Last updated Jan. 12, 2022, by Marta Figueiredo, PhD
✅ Fact-checked by Ana de Barros, PhD
It was approved by the U.S. Food and Drug Administration (FDA) in August 2020 to treat adults and children ages 2 months and older with all types of spinal muscular atrophy (SMA) — making it the country’s third disease-modifying treatment for SMA within four years and the first to be taken orally and at home.
Evrysdi was also approved by the European Commission in March 2021 for patients of the same age group with a clinical diagnosis of SMA type 1, 2, or 3, or not yet showing symptoms (pre-symptomatic) but carrying up to four copies of the SMN2 “backup” gene. The presence of that number of copies suggests the future development of any of those three disease types.
One month later, Health Canada approved the treatment for all patients ages 2 months and older.
According to Roche, the therapy is available in more than 50 countries, including Brazil, Chile, Georgia, Japan, Russia, South Korea, U.K., and Ukraine, and it’s being reviewed for approval in 30 others.
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 and to the muscle weakness and atrophy that characterizes SMA.
SMA patients produce no to low SMN levels due to mutations in the SMN1 gene. While humans have a “backup” SMN gene, SMN2, 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%. 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. (mRNA is a molecule derived from DNA that guides 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.
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 within 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 the therapy’s safety and efficacy in a wide range of SMA patients.
The open-label, two-part Phase 2/3 FIREFISH study (NCT02913482) is following 62 children enrolled at ages 1 to 7 months and with SMA type 1, a severe form of the disease. Part 2’s top-line, one-year data showed that treatment with the now-approved dose of Evrysdi was generally safe and defied SMA’s natural progression, allowing the then-toddlers to reach normal motor milestones and prolonging their survival.
After two years of treatment in part 2, the toddlers continued to attain and maintain motor milestones. Also, most of them were alive (93%), free from permanent ventilation (83%), and were able to swallow (95%) and to be fed orally (92%).
Untreated type 1 infants typically require feeding support by 12 months and need permanent ventilation, or die, at a median age of 13.5 months.
The two-part Phase 2/3 SUNFISH trial (NCT02908685) is following 231 children and young adults, ages 2 to 25, with milder SMA type 2 or 3 — the broadest population in terms of age and disease severity included in an SMA trial to date.
Top-line, one-year data from the study’s part 2, testing the therapy against a placebo in 180 patients unable to walk unaided, showed that Evrysdi significantly improved or stabilized motor function relative to a placebo. Greater gains were observed among younger patients, while older patients mostly showed motor function stabilization.
Two-year results, including one year of Evrysdi treatment in patients originally assigned to a placebo, highlighted the importance of early treatment, as initiating the medication one year later was associated only with stabilization or slight motor gains.
FIREFISH and SUNFISH participants have the opportunity to enter an open-label extension study in which they all will receive Evrysdi for a longer period.
The open-label Phase 2 JEWELFISH study (NCT03032172) is evaluating Evrysdi’s safety, tolerability, pharmacokinetics, and pharmacodynamics in 174 SMA patients, ages 6 months to 60 years, who previously received other SMA-targeting therapies.
Interim data showed that the therapy was generally well tolerated and led to rapid and sustained increases in SMN levels, highlighting Evrysdi’s potential to complement other SMA therapies.
The open-label Phase 2 RAINBOWFISH trial (NCT03779334) is testing Evrysdi in up to 25 newborns and babies up to 6 weeks old with a genetic diagnosis of SMA but not yet showing symptoms. Infants participating in the study will receive the oral therapy for two years, followed by a three-year extension trial.
Preliminary data from the five infants who had completed one year of treatment showed that all or nearly all reached motor milestones within the window of normal development and similar to healthy, typically developing children. All five toddlers also maintained the ability to swallow and to be fed exclusively by mouth.
Roche is also evaluating the safety, food effect, bioavailability, and bioequivalence of two dispersible tablet-formulations of the therapy against its approved liquid formulation in up to 268 healthy adults ages 18 to 55 within a Phase 1 trial (NCT04718181).
Evrysdi, given as a flavored liquid, is administered daily after a meal by mouth or feeding tube at a recommended dose of 0.2 milligrams (mg) for children under 2 years and 0.25 mg for older patients weighing less than 20 kilograms (kg), which is about 44 pounds. Those weighing 20 kg or more should be given 5 mg of Evrysdi per day.
The therapy’s most common side effects include fever, diarrhea, and rash. Upper respiratory tract infection, pneumonia, constipation, and vomiting are also common among type 1 patients. Its use should be avoided in patients with liver impairment.
In the U.S., Evrysdi can be shipped directly to patients’ places of residence through Accredo Health Group, an Express Scripts specialty pharmacy.
More information can be found in the therapy’s label.
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