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FDA Approves Spinal Muscular Atrophy Drug [Updated]

DNA illustration

(National Heart, Lung, and Blood Institute, NIH)

Update 31 December 2016. The New York Times reports today that Biogen set a list price for Spinraza at $125,000, which means the drug will cost a family or insurer $625,000 to $750,000 for the first year, and $375,000 per year after that.

27 December 2016. A drug to treat spinal muscular atrophy, a genetic disorder causing the wasting away of muscle tissue in children and adults, was approved for sale in the U.S. The Food and Drug Administration approved the drug nusinersen, marketed as Spinraza by the biopharmaceutical company Biogen, in Cambridge, Massachusetts on Friday, 23 December.

Spinal muscular atrophy is an inherited disease that affects mainly infants, with about four out of every 100,000 people having the condition. Infants with spinal muscular atrophy type I, the most severe form of the disease, are born with very little muscle tone, weak muscles, and feeding and breathing problems. Often, weakness is first noted in the shoulder muscles and proximal leg muscles. Weakness gets worse over time and eventually becomes severe and often fatal.

Spinal muscular atrophy occurs when a defect in the survival motor neuron gene, known as SMN1, results in low levels of SMN protein. Without this protein, motor neurons die, with no nerve impulses sent from the brain to muscles. Some muscles, therefore, cannot perform their normal functions, causing weakness and impaired movement. Patients lacking a functional SMN1 gene survive only because humans carry a second gene called SMN2 which produces low levels of SMN protein.

Nusinersen fixes the splicing errors caused by the SMN1 gene, by interrupting the protein causing process and replacing the RNA instructions so they bind to the functioning SMN2 gene, enabling normal production of SMN protein. The technology for nusinersen was developed in a collaboration between Cold Spring Harbor Laboratory in New York and the biotechnology company Ionis Pharmaceuticals in Carlsbad, California, later licensed to Biogen for further clinical testing and commercialization.

The technology, known as antisense, uses short DNA or RNA sequences, called oligonucleotides, designed to complement a specific gene sequence. Ionis says it designs antisense drugs to interact precisely with a specific sequence of RNA, with many of the therapies in its pipeline binding to messenger RNAs, or mRNAs, and blocking the production of disease-causing proteins.

Nusinersen was tested in a series of clinical trials, with the key late-stage trial, testing the drug — injected into cerebrospinal fluid near the spinal cord — against a mock procedure where participants received a needle prick, but no drug. The study enrolled 121 children having infantile onset spinal muscular atrophy at sites in North America, Europe, and Asia, with twice as many participants receiving nusinersen as the mock procedure. The research team looked primarily for motor activity in the participants, such as kicking, rolling, and crawling, as well as length of time to require full-time ventilation support or death.

The results show 40 percent of participants receiving nusinersen achieved the motor activity goals, compared to none of the children receiving the mock procedure. In addition, fewer patients receiving nusinersen died than those receiving the mock procedure. The most common side effects are respiratory infections and constipation. FDA is also issuing warnings on the drug for low blood platelet counts and toxicity to the kidneys.

Biogen and Ionis conducted other clinical trials of nusinersen with older participants and other less severe types of spinal muscular atrophy, but the tests were not blinded — both physicians and patients knew the drug being tested — nor were comparison groups used. Nonetheless, the results were consistent with findings from the late-stage trial, thus FDA is clearing the drug for use in children and adults, as well as across the full range of spinal muscular atrophy variations.

Following video from Cold Spring Harbor Lab tells more about nusinersen.

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