General Information

Evrysdi (risdiplam) is a survival of motor neuron 2 (SMN2) splicing modifier.

Evrysdi is specifically indicated for the treatment of spinal muscular atrophy (SMA) in patients of all ages.

Evrysdi is supplied as an oral solution. Evrysdi must be constituted by a pharmacist prior to dispensing. Administer orally once daily after a meal using the provided oral syringe. In infants who are breastfed, Evrysdi should be administered after breastfeeding. Evrysdi cannot be mixed with formula or milk. Instruct patients to drink water after taking Evrysdi to ensure the drug has been completely swallowed. If the patient is unable to swallow and has a nasogastric or gastrostomy tube, Evrysdi can be administered via the tube. The tube should be flushed with water after delivering Evrysdi. The recommended dosage is determined by age and body weight:

2 months to less than 2 years of age: 0.2 mg/kg

2 years of age and older weighing less than 20 kg: 0.25 mg/kg

2 years of age and older weighing 20 kg or more: 5 mg

Mechanism of Action

Evrysdi (risdiplam) is a survival of motor neuron 2 (SMN2) splicing modifier designed to treat patients with spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, risdiplam was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein in the brain. In vitro and in vivo data indicate that risdiplam may cause alternative splicing of additional genes, including FOXM1 and MADD. FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse effects seen in animals.

Clinical Trial Results

The FDA approval of Evrysdi was based on two clinical studies.

Infantile-onset SMA: The open-label, 2-part study included 21 patients who had an average age of 6.7 months when the study began. Efficacy was established based on the ability to sit without support for at least five seconds and survival without permanent ventilation. After 12 months of treatment, 41% of patients were able to sit independently for more than five seconds, a meaningful difference from the natural progression of the disease because almost all untreated infants with infantile-onset SMA cannot sit independently. After 23 or more months of treatment, 81% of patients were alive without permanent ventilation, which is a noticeable improvement from typical disease progression without treatment.

Later-onset SMA: The randomized, placebo-controlled study included 180 patients with SMA aged two to 25 years. The primary endpoint was the change from baseline in MFM32 (a test of motor function) total score at the one-year mark. Patients on Evrysdi saw an average 1.36 increase in their score at the one-year mark, compared to a 0.19 decrease in patients on placebo (inactive treatment).

Approval in infants under two months old was based on interim efficacy and safety data from the RAINBOWFISH study in newborns, which showed that the majority of pre-symptomatic babies treated with Evrysdi achieved key milestones such as sitting and standing with half walking after 12 months of treatment. Of the babies with 2 or 3 copies of the SMN2 gene (n=6), 100% were able to sit after one year of treatment with Evrysdi, 67% could stand and 50% of infants could walk independently. All infants were alive at 12 months without permanent ventilation.