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Presymptomatic Infants Do Best with Nusinersen

— Best results may be with dosing before 6 weeks of age

MedpageToday

BOSTON -- Presymptomatic infants with spinal muscular atrophy (SMA) reached developmental milestones consistent with normal development when treated with nusinersen (Spinraza), according to a second interim analysis reported here.

In the phase II, open-label NURTURE study, the majority of the 20 enrolled infants with Type 1 or Type 2 SMA were once again found to hit targets of normal development, including full head control and sitting independently, Darryl De Vivo, MD, of New York Presbyterian, reported during an oral presentation at the here.

"All of these infants have responded and each of them have made developmental progress largely consistent with normal development," he said.

He cautioned, however, that while symptomatic infants enrolled in the ENDEAR trial, and those dosed later in the disease course -- children ages 2 to 12 enrolled in the CHERISH study -- still do well with the drug, they may not receive as much benefit from treatment as the infants in NURTURE who were treated very early in life: 40% in the first 2 weeks, 40% in the first 3 to 4 weeks, and 20% by the 6th week of life.

"There's a very important take-home message here -- not only for SMA children, but also for a lot of other neurodevelopmental disorders," De Vivo said. "That is, early treatment is essential.

"I would say from our general experience that every day counts under the circumstances. Basically, you are losing the capacity to allow these infants to develop normally if you delay treatment until they become symptomatic, regardless of how little the symptoms are."

"Someone has said that time equals motor neurons," he added. "The more you delay, the less likely you are to rescue the phenotype."

Nusinersen was approved last December for the treatment of SMA, a condition caused by mutations in the SMN1 gene, leading to diminished levels of the survival motor neuron (SMN) protein. The drug is an antisense oligonucleotide that boosts production of the full-length SMN protein in order to restore neuromuscular development and physical function.

The NURTURE trial enrolled 20 infants with presymptomatic SMA, either Type 1 or Type 2, with the former being more severe disease. De Vivo noted that 25 patients have been dosed to date but are not yet ready to be reported out.

All patients were given 12 mg scaled equivalent dose of intrathecal nusinersen, with four loading doses followed by maintenance dosing every 4 months. All patients had to be 6 weeks of age or younger and pre-symptomatic at the first dose. They also had a confirmed genetic diagnosis, and two or three copies of the SMN2 gene.

The study's primary endpoint was the time to death or respiratory intervention. A first interim report of the data in June 2016 showed that infants were achieving motor milestones generally consistent with normal development in contrast to the natural history of SMA Type 1.

By the second interim analysis, infants had been enrolled for a median of 318 days. All were alive, and none had required respiratory intervention, De Vivo reported.

Many of the patients achieved typical age-related milestones, including the following:

  • 15 of 16 patients reached the age for full head control
  • 10 of 12 reached the age for independent sitting
  • Seven of 11 reached the age for standing with or without support
  • Five of nine reached the age for cruising/walking

De Vivo noted that those with more copies of SMN2 generally did better on all these measures. Additionally, three of the nine infants over a year old were able to stand unaided, and two of the infants at about 13 months old could walk independently.

There were no drug discontinuations or withdrawals, and the treatment was safe and well tolerated, he reported. There were no clinically significant adverse changes in laboratory or neurological exams that were considered to be related to nusinersen, and any adverse effect considered possibly related to the drug resolved. These included muscular weakness and weight-bearing difficulty; hyper-reflexia and tachycardia; and pyrexia, increased alanine aminotransferase, and increased aspartate aminotransferase with increased eosinophil, lymphocyte, and white blood cell counts.

De Vivo concluded that the results from this second interim analysis of NURTURE extend those of the earlier analysis, and he emphasized again that all the infants in the study are alive without the need for chronic respiratory support, and are still showing improvements in motor function and hitting motor milestones that are never expected for children with SMA.

Disclosures

De Vivo disclosed financial relationships with AveXis, Biogen, Cytokinetics, Ionis, Roche, Sarepta, and the SMA Foundation.

Primary Source

American Academy of Neurology annual meeting

De Vivo DC, et al "Interim efficacy and safety results from the phase II NURTURE study evaluating nusinersen in presymptomatic infants with SMA" AAN Annual Meeting 2017.