Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities

ABSTRACT

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative neuromuscular disease that presents primarily in children. Abnormalities in the SMN1 gene cause reduced levels of the survival motor neuron (SMN) protein, while a second gene, SMN2, produces low levels of functional SMN protein. Currently available drugs do not cure, so a significant unmet need remains for patients treated after symptom onset.

Areas covered

Drugs available in the clinic, investigational agents and key questions for researchers are discussed. A pragmatic search of the literature was performed to identify therapies in late stages of preclinical, or in early stages of clinical development. This list was compared to the CureSMA pipeline for completeness. Drugs approved for indications that have potential for impact for SMA were included. These drugs target the primary deficiency in SMN protein or other pathways involved in SMA pathophysiology that are not SMN-protein dependent.

Expert opinion

Children treated after the onset of symptoms continue to have significant disability. Given the heterogeneity of the population phenotype evidenced by variable response to initial therapy, age at treatment onset and the need to demonstrate added value beyond approved therapeutics, the clinical development of new drugs will be challenging.

KEYWORDS:

• Antimyostatin
• drug repositioning
• gene therapy
• smn1 gene
• spinal muscular atrophy
• nusinersen
• risdiplam
• onasemnogene abeparvovec
• clinical trials

Article highlights

• Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative neuromuscular disease. Abnormalities in the SMN1 gene cause reduced levels of the survival motor neuron (SMN) protein. Moreover, a second gene, SMN2, produces low levels of functional SMN protein.

• SMA presents primarily in children. There is no cure and hence a significant unmet need remains.

• Three disease-modifying drugs (nusinersen, risdiplam and onasemnogene abeparvovec) are approved by the FDA for treatment of SMA. The purpose of these therapies is to restore the levels of SMN protein; they significantly improve outcomes for affected children.

• The number of surviving motoneurons may constitute a limiting factor of current treatment effects. Patients treated after the onset of symptoms have not exhibited normal motor development. New therapies targeting non-SMN pathways have potential for combination with currently approved drugs for enhanced impact.

• Several candidate drugs are in various stages of development [from academic proof of concept to early phase of clinical development]. These constitute a pipeline for monotherapy or combination therapy.

• These candidate drugs correct for the lack of a functional SMN gene through gene transfer, induce alternative splicing of the SMN2 pre-mRNA to optimize full-length protein expression, improve neuromuscular junction (NMJ) transmission, improve muscle contraction and size, or act by other molecular mechanisms in the motoneurons.

• Given the heterogeneity of the population phenotype evidenced by variable response to initial therapy and age at treatment onset and the need to demonstrate added value beyond approved therapeutics, the clinical development of these new drugs will be challenging.

This box summarizes key points contained in the article.

Declaration of interest

L Servais is a Principal investigator in Roche, Avexis and Biogen trials. He is a member of the board of Biogen/Roche/Avexis/Cytokinetics and conducts research funded through IIT from Roche, Biogen and Avexis. G Baranello is an investigator in spinal muscular atrophy (SMA) trials sponsored by AveXis, Roche and Novartis. He has received compensation for participation at symposia and scientific advisory boards from Roche and AveXis. M Scoto is investigator for Roche, Biogen and Avexis clinical trials, and has received speaker and consultancy honoraria For Roche, Avexis and Biogen. A Daron is investigator for Roche and Avexis clinical trials and received honoraria for consultancy for Scientific Advisory board of Avexis Belgium. M Oskoui is investigator for Roche, Biogen and Cytokinetics SMA clinical trials, and has previously served on the data safety monitoring board for Avexis. 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

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