The FDA has approved Roche and PTC Therapeutics’ risdiplam, an RNA splice-modifying small-molecule drug, for spinal muscular atrophy (SMA).
Drugs that can force the alternative splicing of mRNA templates, shifting protein production profiles, have long been on industry’s watch list. Pioneering approvals in this space include Sarepta’s eteplirsen, for Duchenne muscular dystrophy, and Biogen and Ionis Pharmaceuticals' nusinersen, for SMA. But whereas both these agents are oligonucleotide therapeutics, risdiplam is a small-molecule drug.
Like nusinersen, risdiplam modulates the splicing of the SMN2 gene to promote exon 7 inclusion. This results in the production of a full-length SMN protein, compensating for loss-of-function mutations in SMN1 that otherwise cause the muscle wasting disease. The FDA approved risdiplam on the basis of two studies. In an open-label study in 21 patients with infantile-onset SMA, 41% of patients were able to sit independently for more than 5 seconds after 12 months of treatment. Also, 90% of infants were alive without permanent ventilation at 12 months of treatment and reached 15 months of age or older. Natural history studies of untreated infantile-onset SMA suggest that infants would otherwise not be able to sit independently, and only 25% would survive without permanent ventilation beyond 14 months of age. In a placebo-controlled trial in 180 patients with later-onset SMA, treated patients experienced an increase in motor function, as assessed by the MFM32 test, of 1.36 on treatment, compared with a 0.19 decrease on placebo.
Whereas nusinersen is dosed intrathecally in the clinic, risdiplam is orally available and can be administered at home.
In addition to competition from nusinersen, risdiplam will also face off against Novartis’s gene therapy onasemnogene abeparvovec, which delivers a functional SMN transgene.
Industry’s interest in RNA-targeted small-molecule drugs is growing. In April, Roche partnered with Arrakis Therapeutics on RNA-targeted small-molecule drug discovery. Other biotechs that are working preclinically on RNA-targeted small molecules include Expansion Therapeutics, Skyhawk Therapeutics and Ribometrix.
Nature Reviews Drug Discovery 19, 659 (2020)