BOSTON – Last December, the Food and Drug Administration approved nusinersen (Spinraza) as the only treatment for spinal muscular atrophy (SMA) based in part on startling interim results from a study in infants that ended early so all participants could get access to the drug.

Now the final study results are in, and they’re even more impressive: Patients who took the drug were less than half as likely to die as were those in a sham control group, and motor function improved in more than half of infants who took the medication, compared with none in the sham group.

The findings are “incredibly exciting,” said Charlotte J. Sumner, MD, in a discussant presentation at the annual meeting of the American Academy of Neurology. “The data teaches us that this drug is efficacious.”

However, Dr. Sumner, professor of neurology and neuroscience at Johns Hopkins University, Baltimore, cautioned that the drug is tremendously expensive, challenging to administer, and there are several questions about its use that remain unanswered.

SMA is most often caused by mutations in the SMN1 gene, leading to a loss of the protein called survival motor neuron (SMN), which is essential for the survival of motor neurons, except for a small amount produced from the SMN2 gene. The loss of motor neurons in the spinal cord and brainstem leads to weakness and atrophy of muscles used for crawling, walking, sitting up, controlling head movement, and in severe cases, breathing and swallowing. It affects an estimated 1 in 6,000 newborns and is the most common genetic cause of death in infants. Nusinersen is a antisense oligonucleotide that promotes transcription of the full-length SMN protein from the SMN2 gene.

At the AAN meeting, investigators presented the final results of two nusinersen phase III studies as well as interim data from a separate phase II trial.

The ENDEAR trial, a randomized, double-blind, sham-procedure controlled study, assigned 80 patients to 12-mg scaled equivalent doses of nusinersen delivered intrathecally (four doses over 2 months, then one every 4 months) and 41 to a sham procedure (a needle prick in the lower back). The subjects, aged 30-252 days at first dose, underwent 13 months of treatment and follow-up.

Researchers presented an end-of-study analysis of 110 subjects. They found that 51% of those who received the drug were “motor milestone responders” – meaning they had more modified Hammersmith Infant Neurological Examination Section 2 categories with improvement than worsening – compared with 41% at the interim analysis (P less than .0001). None of the sham group patients improved.

The patients treated with nusinersen lived longer: 39% of those in the sham procedure group died, compared with 16% of those in the nusinersen group (hazard ratio, 0.372; P = .0041). Event-free survival (survival without permanent ventilation) was also better in those who received the drugs: 61% in those who took nusinersen, compared with 32% in those who did not (HR, 0.53; P = .0046)

Also, 71% of those treated with the drug were considered responders at day 183 onward based on an improvement of 4 or more points on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, whereas the response rate was only 3% in the sham group (P less than .0001).

The study authors report that nusinersen was well tolerated with adverse events that “were consistent with those expected in the general population of infants with SMA.” No adverse events were linked to the nusinersen treatment.

Researchers also presented the end-of-study results of the phase III CHERISH trial of 126 patients aged 2-12 years with later-onset SMA who could sit up but not walk. All participants were believed to have a life expectancy of at least 2 years.

The trial is a multicenter, randomized, double-blind, sham-procedure controlled study. The 84 subjects who received the drug improved an average of 3.9 points by the end of study (15 months) on the Hammersmith Functional Motor Scale Expanded score, a measurement of motor function in children with SMA (P = .0000001). The 42 children who received the sham treatment (a small needle prick on the lower back) declined by an average of 1.0 point.

Researchers report that children taking the drug had fewer adverse events, and most were not related to the drug itself.

All surviving participants who completed nusinersen investigational studies are being enrolled in the SHINE open-label extension trial.

Also at the AAN meeting, researchers released interim phase II results from the NURTURE trial, an open-label study of nusinersen in patients with diagnosed but presymptomatic SMA. The study, which is expected to be completed in 2022, recruited participants up to the age of 6 weeks.

The 20 enrolled infants were all alive at a median study period of 317.5 days, and none required assistance with respiration.

In terms of motor function and growth, most were making gains “generally consistent with normal development such as head control, independent sitting, standing and walking independently, as measured by validated scales,” according to a statement released by Biogen.

Three patients developed adverse events that may have been drug related, but the events were resolved and they remained in the trial.

In Dr. Sumner’s discussant presentation on the ENDEAR study, she cautioned that it’s still not known how much older patients with SMA will benefit from the drug treatment. It’s possible that younger patients may gain motor function while older patients will maintain what they have, she said.

In addition, it seems that “certain body segments may respond more robustly than some others. It’s possible that an infant may improve limb strength quite robustly but not lumbar strength.”

She pointed out other questions: Can the drug, which is difficult to administer, be stopped at some point? “We do think of SMA as a disease of development,” she said. “Maybe after development is finished we can withdraw the drug.”

Then there’s the issue of cost and whether insurers are willing to cover the drug. As Dr. Sumner pointed out, the drug is $125,000 per dose and $750,000 over the first year, then $325,000 a year.

It is clear, however, that “the early and efficient diagnosis of SMA is really important, particularly for infantile SMA,” she said. “Time is motor function.”

The studies were funded by Ionis Pharmaceuticals and Biogen. Dr. Sumner reports serving as a consultant for Biogen, Ionis, Avexis, and Roche. She has served on scientific advisory boards for the Cure SMA, SMA Foundation, and Muscular Dystrophy Association nonprofit foundations.

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Nusinersen for early spinal muscular atrophy: Final findings beat interim results