Two drugs now approved in the U.S., and a third is under review

New treatments for 5q spinal muscular atrophy (SMA), a severe, inherited, progressive neuromuscular disease, have changed the course of patients’ lives.

These drugs are part of an ongoing story illustrating how molecular knowledge can identify, implement, and improve treatments in SMA. Disease-modifying therapies — two approved and one under FDA review — are sited along pathways for producing SMN protein, and evidence has supported their efficacy, especially early in the disease.

“Clinical trial data has clearly demonstrated that early intervention with treatment for spinal muscular atrophy improves motor function outcomes and improves survival,” said Crystal Proud, MD, director of the SMA Center at Children’s Hospital of The King’s Daughters in Norfolk, Virginia.

“Without treatment, spinal muscular atrophy leads to progressive muscle weakness, with most patients experiencing a severely shortened lifespan,” Proud wrote in an email to BreakingMED. “Signs and symptoms of spinal muscular atrophy may be under-recognized and there are well-documented delays between the onset of symptoms and the subsequent genetic confirmation of SMA.”

The new treatments highlight the need to screen newborn babies, she indicated: “I am optimistic that newborn screening will capture the majority of patients with SMA to support early institution of treatment, and ultimately lead to improved survival and greater strength of patients impacted by this disease.”

Pathways to Functional SMN Protein

Functional SMN protein is produced by transcription of SMN1 or SMN2 gene instructions into pre-mRNA oligonucleotide sequences containing regions that should (exons) and should not (introns) be included in mature mRNA that will be transcribed into protein. The process of removing introns from a pre-mRNA transcript, resulting in sequential, adjacent exons (mature mRNA) is called splicing.

In SMA, the SMN1 gene is deleted or mutated, and the main source of SMN protein is gone. The inefficiency of SMN2 production of functional protein derives from a small difference between the two genes which often results in a mis-splice that omits the normally included exon 7 from the mature mRNA. Translation of this mRNA results in shorter, rapidly degraded, nonfunctional SMN.

Between 10% and 40% of SMN protein produced by SMN2 avoids this fate and has normal length and functionality. Having fewer than the usual two copies of SMN2 in this setting leads to more severe SMA, while having more leads to later onset of less severe disease. These insights provided targets for therapy aimed at boosting functional SMN levels.


Nusinersen (Spinraza), an antisense oligonucleotide given by intrathecal injection, was approved in 2016 as the first disease-modifying therapy for children and adults with all SMA types.

Support for FDA approval included two phase III trials, ENDEAR and CHERISH. ENDEAR looked at 121 patients with SMA type I and was stopped early after interim analysis showed primary end points favored nusinersen. In the final analysis, a significantly higher percentage of infants in the nusinersen group had a motor-milestone response than in the control group (37 of 73 in the nusinersen group, 0 of 27 in controls). The likelihood of event-free survival also was higher in the nusinersen group (HR for death or permanent assisted ventilation 0.53; P=0.005). Incidence and severity of adverse events were similar in the two groups.

CHERISH studied 126 SMA patients who had symptom onset after 6 months of age. The trial was stopped after interim analysis showed increase in motor scores in the nusinersen group and decrease in the sham treatment group, with a least-squares mean difference in change of 5.9 points (95% CI 3.7 to 8.1; P< 0.001). Overall incidence of adverse events was similar in both groups.

The most common adverse effects in the trials included upper and lower respiratory infections and constipation. The medication carries warnings for thrombocytopenia and renal toxicity.

Both studies suggested earlier treatment was more efficacious. In the ongoing NURTURE study of pre-symptomatic infants, data showed an 88% rate of independent walking after median 2.9 years of follow-up, and benefits appear to be sustained. Observational data also has shown evidence for nusinersen’s safety and efficacy in adults with SMA.

Onasemnogene abeparvovec

Onasemnogene abeparvovec (Zolgensma) was approved in 2019 for infantile-onset SMA in children less than 2 years old with bi-allelic SMN1 mutations. The single-dose intravenous drug delivers a working SMN gene enclosed in a viral capsid.

The FDA’s decision was based on an ongoing and a completed trial involving a total of 36 pediatric patients with infantile-onset SMA. In START, patients with SMA type I who had a single infusion of onasemnogene abeparvovec showed longer survival, better achievement of motor milestones, and better motor function than historical cohorts.

In STR1VE, recent data presented at meetings have indicated that 90% of infants met the co-primary endpoint of event-free survival at 14 months and 50% met the co-primary endpoint of sitting for 30 or more seconds at 18 months of age. The ongoing open-label, single-arm SPR1NT study also is exploring treatment in pre-symptomatic patients with SMA and two or three copies of SMN2 who are under 6 weeks old.

Most common adverse effects seen with onasemnogene abeparvovec were elevated aminotransferases and vomiting, and the drug carries warnings for thrombocytopenia and elevated tropinin-I.


Risdiplam is an investigational, orally administered, centrally and peripherally distributed SMN2 pre-mRNA splicing modifier that increases functional SMN protein levels. It currently is under FDA review, with a decision expected later this summer.

Evidence supporting risdiplam has been presented at meetings and spans the SMA disease spectrum:

  • FIREFISH, an ongoing open-label study of risdiplam, showed that infants age 1-7 months with SMA type I who were treated with investigational risdiplam for a year experienced significant gain in motor function.
  • The ongoing SUNFISH trial demonstrated significantly improved motor function and improvements in independence in daily living activities in patients age 2 to 25 years with SMA type II or type III.
  • In the JEWELFISH study of people with all types of SMA who previously were treated with other SMA therapies, risdiplam led to sustained increases in SMN protein levels.

Pooled safety data from these trials reported no treatment-related withdrawals, no evidence of retinal toxicity (which had been observed in earlier animal studies), stable hematologic parameters, and no evidence of QT prolongation. Serious adverse events were greater than 7 times higher for SMA type I versus types II or III and included respiratory tract infections and respiratory failure.

Another study, RAINBOWFISH, is underway to investigate risdiplam in babies from birth to 6 weeks of age with genetically diagnosed SMA who do not yet have symptoms.

Questions Remain

Striking responses seen with these treatments may give the impression that SMA has been solved, noted Charlotte Sumner, MD, of Johns Hopkins University, but this misperception is “an unfortunate casualty arising from dramatic success,” she said.

Success breeds new questions, Sumner observed. These include why current therapies differ in their efficacy, whether optimal timing of starting therapy varies in different patients, and how to best monitor therapeutic efficacy.

“Can or should current therapeutics be combined?” Sumner wrote in an email to BreakingMED. “Can novel therapeutics that act with current drugs be designed to further improve therapeutic efficacy?”

A better understanding of SMA also is needed, she indicated. “What are the molecular and cellular events that cause motor neuron dysfunction and death as a result of SMN protein deficiency?” she asked. “Can these be targeted therapeutically?”

  1. Two approved disease-modifying treatments for 5q spinal muscular atrophy (SMA) and one under FDA review focus on ways to transcribe and translate functional SMN protein.

  2. Clinical trial data have shown that treating SMA early with these drugs improves motor function outcomes and survival.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Trials of nusinersen were funded by Biogen and Ionis Pharmaceuticals. Onasemnogene abeparvovec trials were funded by Novartis. Studies of risdiplam were funded by Genentech, a member of the Roche Group.

Proud reported relationships with AveXis and Biogen.

Sumner reported relationships with Biogen, Roche, Genentech, AveXis, Cytokinetics, and Proneurotech. She serves as an associate editor at Journal of Clinical Investigation.

Cat ID: 130

Topic ID: 82,130,730,130,192,925