Evrysdi (Risdiplam) for SMA

Last updated Nov. 23, 2022, by Marisa Wexler, MS

✅ Fact-checked by Ana de Barros, PhD

What is Evrysdi for SMA?

Evrysdi (risdiplam) is an approved daily therapy for spinal muscular atrophy (SMA). It was developed by Roche and its subsidiary Genentech, in collaboration with PTC Therapeutics and the SMA Foundation. Roche and Genentech market it.

Evrysdi was first approved by the U.S. Food and Drug Administration (FDA) in August 2020, making it the country’s third disease-modifying treatment for SMA within four years. Evrysdi is the first FDA-approved SMA treatment that can be taken orally or via feeding tube, and the first that can be administered at home.

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 (SMN) protein. 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 “backup” SMN gene, called SMN2. While SMN2 also provides instructions for making SMN protein, a slight difference in its DNA sequence results in an event called alternative splicing, which limits the amount of working SMN it produces to 10–15% of what’s produced by SMN1. Still, for this reason, the number of SMN2 gene copies a patient has helps to determine SMA severity, as a higher number is associated with the development of milder forms of the disease.

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 what results: 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 cross the blood-brain barrier and 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. The blood-brain barrier is a semipermeable membrane that shields the brain and spinal cord from the external environment. 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 is currently approved in the U.S. to treat all types of SMA in patients of all ages. The therapy is also approved in Europe and Canada for patients ages 2 months and older.

According to Roche, Evrysdi is available in more than 80 countries, including Brazil, Chile, Georgia, Japan, Russia, South Korea, 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 should be avoided in patients with hepatic (liver) impairment.

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.

For patients ages 2 and older who weigh at least 20 kg (about 44 pounds), the recommended daily dosage is 5 mg. For younger and lighter patients, Evrysdi is dosed according to age and body weight:

  • less than two months: 0.15 mg/kg [source]
  • 2 months to less than 2 years: 0.2 mg/kg
  • 2 years and older, weighing less than 20 kg: 0.25 mg/kg

Evrysdi in clinical trials

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

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 its 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 sizeable 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 non-ambulatory (cannot walk) participants 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 among younger ones. 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 where all are being treated with Evrysdi. Results after two years and three years generally showed 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, compared 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 180 children with SMA, ages 2 to 10, who are able to walk.

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:

  • upper 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 lactating. In animal models, administering Evrysdi during pregnancy had toxic effects on the developing fetus.

Although there are no data on the presence of risdiplam 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.

SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.