Risdiplam
Risdiplam, sold under the brand name Evrysdi, is a small-molecule survival motor neuron 2 (SMN2) splicing modifier used to treat spinal muscular atrophy (SMA), a rare genetic neuromuscular disorder caused by mutations in the SMN1 gene that lead to insufficient SMN protein production. By promoting the inclusion of exon 7 in SMN2 mRNA transcripts, risdiplam increases systemic levels of full-length SMN protein, addressing the underlying cause of SMA and improving motor function in affected patients.[1][2] Approved by the U.S. Food and Drug Administration (FDA) in August 2020 for patients two months of age and older, it represents the first oral, at-home SMA therapy, available as a powder for oral solution or, since February 2025, a dispersible tablet for individuals aged two years and older weighing more than 44 pounds.[3][4] Developed collaboratively by PTC Therapeutics, the SMA Foundation, and Roche/Genentech, risdiplam received orphan drug designation from the FDA in 2017 and from the European Medicines Agency in 2019, followed by FDA breakthrough therapy status in 2019, accelerating its path to approval based on promising early clinical data.[5] The drug's efficacy was demonstrated in pivotal phase 3 trials, including FIREFISH for infantile-onset (type 1) SMA and SUNFISH for later-onset (types 2 and 3) SMA. In FIREFISH, 29% of treated infants achieved the ability to sit without support for at least five seconds after 12 months, compared to 0% in historical controls, with 85% event-free survival (no death or permanent ventilation).[6] In SUNFISH, patients receiving risdiplam showed a statistically significant 1.36-point improvement in the Motor Function Measure-32 (MFM-32) scale after one year, versus a 0.19-point decline in the placebo group, indicating sustained motor benefits over 24 months.[3][1] Risdiplam is administered once daily after a meal, with dosing weight- and age-based: 0.15 mg/kg for infants under two months, up to a fixed 5 mg for adults and children over 20 kg. Common adverse effects include fever, diarrhea, rash, and respiratory infections, particularly in younger patients, though serious events like pneumonia occur in a minority.[1] Ongoing studies, such as JEWELFISH and RAINBOWFISH, continue to evaluate its safety and effectiveness in broader populations, including those previously treated with other SMA therapies like nusinersen or onasemnogene abeparvovec, confirming stable or improved motor outcomes with long-term use up to 30 months.[7][8] As of 2025, risdiplam remains a cornerstone of SMA management, offering a noninvasive alternative that enhances accessibility for lifelong treatment.Medical uses
Indications
Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients of all ages, including those with types 1, 2, and 3 disease.[9] This approval covers symptomatic patients across these SMA subtypes, where risdiplam addresses the underlying genetic defect by enhancing survival motor neuron (SMN) protein production.[9] The indication was extended in 2022 to include infants under 2 months of age based on interim data from the RAINBOWFISH trial, which demonstrated significant motor and survival benefits in presymptomatic infants; full results were published in 2025.[10][11] This expansion supports early intervention through newborn screening programs, allowing treatment initiation before symptom onset in infants with confirmed biallelic SMN1 mutations.[11] In adults with 5q-SMA, risdiplam is utilized, as evidenced by a 2025 observational cohort study published in eClinicalMedicine (The Lancet).[12] The study highlighted stable or improved motor function in treatment-naïve adults, underscoring its applicability in later-onset and advanced disease presentations.[12] Investigational use of risdiplam in combination with gene therapies, such as onasemnogene abeparvovec, is being explored, with 2025 data showing feasibility and potential additive efficacy in post-gene therapy SMA patients.[13] As the first approved oral therapy for SMA, risdiplam facilitates at-home administration, improving accessibility for patients across age groups.[14]Dosage and administration
Risdiplam is administered orally once daily, with dosing determined by the patient's age and body weight. For infants younger than 2 months of age, the recommended dose is 0.15 mg/kg body weight using the oral solution formulation.[1] For children aged 2 months to less than 2 years, the dose is 0.2 mg/kg body weight, also via oral solution.[1] In patients 2 years and older weighing less than 20 kg, the dose is 0.25 mg/kg body weight with the oral solution.[9] For those 2 years and older weighing 20 kg or more, a fixed dose of 5 mg is used, which may be given as either the oral solution or the tablet formulation approved by the FDA in February 2025.[9][15]| Age Group | Body Weight | Recommended Dose | Formulation |
|---|---|---|---|
| < 2 months | All | 0.15 mg/kg once daily | Oral solution |
| 2 months to < 2 years | All | 0.2 mg/kg once daily | Oral solution |
| ≥ 2 years | < 20 kg | 0.25 mg/kg once daily | Oral solution |
| ≥ 2 years | ≥ 20 kg | 5 mg once daily | Oral solution or tablet |