Dr. Knox is Pediatric Neurology Resident, Department of Pediatrics, Division of Child Neurology, Weill Cornell Medicine/New York Presbyterian Hospital, New York. Dr. Segal is Assistant Professor of Clinical Pediatrics, Weill Cornell Medical College
Dr. Knox and Dr. Segal report no financial relationships relevant to this field of study.
SYNOPSIS: In a randomized, double-blind, sham-controlled study of infants with spinal muscular atrophy (SMA) type 1, nusinersen treatment led to significant improvement in motor milestones and survival without significant adverse reactions. A safety trial of gene therapy for SMA type 1 demonstrated prolonged ventilator-free survival and improved motor milestones with minimal side effects.
SOURCES: Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017;377:1723-1732.
Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017;377:1713-1722.
In the Greek myth of the judgment of Paris, the prince Paris must choose among three goddesses, Aphrodite, Hera, and Athena, each with unique offerings, for the prize of the golden apple. We find ourselves in a similar circumstance, as several novel therapeutics are in the pipeline to treat spinal muscular atrophy (SMA), a debilitating neurologic disorder with an incidence of 1 in 10,000 live births. SMA type 1 is the most severe, presenting before age 6 months and usually resulting in death by age 2 years. SMA is caused by homozygous mutation or deletion of the SMN1 gene. However, there is a paralogue gene, SMN2, which normally produces low levels of functional SMN protein. Disease severity is correlated with the copies of SMN2, with more copies of SMN2 leading to a milder phenotype. Nusinersen, an antisense oligonucleotide drug, modulates SMN2 splicing to produce more functional SMN protein. In December 2016, the FDA made the decision to approve nusinersen for all types of SMA. The interim analysis of the Phase III sham-controlled study of nusinersen in patients with SMA type 1, which led to the landmark FDA decision, was published in the Nov. 2, 2017, issue of The New England Journal of Medicine. Additionally, this issue included the report of a Phase I safety study of a gene therapy approach that delivers a copy of SMN1, attractively packaged as a single-dose treatment for SMA type 1.
Finkel et al performed the first randomized, double-blind, sham-controlled Phase III study of nusinersen on 73 infants with SMA type 1 without significant respiratory disease (ENDEAR Trial). Subjects were assigned randomly to receive intrathecal nusinersen or sham treatments on days 1, 15, 29, and 64, with maintenance doses on days 183 and 302. They assessed motor function using two validated tools, the Hammersmith Infant Neurological Examination and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). The authors reported that in the final analysis, 51% of nusinersen-treated infants had a motor-milestone response compared to 0% of sham treated. The secondary outcome measure was event-free survival, defined as the proportion of infants who were alive without the use of permanent assisted ventilation, and, again, the authors noted a statistically significant difference between sham and treated patients. Adverse events were similar between both groups and included respiratory infections, pyrexia, and constipation, all of which likely were related to SMA and not the treatment. This study was terminated early for efficacy.
Mendel et al reported data on the first gene-replacement therapy for SMA using a single dose of intravenous adeno-associated virus 9 with functional SMN gene (scAAV9). Fifteen infants received low- or high-dose scAAV9 by 7 months of age and were subsequently assessed for adverse events, survival, need for permanent ventilator assistance, and motor milestones. All patients survived to at least 20 months without permanent ventilation compared to 8% of a historical control cohort not requiring permanent ventilation. Using CHOP-INTEND scores, patients in low- and high-dose cohorts had clinically significant improvement in motor milestones, with the high-dose cohort increasing scores by ~25 points. Of note, gene therapy was associated with an asymptomatic transaminitis, which was treated successfully with oral prednisolone.
These studies represent exciting advances in SMA therapeutics with two novel mechanistic approaches to increase functional SMN protein, leading to meaningful gains in motor milestones, improved functional status, and, most importantly, survival. Although nusinersen currently is FDA-approved for all types of SMA, clinicians soon will be faced with the difficult choice of which agent to use. Nusinersen currently is being delivered with multiple intrathecal doses for an unknown duration with a hefty price tag of $125,000 per dose, which is being negotiated in a dynamic insurance landscape. scAAV9 may be an attractive alternative, as it is given intravenously as a single dose and may prove efficacious with systemic SMA symptoms. However, this may come with a higher side effect profile, as seen with the transaminitis evident in the Phase I study. Oral agents are also in the pipeline, and include RO6885247 and RG7800, both SMN2-splicing modifiers, as well as small molecules targeting other pathways. The future likely holds trials with side-by-side comparisons of different agents as well as combinations of treatments targeting different molecular pathways all leading to exciting advances in this field and new hope for patients and their families.