LOS ANGELES — Four years ago, individuals with spinal muscular atrophy (SMA) had no therapies that could slow the disease. Today, three disease-modifying drugs have approval from the U.S. Food and Drug Administration and at least five more have begun clinical trials.
The dramatic shift may be attributed to two transformative trends. Turbocharged by social media platforms, efforts by patients, caregivers, advocacy organizations and rare disease research foundations to connect with each other, give greater voice to their issues, and attract researchers and investment have seen unprecedented success over the last decade. At the same time, breakthroughs in genetic analysis have provided insights into rare inherited diseases that illuminate pathways to mitigation or a cure for the first time.
For one scientist, these two developments intersected in a way that changed the course of his research and many patients’ lives. Chien-Ping Ko, PhD, a neuroscientist at the University of Southern California in Los Angeles, had focused for years on neuromuscular connections. That work led him to study the neuromuscular junction, the path from particular neurons to specific muscles, in mice with SMA to better understand why the disease severely affected some muscles and largely spared others.
Ko’s view of the work suddenly took a personal turn when a family with two daughters with SMA visited his lab. Both girls used wheelchairs and had limited ability to move on their own. “The mother said, ‘If we could help them just comb their hair, that would be a big relief.’ I didn’t even think about such a simple thing, how one minor improvement could make such a big difference,” Ko said.
Ultimately, Ko figured out why muscles and nerve connections fail quickly in some children with SMA–keeping them from not just combing their hair, but from even breathing on their own—and why those connections work in others for years. Then he shared that knowledge with pharmaceutical companies to enable them to make more effective and more targeted drugs. Throughout, the National Institutes of Health and several rare disease research organizations provided critical funding.
In a rare experience for a scientist who labors in basic research and preclinical studies, Ko saw his work culminate in an FDA-approved drug. With his colleagues at USC, and researchers from the SMA Foundation and two pharmaceutical companies, Ko discovered risdiplam.1
Approved in August 2020, risdiplam contains a survival of motor neuron 2 (SMN2)-directed RNA splicing modifier that increases the production of full-length SMN2 mRNA, which increases SMN protein levels in the central nervous system and peripheral organs and tissues. Higher protein levels mitigate the muscle atrophy and other complications caused by having no functional SMN1 gene. Risdiplam (Evrysdi) is indicated for SMA patients two months of age and older. Studies are in progress for use of the drug in infants younger than six weeks at first dose.
“Evrysdi is the first drug for this disease that can be taken orally, providing an important treatment option for patients with SMA, following the approval of the first treatment for this devastating disease less than four years ago,” said Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research.
The daily therapy leads to significant improvement. After one year of treatment, 41% of the 21 infants in the study with type 1 SMA could sit without support for at least five seconds, “a meaningful difference from the natural progression of the disease because almost all untreated infants with infantile-onset SMA cannot sit up independently,” the FDA noted. After 24 months, 81% of children taking risdiplam required no permanent ventilation, also a notable improvement compared to typical disease progression.
Among 180 patients enrolled in the ongoing randomized, placebo-controlled SUNFISH study of risdiplam in patients aged two to 25 with later-onset SMA, those on risdiplam achieved an average 1.36 point increase in the MFM32 test of motor function after one year compared to an 0.19 decrease in those on placebo. This is the only placebo-controlled trial in adults with types 2 and 3 SMA conducted to date.
An update to the SUNFISH results presented at the virtual Cure SMA Annual Conference in June 2020 found a 3.99 point improvement in patients receiving risdiplam at 24 months and a doubling of blood SMN protein levels after four weeks that was maintained for at least two years.
The first drug approved for SMA, nusinersen, also modifies the alternative splicing of SMN2 seen in SMA. Approved in December 2016, nusinersen is an antisense oligonucleotide administered via spinal injection. Treatment with the drug starts with four loading doses within two months, followed by maintenance doses every four months.
Approved in 2019, the third treatment, onasemnogene abeparvovec-xioi, is a gene therapy indicated for use in babies under age two with SMA type 1 (infantile-onset). Onasemnogene abeparvovec-xioi is administered as a one-time intravenous injection. An adeno-associated virus vector delivers a fully functional copy of the SMN gene to the target motor neuron cells, correcting the primary cause of SMA and leading to expression of the SMN protein in the neurons.
- Ratni H, Ebeling M, Baird J, Bendels S,et. Al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Aug 9;61(15):6501-6517. doi: 10.1021/acs.jmedchem.8b00741. Epub 2018 Jul 25. PMID: 30044619.