In most patients with spinal muscular atrophy (SMA), a deletion mutation in exon 7 of the SMN1 gene is the cause of the disease.1,2 SMN1 is the principal producer of Survival Motor Neuron (SMN) protein. A lack of SMN protein, in turn, causes many of the signs and symptoms of SMA.3 SMN2, a related gene, is also able to produce SMN protein. To some degree, the presence of SMN2 is partially protective—the number of SMN2 copies correlates with survival duration and inversely correlates with the weakness.2 Unfortunately, the gene product of SMN2 is unstable.4 Consequently, SMN2 gene products are unable to fully overcome deletion of the SMN1 gene.5,6
Nonetheless, researchers have capitalized on the fact that many patients with SMA have at least one normal copy of SMN2. Certain small molecules have been shown to enhance the stability of the endogenous SMN2 gene product.7 Stabilizing SMN2 gene products at least partially rescues many of the disease phenotypes in a mouse model of severe SMA such as motor dysfunction, neuromuscular degeneration, and shortened lifespan.7,8
Risdiplam (RG7916, RO7034067; developed by Roche) is a small molecule investigational therapeutic that can modify the splicing patterns of SMN2 mRNA. A phase I trial showed Risdiplam was safe and well-tolerated in healthy adult volunteers.8 Moreover, the compound increased full-length SMN2 mRNA levels in ex vivo blood samples, while decreasing SMN2 mRNA fragments that are the typical SMN2 gene products in all humans.8,9
Risdiplam is currently being tested in a number of phase II clinical trials with the names FIREFISH,
SUNFISH, and JEWELFISH. FIREFISH (NCT02913482) is an open-label study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of the small molecule in infants with SMA Type 1. The first part of the trial is to find a clinically appropriate dose and the second part expands the trial using that dose. SUNFISH (NCT02908685) is randomized, double-blind, placebo-controlled clinical trial in patients aged 2 to 25 with SMA Type 2 and SMA Type 3. JEWELFISH (NCT03032172) also focuses on patients with SMA Type 2/3, but includes only those who have been treated with SMN2-targeting therapies in previous trials.
Primary completion dates for pivotal trials are in 2019/2020; however, some preliminary safety data have been presented. The molecule is (so far) considered safe and well-tolerated with some indication of benefit in patients with SMA.8,10
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2. Wirth B. An Update of the Mutation Spectrum of the Survival Motor Neuron Gene (Smn1) in Autosomal Recessive Spinal Muscular Atrophy (Sma). Hum Mutat. 2000;15(3):228-237. doi:10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9
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5. Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, Incidence and Carrier Frequency of 5q-Linked Spinal Muscular Atrophy – a Literature Review. Orphanet J Rare Dis. 2017;12(1):124. doi:10.1186/s13023-017-0671-8
6. Peeters K, Chamova T, Jordanova A. Clinical and Genetic Diversity of Smn1-Negative Proximal Spinal Muscular Atrophies. Brain. 2014;137(Pt 11):2879-2896. doi:10.1093/brain/awu169
7. Naryshkin NA, Weetall M, Dakka A, et al. Motor Neuron Disease. Smn2 Splicing Modifiers Improve Motor Function and Longevity in Mice with Spinal Muscular Atrophy. Science. 2014;345(6197):688-693. doi:10.1126/science.1250127
8. Shorrock HK, Gillingwater TH, Groen EJN. Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy. Drugs. 2018;78(3):293-305. doi:10.1007/s40265-018-0868-8
9. Sturm S, Gunther A, Navé S, et al. The Smn2 Splicing Modifier Rg7916 Induces a Dose-Dependent Increase of Full Length Smn2 Mrna. Paper presented at: Annals of Neurology2016.
10. Mercuri E, Kirschner J, Baranello G, et al. Clinical Studies of Rg7916 in Patients with Spinal Muscular Atrophy: Sunfish Part 1 Study Update. Neuromuscular Disorders. 2017;27:S209. doi:10.1016/j.nmd.2017.06.415