Rare Disease Report

Antisense Therapy vs Gene Therapy for Spinal Muscular Atrophy

NOVEMBER 02, 2017
James Radke
Today, 2 clinical studies involving game changing treatments for spinal muscular atrophy (SMA) were published today in the New England Journal of Medicine.

The first study was the clinical trial that led to the antisense drug, Spinraza (nusinersen), getting approved last December.1 An approval that was seen as a groundbreaking achievement in the rare disease community. Just last week, Ionis Pharmaceuticals and Biogen, won the Prix Galien Best Biotechnology Product Award for Spinraza.

The second study published is a phase 1 gene therapy trial. Results from that study may be even more impressive that the results seen with Spinraza.2

SMA is a genetic disease in which mutations in the survival motor neuron (SMN1) gene result in a deficiency in the survivor motor neuron (SMN) protein that in turn leads to widespread splicing defects in motor neurons. Severity of the condition varies from patient to patient, but the muscles most commonly affected include those near the shoulders, hips, thighs, and upper back. In the most severe cases, the children are completely unable to move.

Infants with Type I SMA, the most severe form of the disease, have a life expectancy of less than 2 year. Children with Type II SMA have some SMN protein, but are still have a shortened lifespan and are incapable of standing without assistance. Children with Type III SMA have a normal lifespan but have numerous lifelong physical disabilities.

Spinraza is an antisense oligonucleotide drug that modifies pre–messenger RNA splicing of the SMN2 gene to promote increased production of full-length SMN protein. The drug’s approval was based on a Phase 3 study by Richard S. Finkel, M.D. and colleagues, who published the data in the New England Journal of Medicine. The study was terminated early when it was observed that the administration of Spinraza (nusinersen) in 51 infants with Type I SMA had such a profound improvement in their motor function. At that time, 21 of 51 infants given Spinraza had a motor-milestone response compared to 0 of 27 infants given placebo (P < .001). In the final analysis, 37 of 73 patients given Spinraza had a motor-milestone response compared to 0 of 37 patients given placebo. Furthermore, the study concluded that the likelihood of overall survival was higher in the Spinraza group than in the control group (hazard ratio for death, 0.37; P = .004).

While the Spinraza study was impressive, a new study using a single-dose gene therapy in infants with type I SMA may be even more remarkable. Jerry R. Mendell, M.D. and colleagues posted their results, also in the New England Journal of Medicine,  of 15 infants with type I SMA given intravenous adeno-associated virus (AAV) serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three infants received a low dose (6.7×1013 vg /kg), and 12 received a high dose (2.0×1014 vg/kg) of the gene therapy. Although the primary outcome measure was safety, the most striking outcome observed in the study was that all 15 infants were still alive at the age of 20 months. This is in stark contrast to the 8% survival rate observed at the age of 20 months in historical controls. Even more striking was the observation that of the 12 infants who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Regarding safety, elevated serum aminotransferase levels were observed in 4 patients that were successfully treated with prednisolone.

Regardless of which treatment becomes the norm in the years to come, the data presented in both trials indicate that the days of SMA being a death sentence are officially over.

  1. 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. DOI: 10.1056/NEJMoa1702752
  2. Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New Engl J Med. 2017; 377:1713-1722. DOI: 10.1056/NEJMoa1706198
image courtesy wikimedia commons.

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