In August 2020, the US Food and Drug Administration approved risdiplam, marketed under the brand name EvrysdiTM by Genentech, Inc., for the treatment of spinal muscular atrophy (SMA). Evrysdi is a survival of motor neuron 2 (SMN2) gene splicing modifier indicated for the treatment of SMA in patients 2 months of age and older.

Evrysdi is designed to treat patients with SMA caused by chromosome q5 mutations that result in a deficiency of survival of motor neuron protein.  The drug increases exon 7 inclusion in SMN2 messenger ribonucleic acid transcripts, leading to production of full-length survival of motor neuron protein in the brain. 

Clinical Trials

Approval of Evrysdi was based on two 2-part clinical trials, Study 1 (FIREFISH; Identifier: NCT02913482) and Study 2 (SUNFISH; Identifier: NCT02908685), which evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in patients with infantile-onset and later-onset SMA. 
FIREFISH assessed the safety and efficacy of Evrysdi in patients with Type 1 SMA (onset of symptoms between 28 days and 3 months of age). SUNFISH investigated the efficacy, safety, pharmacokinetics, and pharmacodynamics of Evrysdi in patients with Type 2 or Type 3 SMA. 

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In FIREFISH, efficacy of Evrysdi was established based on 2 criteria:

  • Ability to sit unsupported for at least 5 seconds; and
  • Survival without requiring permanent ventilation.

The first criterion was measured using Item 22 of the Bayley Scales of Infant and Toddler Development, Third Edition gross motor scale. Permanent ventilation was defined as requiring tracheostomy, greater than 21 consecutive days of noninvasive ventilation (≥16 h/d), or intubation, without the presence of an acute reversible event. 

Baseline demographics of patients enrolled in Part 1 of FIREFISH were: 71%, female; 81%, White; and 19%, Asian. All patients included in the study had either (1) genetic confirmation of homozygous deletion or (2) compound heterozygosity predictive of loss of SMN1 function and 2 copies of SMN2

Median age of onset of clinical symptoms of patients enrolled in Part 1 of FIREFISH was 2.0 months (range, 0.9-3.0); median age at enrollment was 6.7 months (range, 3.3-6.9). Median time between onset of symptoms and first dose of Evrysdi was 4.0 months (range, 2.0-5.8). Median duration of treatment was 14.8 months (range, 0.6-26.0); 19 patients received Evrysdi for a minimum duration of 12 months. 

Results of FIREFISH showed that 7 of 17 (41%) patients who received the recommended dosage of Evrysdi had the ability to sit independently for at least 5 seconds after 12 months of therapy. In addition, 19 of 21 (90%) patients were alive and did not require permanent ventilation (and reached ≥15 months of age) after 12 months of treatment. Moreover, 17 of 21 (81%) patients were alive and did not require permanent ventilation after at least 23 months of treatment with Evrysdi (and reached ≥28 months of age; median age, 32 months [range, 28-45]). 

These findings indicate that treatment with Evrysdi results in a clinically significant deviation from the natural history of untreated infantile-onset SMA (ie, in which patients would not have the ability to sit independently and no more than 25% would survive without requiring permanent ventilation after 14 months of age). 

In Study 2 (SUNFISH), efficacy was assessed using the 32-item Motor Function Measure 32 (MFM32) score, which measures motor function abilities related to daily function. The total MFM32 score is reported as a percentage of the maximum possible score, with higher scores indicating increased motor function. The primary endpoint of SUNFISH Part 2 was change in MFM32 score from baseline to month 12. 

Key secondary endpoints included the proportion of patients with a 3-point or greater change in MFM32 total score from baseline to month 12, as well as change in the total Revised Upper Limb Module (RULM) score from baseline to month 12. RULM assesses motor performance of the upper limb in patients with SMA, testing proximal and distal motor function of the arm. Total RULM scores range from 0 (no items can be performed) to 37 (all activities are performed without compensatory maneuvers). 

Baseline demographics of patients included in SUNFISH Part 2 were: 51%, female; 67%, White; 19%, Asian; 71%, Type 2 SMA; and 29%, Type 3 SMA. Median age of enrolled patients at the beginning of treatment was 9.0 years (range, 2-25), and median time between onset of symptoms and first dose of Evrysdi was 102.6 months (range, 1-275). Approximately two-thirds (67%) of patients were identified at baseline as having scoliosis, 32% of whose condition was characterized as severe. Mean baseline MFM32 and RULM scores of the patients included in the analysis were 46.1 and 20.1, respectively. 

Baseline demographic characteristics were reasonably balanced overall between Evrysdi and placebo groups. It was noted, however, that only 63% of patients in the Evrysdi group had scoliosis compared with 73% in the placebo group. 

Findings of SUNFISH revealed both a clinically meaningful and statistically significant difference in change of MFM32 total score from baseline to month 12 in patients given Evrysdi compared with those who received placebo. 

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Dosage and Administration

Evrysdi is supplied as 60 mg of dry powder in an amber glass bottle that is constituted to a 0.75-mg/mL oral solution (60 mg/80 mL Evrysdi) by a pharmacist prior to dispensing. Each bottle is packaged with a bottle adapter, two 6-mL reusable oral syringes, and two 12-mL reusable oral syringes.

Patient Counseling
Patient Counseling
Evrysdi should be dispensed as a liquid from the pharmacy; do not use if medicine in the bottle is a powder.

The recommended dosage of Evrysdi is based on age and body weight of the patient. For patients 2 months to less than 2 years of age, the recommended daily dosage is 0.2 mg/kg. For patients 2 years of age and older weighing less than 20 kg, the recommended daily dosage is 0.25 mg/kg. For patients 2 years of age and older weighing at least 20 kg, the recommended daily dosage is 5 mg. 

Evrysdi is taken by mouth once daily after a meal at the same approximate time each day. Patients should be instructed to drink water following administration to ensure that the medication has been swallowed completely. 

If a dose of Evrysdi is missed, it should be taken immediately if administration would still be within 6 hours of that missed dose. Otherwise, the dose should be skipped and Evrysdi should be administered at the regularly scheduled time the following day. If a dose was not completely swallowed or vomiting occurred after administration of Evrysdi, another dose should not be taken and the patient should continue regularly scheduled dosing the following day. 
In breastfed infants, Evrysdi should be administered after breastfeeding; it should not be mixed with formula or milk. Evrysdi can be administered via a nasogastric or gastrostomy tube. Flushing the tube with water following delivery of the medication is recommended.

Contraindications, Warnings, Precautions, and Adverse Reactions

Safety findings of Evrysdi for later-onset SMA are based on data obtained from Study 2 (SUNFISH) Part 2, which included 180 patients 2 to 25 years old with Type 2 or 3 SMA. Adverse reactions experienced by at least 5% of patients receiving Evrysdi that occurred at an incidence of at least 5% compared with patients receiving placebo were fever (22% and 17%, respectively), diarrhea (17% and 8%), rash (17% and 2%), mouth and aphthous ulcers (7% and 0%), arthralgia (5% and 0%), and urinary tract infection (5% and 0%). 
Safety findings of Evrysdi for infantile-onset SMA are based on data from Study 1 (FIREFISH) Parts 1 and 2, which included 62 patients with Type 1 SMA. Patients included in the study were 2 to 7 months old at treatment initiation. Patients received Evrysdi for up to 30 months (31 patients received therapy for >12 months). The most frequently reported adverse reactions in patients receiving Evrysdi in FIREFISH were similar to those observed in patients in SUNFISH. Adverse reactions that were reported in at least 10% of patients in FIREFISH receiving Evrysdi included upper respiratory tract infection, pneumonia, constipation, and vomiting. 

Drug Interactions

Coadministration of Evrysdi and substrates eliminated by multidrug and toxin extrusion (MATE) 1 or MATE2-K protein transporters should be avoided because Evrysdi can increase the plasma concentrations of these medications. If coadministration is necessary, drug-related toxicity should be monitored, and dosage reduction of the coadministered medication should be considered. 

Considerations for Specific Populations

There are insufficient data on the developmental risk associated with administering Evrysdi to pregnant women. Animal study data revealed that clinically relevant or higher drug exposure during pregnancy and lactation was associated with developmental adverse effects such as embryofetal mortality, malformations, and decreased fetal body weight, as well as reproductive impairment in offspring. Pregnant women should be counseled on the potential risks of Evrysdi use during pregnancy. 
No data currently exist on the presence of Evrysdi in breast milk, its effect in a breastfed child, or its effect on milk production. Animal studies revealed Evrysdi to be excreted in the milk of lactating rats receiving orally administered treatment. The benefits of breastfeeding, a mother’s clinical need for Evrysdi, and potential adverse effects of Evrysdi and the underlying maternal condition on the breastfed child should be considered.
Animal studies in juvenile and adult rats and in monkeys revealed clinically relevant plasma exposure of Evrysdi to be associated with adverse effects on reproductive organs in males. Male patients should be counseled on the potential effects of Evrysdi on their fertility and advised to consider sperm preservation prior to receiving therapy. 
Prior to initiating Evrysdi, it is recommended that female patients of reproductive potential complete a pregnancy test. Additionally, effective contraception should be used by female patients of reproductive potential during treatment with Evrysdi and for at least 1 month after the last dose. 

The efficacy and safety of Evrysdi have been established in pediatric patients 2 months of age and older. Safety and effectiveness have not been established in pediatric patients less than 2 months of age. The studies did not include patients aged 65 years and older to determine whether the efficacy and safety of Evrysdi differ from what is established in younger patients.
The effects of Evrysdi on patients with hepatic impairment have not been studied. Because Evrysdi is metabolized primarily by the liver, it should be avoided in patients with hepatic impairment. 

Key Takeaways

  • Evrysdi is approved for use in patients 2 months of age and older for the treatment of SMA.
  • Evrysdi should be administered by mouth once daily after a meal at approximately the same time every day using the reusable oral syringe provided.
  • Patients should receive the constituted oral solution of Evrysdi from the pharmacy and should store it in a refrigerator.
  • Coadministration with drugs that are substrates of MATE transporters should be avoided.


Evrysdi. Prescribing information. Genentech; 2020. Accessed January 26, 2021.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.

Reviewed April 2021