Nusinersen for Adolescents and Adults with Spinal Muscular Atrophy: A Review of Clinical Effectiveness [Internet]

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of alpha motor neurons in the anterior horn of the spinal cord, which leads to progressive weakness of the muscles., The majority of SMA cases (95%) are due to an autosomal recessive disorder caused by homozygous deletion and/or mutation of the alleles of the survival motor neuron 1 (SMN1) gene, causing deficiency in the survival motor neuron protein., A second set of genes, SMN2, is able to produce small amounts of the SMN protein., The number of available SMN2 gene copies and the extent of the expression of these genes modulate the severity of the disease.–Nusinersen (Spinraza) has Health Canada’s approval for the treatment of 5q SMA. Nusinersen is an antisense oligonucleotide that binds to the SMN2 pre-messenger ribonucleic acid, this leads to increasing the proportion of exon 7 in SMN2 messenger ribonucleic acid transcripts, which ultimately is translated into functional SMN protein. Nusinersen is administered via intrathecal injections of 12 mg in 5 mL solution at day 0, 14, 28, and 63, then given at four month intervals.Nusinersen was reviewed through the CADTH Common Drug Review originally in 2017 and as a resubmission in 2019. On February 20, 2019, the CADTH Canadian Drug Expert Committee (CDEC) issued a recommendation to reimburse nusinersen for the treatment of 5q SMA if patients met the following conditions: Genetic documentation of 5q SMA homozygous gene deletion, homozygous mutation, or compound heterozygote. Patients who: are pre-symptomatic with two or three copies of SMN2, or have had disease duration of less than six months, two copies of SMN2, and symptom onset after the first week after birth and on or before seven months of age, or are 12 years of age or younger with symptom onset after six months of age, and never achieved the ability to walk independently. Patient is not currently requiring permanent invasive ventilation. The CADTH CDEC recommendation identified the effectiveness of nusinersen treatment in patients older than 12 years of age as an evidence gap. The health technology assessment report that was the basis of this CDEC recommendation included two abstracts of descriptive case series of adult patients treated with nusinersen. However, these two abstracts did not provide sufficient information regarding the study design, patient information, or clinical outcomes, and could not be used as valid sources to inform on the potential effectiveness or safety of nusinersen in adolescent and adult patients with SMA. Since then, new studies examining nusinersen treatment in adult patients with SMA have been published.The aim of this Rapid Response is to provide a peer-reviewed summary with critical appraisal of the recent evidence on the clinical effectiveness of nusinersen for the treatment of adult and adolescent patients with SMA who are older than 12 years of age.