Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)

ABSTRACT

Introduction

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease which is characterised by muscle atrophy and early death in most patients. Risdiplam is the third overall and first oral drug approved for SMA with disease-modifying potential. Risdiplam acts as a survival motor neuron 2 (SMN2) pre-mRNA splicing modifier with satisfactory safety and efficacy profile. This review aims to critically appraise the place of risdiplam in the map of SMA therapeutics.

Areas covered

This review gives an overview of the current market for SMA and presents the mechanism of action and the pharmacological properties of risdiplam. It also outlines the development of risdiplam from early preclinical stages through to the most recently published results from phase 2/3 clinical trials. Risdiplam has proved its efficacy in pivotal trials for SMA Types 1, 2, and 3 with a satisfactory safety profile.

Expert opinion

In the absence of comparative data with the other two approved drugs, the role of risdiplam in the treatment algorithm of affected individuals is examined in three different patient populations based on the age and diagnosis method (newborn screening or clinical, symptom-driven diagnosis). Long-term data and real-world data will play a fundamental role in its future.

KEYWORDS:

• Central nervous system (CNS)
• neuromuscular disorders
• risdiplam
• RNA splicing modifier
• SMN protein
• SMN1 gene
• SMN2 gene
• spinal muscular atrophy (SMA)

Article highlights

• Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease caused by a homozygous deletion or loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene, which codes for the survival motor neuron protein (SMN).

• A paralogous gene in humans, SMN2, produces functional SMN protein, but at low and insufficient levels due to naturally occurring alternative splicing that leads to a truncated transcript.

• Risdiplam is a small molecule that acts as an SMN2 pre-mRNA splicing modifier; it promotes the inclusion of exon 7.

• Risdiplam is delivered orally and has proved its efficacy in pivotal trials for SMA Types 1, 2, and 3 with a satisfactory safety profile. It was approved for clinical use by the US Food and Drug Administration in 2020.

• Currently, there are four ongoing clinical trials assessing risdiplam in different age groups and SMA types: the FIREFISH (NCT02913482), the SUNFISH (NCT02908685), the JEWELFISH (NCT03032172), and the RAINBOWFISH (NCT03779334) trials.

• Two other drugs (nusinersen and onasemnogene-abeparvovec-xioi), which aim to restore the SMN deficiency in motor neurons have been previously approved; all three approved drugs have different mechanisms and routes of administration.

• In the absence of comparative data between the approved drugs, three different patient populations need to be taken into consideration when trying to identify the role of risdiplam in the treatment algorithm of SMA.

This box summarizes key points contained in the article.

Declaration of interest

L Servais has been a consultant for F. Hoffmann-La Roche Ltd. He is a member of the Steering committee of MANATEE and RAINBOWFISH and coordinating investigator of Newborn Screening (NBS) for SMA in the UK and in Belgium, of which F. Hoffmann-La Roche Ltd. is a co-funder. S Ramdas is a member of the advisory boards for F. Hoffmann-La Roche Ltd., Novartis, and Sarepta. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer received consultant honoraria from Roche and Biogen and speakers fees (as well as research support) from Biogen, Roche and Novartis

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Supplementary material

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Additional information

Funding

The work was supported by the Onassis Foundation, of which T Markati is a Scholar (Scholarship ID: F ZQ 040-1/2020-2021).