|Other names||RG7916; RO7034067|
|Drug class||SMN2-directed RNA splicing modifier|
|Main uses||Spinal muscular atrophy (SMA)|
|Side effects||Fever, diarrhea, rash, pneumonia, vomiting|
|Typical dose||0.2 mg/kg up to 5 mg OD|
|Chemical and physical data|
|Molar mass||401.474 g·mol−1|
|3D model (JSmol)|
Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA). This includes type 1, type 2, and type 3 disease. It is used in those who are at least two months old. It is taken by mouth.
Risdiplam was approved for medical use in the United States in 2020 and Europe in 2021. In the United States 60 mg costs about 11,700 USD as of 2021. In the United Kingdom this amount costs the NHS about £7900.
In the infantile-onset SMA study, an open-label trial with 41 participants, efficacy was established based on the ability to sit without support for at least five seconds. After 12 months of treatment, 29% of participants were able to sit independently for more than five seconds. After 23 or more months of treatment, 81% of participants were alive without permanent ventilation. Although the study did not perform direct comparisons against children receiving a placebo (inactive treatment), these results compare favourably with the typical course of the untreated disease.
The study of later-onset SMA was a randomised controlled trial that enrolled 180 participants, aged between 2 and 25 years, with less severe forms of the disease. Participants treated with risdiplam for 12 months showed improvements in motor function compared to participants given a placebo.
An open-label phase II-III study enrolled 21 infants age 1 month to 7 months and concluded its dose-determination and safety initial phase in 2021. Retinotoxicity, a side effect seen in animal models, was not observed in the study population. It also showed an increase in blood levels of functional SMN protein.
In two clinical trials, the following adverse events occurred at least 5% more frequently in patients treated with risdiplam than in the placebo group: fever, diarrhoea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections. Additional adverse events for the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting.
Mechanism of action
Risdiplam addresses the underlying cause of SMA: a reduced amount of survival motor neuron (SMN) protein. The protein is encoded by the SMN1 and SMN2 genes. SMA is caused by mutations in SMN1 that code for inactive forms of the protein. The activity of the SMN2 gene, which produces much smaller quantities of SMN, tends to determine the severity of disease.
The compound is a pyridazine derivative that modifies the splicing of SMN2 messenger RNA to include exon 7, resulting in an increase in the concentration of the functional SMN protein in vivo.
Society and culture
The US Food and Drug Administration (FDA) awarded marketing approval to Genentech on August 7, 2020. The FDA earlier granted the application for risdiplam fast track, priority review, and orphan drug designations. Genentech was also awarded a rare pediatric disease priority review voucher.
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