Risplidam improves motor function in babies with spinal muscular atrophy

Until recently, babies and children with spinal muscular atrophy (SMA) lacked any type of treatment capable of stopping the disease from progressing. In SMA, damaged motor neurons in the spinal cord fail to correctly send messages to the muscle cells. As a result, infants and children with SMA may not be able to hold their head up, sit, or walk.

In this week’s New England Journal of Medicine, Basil Darras, MD of Boston Children’s Hospital and colleagues report good results with risdiplam, the latest of several disease-modifying treatments for SMA to be developed over the past decade. Unlike earlier treatments, it is a small-molecule drug that can be taken orally.

The open-label trial enrolled 41 infants at 14 centers and treated them with risdiplam. Compared with historical control subjects who were not treated, infants receiving risdiplam had improvements in motor function, including the ability to sit unassisted for a period of time. The children were more likely than the controls to achieve other motor milestones and lived longer than would be expected.

Like the earlier treatments, risplidam is targeted at correcting SMA’s root cause — a mutated gene that fails to produce enough amounts of an essential protein.

SMA is a genetic condition that results from having two mutated survival of motor neuron (SMN) genes, SMN1 and SMN2. As a result, the body cannot produce enough of the essential SMN protein needed for normal motor neuron function.

SMA can be grouped into four types ranging from SMA-1, the most severe form where symptoms are present within the first six months of life, to SMA-4, which usually starts in young adulthood and causes mild motor impairment. About 60 percent of infants born with SMA have Type 1; they usually die within two to three years.

A decade of clinical success

Boston Children’s Hospital has been heavily involved in the development and clinical testing of these therapies over the past decade, and has been looking to understand and describe the natural history of SMA for more than 50 years. In 1961, two Boston Children’s physicians, Randolph Byers, a neurologist, and Betty Banker, a neuropathologist, published the first paper defining infantile SMA.

In 2004, Darras co-founded the Pediatric Neuromuscular Clinical Research Network (PNCRN) for SMA, a consortium of research centers including Boston Children’s, to accelerate the search for treatments.

“One site alone cannot do a clinical trial for a rare disease,” Darras says. “Because we were able to bring the researchers together in the PNCRN, we could successfully complete the needed natural history studies, And we were able to develop the outcome measures which were put in place in the clinical trials to measure drug efficacy.”

Within seven years, the first SMA drug – nusinersen (Spinraza) – was in clinical trials at Boston Children’s and other centers. Administered into the spinal canal by lumbar puncture, nusinersen is an antisense oligonucleotide that works by directing the “back-up” SMN2 gene to make more SMN protein. Boston Children’s was the first hospital in the world to enroll an infant into the ENDEAR clinical trial in August 2014, and the drug received FDA approval in December 2016. Since then, Darras’ team has treated over 100 infants, children, and adults with nusinersen.

In May 2019, gene replacement therapy became an option for babies and children younger than 2 years with SMA after successful clinical testing at Boston Children’s. Given as a single, one-time infusion, the treatment delivers a correct version of the SMN1 gene. To date, the SMA Program has treated about 30 babies with gene replacement therapy.

And in August 2020, the FDA approved risdiplam (Evrysdi), a small-molecule drug, for adults and children 2 months and older. Again, Darras’ team was at the center of the clinical trials, leading to the report in this week’s New England Journal of Medicine. Similar to nusinersen, risdiplam triggers the body to make more SMN protein, but in a different way. Instead of requiring a spinal tap, risdiplam is given as an oral medication daily. Currently, about 15 children and adults are receiving risdiplam through the SMA Program at Boston Children’s.

Newborn SMA screening

In January 2018, Massachusetts became one of the first two states in the country to enact newborn screening for SMA, thanks in part to lobbying by Darras. Today, 32 states have programs in place or in development.  All 50 states are expected to enact screening programs by 2022.

“By the time an infant with SMA-1 comes to me, they have already lost 50 percent or more of their motor neurons,” he says. “If we can find them before they become symptomatic, we can begin drug treatment very early and make a real difference for these children quite often by preventing the disease.”

Darras and the SMA Program continue to research new treatments, such as the use of a monoclonal antibody to enhance the growth of muscle fibers in children with SMA.

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About Boston Children’s Hospital

Boston Children’s Hospital is ranked the #1 children’s hospital in the nation by U.S. News & World Report and is the primary pediatric teaching affiliate of Harvard Medical School. Home to the world’s largest research enterprise based at a pediatric medical center, its discoveries have benefited both children and adults since 1869. Today, 3,000 researchers and scientific staff, including 9 members of the National Academy of Sciences, 23 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s is now a 415-bed comprehensive center for pediatric and adolescent health care. For more, visit our Answers blog and follow us on social media @BostonChildrens, @BCH_Innovation, Facebook and YouTube.