Spinal Muscular Atrophy (SMA)

Evrysdi® (risdiplam) is an oral, disease-modifying therapy approved by the US Food and Drug Administration FDA for the treatment of spinal muscular atrophy (SMA) in patients aged 2 months and older.1

FDA approval was given in 2020, making it the third approved disease-modifying treatment for SMA behind Spinraza® (nusinersen) and Zolgensma® (onasemnogene abeparvovec-xioi) but the first oral treatment.

Evrysdi is currently approved in 38 countries with approvals pending in an additional 33.2

Evrysdi was developed by Genentech, a subsidiary of Roche, in collaboration with PTC Therapeutics and the SMA Foundation.3

Mechanism of Action

SMA is caused by mutations or deletions of the SMN1 gene, which produces the survival motor neuron (SMN) protein. SMN is critical for the function and maintenance of motor neurons through involvement in a number of homeostatic pathways, including the creation and transport of mRNA, modification of the dendrites and axons, and autophagy.4 A second gene, located on the same chromosome and called SMN2, can also produce SMN protein.

The SMN1 and SMN2 genes are identical except for a swap from cytosine to thymine in exon 7.5 This swap results in roughly 85% of the SMN protein created by SMN2 to lack exon 7, producing an unstable molecule that is quickly degraded.5 Without a functioning SMN1 gene, patients with SMA are dependent on the limited amount of SMN produced by SMN2. Inadequate SMN production results in the progressive death of motor neurons. The speed of this progression is determined in large part by the number of SMN2 copies a patient has, ranging from 1 to 8,6 with higher numbers resulting in less affected patients.

Evrysdi works by including exon 7 in the products of SMN2, increasing the amount of functional SMN protein created.7 The exact mechanism through which Evrysdi works is currently not fully known but proposed mechanisms involve the recruitment of splicing factors such as Far Upstream Element Binding Protein 1 (FUBP1) and KH-type Splicing Regulatory Protein (KHSRP) to retain exon 7, as well as the recruitment of U1 snRNP to aid in the excision of the downstream intron 7.7

Read about all of the FDA approved therapies for spinal muscular atrophy.


Warnings, Precautions, and Adverse Reactions

Evrysdi should not be taken with multidrug and toxin extrusion (MATE) substrates as it may increase the activity of MATE1 and MATE2-K transporters. Patients with impaired hepatic function should not use Evrysdi, as the liver is its primary location of metabolism.8

Animal studies found that the use of Evrysdi during pregnancy resulted in adverse developmental effects on offspring. The presence of Evrysdi in breast milk has not been studied. The risks and benefits of the use of Evrysdi in female patients who are pregnant, may become pregnant, or may be breastfeeding should be considered.8

The most common (≥10%) adverse reactions seen in clinical trials of Evrysdi included fever, diarrhea, and rash in children and adults with type 2 or 3 SMA.8 Infants and children with type 1 SMA experienced those same reactions as well as upper respiratory tract infections, pneumonia, constipation, and vomiting.8 To a lesser extent, some patients also experienced mouth and aphthous ulcers, arthralgia, and urinary tract infections.8

Get detailed prescribing information on the Evrysdi monograph page at Rare Disease Advisor.

Clinical Trial Results

A number of clinical trials have or are investigating the use of Evrysdi in humans. A phase 1 single ascending-dose study recruited 33 healthy male patients aged 18 to 45 years. The study found treatment was well tolerated, had dose-dependent pharmacokinetics, and increased SMN2 mRNA.9 The positive results of the trial enabled further studies of Evrysdi in patients with SMA.


A phase 2-3 open-label study, called FIREFISH (NCT02913482) is investigating Evrysdi in infants aged 1 to 7 months with SMA type 1. The study is divided into 2 parts. In part 1, 4 infants were given a low dose, 0.08 mg/kg, of Evrysdi daily for 12 months and 17 patients were given a high dose, 0.2 mg/kg.

Results of the trial showed that SMN levels had increased from 1.31 ng/ml at baseline to 3.05 ng/ml at 12 months for the low dose group and from 2.54 ng/ml to 5.66 ng/ml for the high dose group.10 A total of 7 of 17 patients in the high dose group and 0 out of 4 from the low dose group were able to sit without support for at least 5 seconds.10 A total of 19 of the 21 patients were alive without the need for permanent ventilation 12 months after treatment and 17 were still alive 23 months after treatment.11

The results from part 1 of the trial informed the decision to use the higher dose for part 2 of the trial and were also used in the regulatory filings along with data from another study called SUNFISH. Another 41 infants have been recruited to the second part of the trial where they will receive 0.2 mg/kg of Evrysdi daily for 24 months followed by a 3-year extension. The trial is due to conclude in November 2023.


SUNFISH (NCT02908685) is another 2-part clinical trial of Evrysdi. It investigated the treatment in patients with SMA type 2 or 3, aged 2 to 25 years. Part 1 of the trial was performed to establish dosing for part 2 and recruited 51 patients. The second part of the trial was a randomized, multicenter, placebo-controlled trial that recruited 180 patients to receive 2:1 Evrysdi or a placebo for 12 months before switching to Evrysdi for another 12 months.1 Participants in both groups ranged from those who were ambulatory to those unable to even sit.

Results from part 1 of the trial showed that patients given Evrysdi had a 3.99 point difference (P <.0001)12 in score from baseline compared to a natural history cohort on the Motor Function Measure 32 (MFM32) scale13 after 24 months. Evrysdi also achieved a doubling in blood SMN levels 4 weeks into treatment that was sustained through 24 months.12

Part 2 of the trial showed that treatment resulted in an average 1.55 point difference (P <.0156) in change from baseline MFM32 scores compared to patients receiving placebo after 12 months.12 Patients in part 2 of the trial will continue being monitored for up to 24 months and then will have the option to join a 3-year open-label extension. Results from the first 12 months of part 2 of SUNFISH along with part 1 of FIREFISH were used in the regulatory approval of Evrysdi for children, adolescents, and adults. The study is estimated to conclude in September 2023.


An open-label phase 2 trial in SMA patients aged 6 months to 60 years, called JEWELFISH (NCT03032172), is investigating the use of Evrysdi in patients previously given other treatments for SMA, including Spinrazaor Zolgensma. The trial recruited 174 patients, 83 having received other Roche investigational compounds, 76 previously given Spinraza, and 14 treated with Zolgensma.12 The JEWELFISH trial is ongoing and preliminary results indicate no additional safety risks to patients previously treated for SMA, compared to those who are treatment-naïve, and showed twofold increases in SMN levels — similar to those seen in the SUNFISH trial.14 JEWELFISH is expected to conclude in December 2024.


The RAINBOWFISH trial (NCT03779334) is currently recruiting infants up to 6 weeks old with a genetic diagnosis of SMA but without symptom onset. The study aims to recruit up to 25 patients at clinical trial sites throughout the world. Infants will receive Evrysdi daily for 24 months with a 3-year extension.15 Patients with 2 copies of SMN2 will be tested for the ability to sit without support for 5 seconds after 12 months of treatment.15 A number of pharmacokinetic, growth, and motor functions will also be monitored.15 Interim results from the trial demonstrated that presymptomatic infants with SMA who were treated with Evrysdi were able to reach motor function milestones. Those milestones included sitting without support, rolling, crawling, standing unaided, and walking independently.16 The estimated study completion is January 2027.

Reviewed by Michael Sapko, MD on 7/1/2021


  1. Evrysdi. Prescribing information. Genentech, Inc. 2020. Accessed June 11, 2021.
  2. Roche’s Evrysdi approved by European Commission as first and only treatment for spinal muscular atrophy. News release. Roche. March 30, 2021.
  3. Evrysdi. Cure SMA. Published June 28, 2019. Accessed June 7, 2021.
  4. Chaytow H, Huang Y-T, Gillingwater TH, Faller KME. The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci. 2018;75(21):3877-3894. doi:10.1007/s00018-018-2849-1.
  5. Lorson CL, Rindt H, Shababi M. Spinal muscular atrophy: mechanisms and therapeutic strategies. Hum Mol Genet. 2010;19(R1):R111-8. doi:10.1093/hmg/ddq147
  6. SMN2 gene. MedlinePlus. Accessed June 7, 2021.
  7. Singh RN, Ottesen EW, Singh NN. The first orally deliverable small molecule for the treatment of spinal muscular atrophy. Sage Journals. 2020;15:2633105520973985. doi:10.1177/2633105520973985
  8. The safety profile of Evrysdi has been evaluated in 3 clinical trials. Evrysdi-hcp.com.  Accessed June 7, 2021.
  9. Sturm S, Günther A, Jaber B, et al. A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. Br J Clin Pharmacol. 2019;85(1):181-193. doi: 10.1111/bcp.13786
  10. Baranello G, Darras BT, Day JW, et al. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med. 2021;384(10):915-923. doi:10.1056/NEJMoa2009965
  11. Data in infants with type 1 SMA treated with Evrysdi. Evrysdi-hcp.com. Accessed April 17, 2021. 
  12. Roche announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with spinal muscular atrophy (SMA). News release. Roche. June 12, 2020. 
  13. Trundell D, Le Scouiller S, Le Goff L, Gorni K, Vuillerot C. Assessment of the validity and reliability of the 32-item Motor Function Measure in individuals with type 2 or non-ambulant type 3 spinal muscular atrophy. PLoS One. 2020;15(9):e0238786. doi:10.1371/journal.pone.0238786
  14. JEWELFISH: Safety and pharmacodynamic data in non-naïve patients with spinal muscular atrophy (SMA) receiving treatment with risdiplam. MDAconference.org.  Accessed April 18, 2021.
  15. RAINBOWFISH: A study of risdiplam in newborns with presymptomatic spinal muscular atrophy (SMA). MDAconference.org. Accessed June 7, 2021.
  16. Pre-symptomatic infants with spinal muscular atrophy achieved same motor milestones as healthy children after treatment with Evrysdi™ in RAINBOWFISH. News release. PTC Therapeutics, Inc. June 10, 2021.