 5 mg.

Evrysdi in clinical trials

Evrysdi’s safety, tolerability, pharmacokinetics, and pharmacodynamics were first investigated in almost 60 healthy volunteers in two Phase 1 clinical trials (NCT02633709 and NCT03920865). Pharmacokinetics refers to a medication’s movement into, through, and out of the body, while pharmacodynamics relates to its effects on the body.

Based on Evrysdi’s favorable safety profile and biological effect in healthy volunteers, Roche launched a clinical program of four Phase 2 or Phase 3 trials — FIREFISH, SUNFISH, JEWELFISH, and RAINBOWFISH — to further test the therapy’s safety and effectiveness in a wide range of SMA patients.

FIREFISH study in SMA type 1

The open-label Phase 2/3 FIREFISH study (NCT02913482) enrolled 62 infants, ages 1 to 7 months, with symptomatic SMA type 1, a severe form of the disease. The first portion of this two-part study identified an optimum dosage of Evrysdi. In the second part, 41 babies were treated at the now-approved dose.

After one year, 38 of the 41 babies in the second part were still alive and a sizable majority did not require ventilation (85.4%) and were able to feed orally (89%). Nearly a third (29%) of the children were able to sit unsupported for five seconds and almost half (43.9%) achieved upright head control.

All the children alive after one year were still alive a year later and most were still able to feed orally and did not require ventilation support. By two years of treatment, more than half (61%) could sit unsupported for at least five seconds. None could stand or walk independently at two years, though two of the children were able to crawl on their hands and knees. Collectively, these results show a marked contrast with the natural progression of SMA type 1.

SUNFISH study in SMA types 2 and 3

The two-part Phase 2/3 SUNFISH clinical trial (NCT02908685) enrolled 231 children and young adults with SMA type 2 or 3, ages 2 to 25. After the initial dose-finding part of this study, 180 participants unable to walk (nonambulatory) were included in the placebo-controlled portion, where they were treated with Evrysdi or given a placebo for one year.

After one year, standardized measures of motor function had stabilized or improved for most patients on Evrysdi, with improvements generally more common in younger participants. Among young patients (ages 2 to 5), more of those on Evrysdi than a placebo had a clinically meaningful improvement in motor function (78.1% vs. 52.9%). Among older patients (ages 18 to 25), the proportion with stable motor function was higher with Evrysdi than a placebo (57.1% vs. 37.5%).

At the end of the placebo-controlled part of the trial, participants had the option to continue into an open-label extension in which all are being treated with Evrysdi. Results after four years generally showed that improvements or stabilization in motor function was maintained.

JEWELFISH trial in previously treated patients

The open-label Phase 2 JEWELFISH study (NCT03032172) enrolled 174 SMA patients, ages 6 months to 60 years, who previously received other SMA-targeting therapies. These include Genentech’s investigational compounds, Biogen’s Spinraza (nusinersen) — the first approved SMA-targeted therapy — and Novartis’ one-time gene therapy Zolgensma (onasemnogene abeparvovec-xioi).

Results showed that, after one year on Evrysdi, measures of motor function were generally stable in these patients, relative to the progressive worsening that typically characterizes untreated SMA. The rate of SMA-related safety events decreased after a few months on Evrysdi. Two-year data also showed stabilized motor function as well as increased SMN protein production.

RAINBOWFISH trial in presymptomatic infants

The Phase 2 RAINBOWFISH trial (NCT03779334) enrolled 25 newborns, ages 6 weeks or younger, who had been genetically diagnosed with SMA, but had not yet begun displaying any overt symptoms of the disease.

Preliminary data from the first five patients treated for at least one year showed that all were alive and had retained the ability to swallow. All of the babies were able to sit independently, and most reached motor milestones such as being able to crawl, stand, and walk. Some babies hit these milestones within developmentally typical timeframes, while the time to reach them was delayed in others.

Other ongoing trials

The Phase 2/3 study MANATEE (NCT05115110) is testing Evrysdi in combination with GYM329 (RO7204239), an experimental therapy targeting muscle growth that Roche is developing. The study aims to recruit approximately 259 children and adults with SMA, ages 2 to 25.

Genentech also is sponsoring the Phase 4 trial WeSMA (NCT05232929) that aims to collect long-term safety and efficacy data for about 500 people with SMA who are on Evrysdi. The study is open to patients of all ages and with all types of SMA.

Common side effects of Evrysdi

The most common side effects of Evrysdi reported in clinical trials of patients with late-onset forms of SMA were:

• fever
• diarrhea
• rash.

The safety profile of Evrysdi in infants with SMA is overall similar to that reported in older patients, though some additional side effects are common in very young patients. These include:

• respiratory tract infection
• constipation
• vomiting
• cough.

Use in pregnancy and breastfeeding

Use of Evrysdi has not been thoroughly studied in patients who are pregnant or breastfeeding. In animal models, administering Evrysdi during pregnancy had toxic effects on the developing fetus.

Although there are no data on the presence of Evrysdi in human milk, the effects on the breastfed infant, or the effects on milk production, patients who are breastfeeding or plan to breastfeed while on the medication are advised to discuss this topic with their healthcare team.

Those who are or have been pregnant while on Evrysdi may enroll in the Roche-sponsored Evrysdi Pregnancy Registry, which is monitoring the outcomes of pregnant women and babies exposed to the medication during pregnancy.

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