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Statement on first drug approved to treat spinal muscular atrophy receives AAP endorsement :

December 24, 2018

The Academy has endorsed an American Academy of Neurology (AAN) statement on the use of nusinersen, the first drug approved for the treatment of any form of spinal muscular atrophy (SMA). The disease causes loss of anterior horn cells and progressive muscle weakness and disability.

The special article, Evidence in focus: Nusinersen use in spinal muscular atrophy, was published in Neurology,

The statement is the product of a new AAN process to allow its methodologists to work with subject experts to quickly classify, summarize and comment on available evidence on a topic of clinical importance. Nusinersen was chosen for this pilot project due to its Food and Drug Administration (FDA) approval in December 2016 and because it is the first drug approved to treat SMA.

The most severe form of SMA, referred to as type I, leads to death or permanent ventilator dependence within the first few years of life. Nusinersen is one of just a handful of antisense oligonucleotide treatments approved by the FDA and the first that is delivered intrathecally to patients at regular intervals.

Patients with SMA lose survival motor neuron (SMN) protein, the product of the SMN1 gene in the 5q13.2 region. They are potentially amenable to treatment with nusinersen, which modifies the mRNA from a nearly identical gene, SMN2, leading to increased SMN protein production.

Review of evidence

The group working on this project reviewed several studies of nusinersen use in infants and children with SMA. Efficacy data were drawn from two Class I randomized, placebo-controlled treatment trials and one Class III trial with historical controls. Safety and tolerability data were used from two uncontrolled studies with open-label designs.

The first Class I study (ENDEAR) enrolled 122 infants with SMA type 1 (two copies of the SMN2 gene and symptoms noted prior to 6 months of age) and randomized 81 to treatment with nusinersen and 41 to a control group that received sham intrathecal treatments. The study was halted early due to a positive interim analysis showing that the treated infants were more likely to acquire motor milestones (41% vs. 0%, p <0.001) and to have event (death or permanent ventilator dependence)-free survival (61% vs. 32%, p = 0.005).

The second Class I study (CHERISH) included 126 children ages 2-12 with SMA type 2 (symptoms first noted after 6 months of age, able to sit but never able to walk independently) and randomized 84 to treatment with nusinersen and 42 to the sham control group. This study also was terminated at the interim analysis, with the treatment group showing significantly better motor function on the 66-point Hammersmith Functional Motor Scale–Expanded measure increasing by 4 points while the control group dropped by 1.9 points.

The working group summarized these data and provided commentary about the clinical context for nusinersen use, including the early experiences of patients, parents and physicians who participated in the clinical decision-making process and have grappled with the logistical challenges of obtaining insurance authorization. These include documenting functional motor outcomes using the scales from the pivotal trials and arranging for repeated intrathecal infusions that may require coordinating care with interventional radiologists and anesthesiologists. While the FDA approved nusinersen for patients of all ages and with all types of SMA, many insurers treat nusinersen as an experimental drug for patients who are older than those included in the pivotal trials or who have more than two copies of the SMN2 gene.

The paper concludes with suggestions for future research, including ongoing monitoring for safety considerations, particularly given the small number of children involved in the clinical trials. Post-marketing data collection has identified a small (about 1 in 1,000) risk of non-obstructive hydrocephalus unrelated to bleeding or infection in patients receiving treatments, possibly related to repeated lumbar punctures rather than to the medication, but the product label has been updated to reflect this risk.

Dr. Michelson, a pediatric neurologist, is a lead author of the special article.

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