Gene Therapy, Antisense Show Big Gains in Spinal Muscular Atrophy

Ricki Lewis, PhD

November 01, 2017

Treatment with either of two different biotechnologies increases motor skills and extends survival in some infants with spinal muscular atrophy (SMA), according to the results of studies published online today in the New England Journal of Medicine.

The two treatments — an antisense oligonucleotide drug called nusinersen and gene therapy with AVXS-101 — each enabled motor neurons of severely affected young children to produce a critical protein and induce clinical improvements. The effects of the gene therapy are particularly striking, with many children achieving milestones not seen previously among affected children.

SMA results from mutation in the "survival motor neuron" gene SMN1. Approximately 60% of children with SMA have type 1, with symptoms beginning at or before 6 months of age. Without respiratory support, median life expectancy for these infants is less than 2 years. Incidence of SMA in the United States is 1 in 11,000 live births.

The disease is unusual in that two SMN genes are near each other on the same chromosome. Most patients have mutations in both copies of SMN1 and have zero, one, or two copies of SMN2. Patients with two copies of SMN2 have milder cases because the second gene enables synthesis of a low level of the SMN protein that SMN1 cannot produce.

Antisense Drug Improves Protein Production

The antisense drug nusinersen (Spinraza, Biogen) is a short DNA-like molecule that binds SMN2 where it differs in sequence from SMN1, which is at a crucial splice site that is disabled in SMN2. Binding at this splice site means the SMN2 gene can then encode correctly spliced messenger RNAs, enabling the cell to produce much more SMN protein.

Previously reported data from an open-label, dose-escalation, phase 2 study showed that infants who received nusinersen had improved motor function and prolonged survival compared with historical natural history reports on untreated infants.

Now, Richard Finkel, MD, from the Division of Neurology at Nemours Children's Hospital in Orlando, Florida, and colleagues report results from a double-blind, sham-controlled phase 3 study showing the antisense drug improves outcomes for children with infantile SMA and two copies of SMN2.

Patients were randomly assigned 2:1 for treatment vs a sham procedure, which was a small needle prick covered by a bandage. Of the 121 infants, 80 were in the nusinersen group and 41 in the control group.

A prespecified interim assessment performed when approximately 80 infants were enrolled showed 21 (41%) of 51 children treated with nusinersen met the motor milestone, defined as improvement in the Hammersmith Infant Neurological Examination, compared with none (0%) of the 27 controls (P < .001).

On the basis of those interim data, the randomized trial was closed early, and children were invited to continue as part of an open-label extension trial. Final results of that analysis showed 37 (51%) of 73 treated patients improving (22% attained full head control, 10% could roll over, 8% could sit, and 1% could stand) compared with zero of 37 infants in the control group.

Event-free survival, defined as time to death or use of permanent assisted ventilation, was also significantly higher among the treated children, especially those with the shortest disease duration at the time of screening. At the final analysis, 39% of the infants in the nusinersen group and 68% in the control group had died or were on permanent assisted ventilation. The overall risk of death or need for permanent assisted ventilation was 47% lower in the nusinersen group than in the control group (hazard ratio, 0.53; 95% confidence interval, 0.32-0.89; P = .005).

In December 2016, The US Food and Drug Administration approved use of nusinersen. However, the investigators caution that nusinersen is not a magic bullet. "Several of the infants who received nusinersen died, none achieved normal motor development, and some needed continued feeding and ventilatory support," they write.

Gene Therapy Improves Function

In the second approach, Jerry Mendell, MD, from the Research Institute at Nationwide Children's Hospital and colleagues introduced SMN1 genes, using adeno-associated virus 9 as the vector, into 15 patients with deletions in both SMN1 genes and retention of both copies of SMN2.

Three patients received a low dose (6.7 × 1013 viral genomes/kg), and 12 received a high dose (2.0 × 1014 viral genomes/kg) in a single intravenous infusion. The primary outcome was safety, and the secondary outcome was time until death or need for permanent ventilator assistance. Using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale of motor function, the researchers compared milestones among the high-dose cohort with natural history data from 34 patients.

All patients were alive and event-free at 20 months of age compared with just 8% in the natural history group at the same point. CHOP INTEND scores soared after the higher-dose treatment, increasing 9.8 points by 1 month and 15.4 points by 3 months. Of the 12 patients treated with the higher dose, 11 were able to sit unassisted, 9 could roll over, 11 could eat and speak, and 2 walked independently: skills unheard of in natural history studies. The lower-dose patients had slightly higher scores than those from the natural history cohort.

In up to 2 years of follow-up, none of the 15 children has regressed. Repeat gene therapy, if needed, would be contraindicated in patients who develop antibodies to adeno-associated virus 9.

Limitations of both strategies include short follow-up time and the challenge common to all treatments for lethal diseases: What new manifestations will emerge as survival surpasses natural limits?

In an accompanying editorial, Ans T. van der Ploeg, MD, PhD, from the Center for Lysosomal and Metabolic Diseases at Erasmus University Medical Center in the Netherlands, points out that both approaches demonstrated "significant improvement in motor outcomes and survival," even though the study designs differ and the children in the gene therapy trial were younger (median, 3.4 vs 5.4 months old). Ongoing research is assessing administration of nusinersen presymptomatically in patients with a family history of SMA, and eventually newborn screening may identify patients with no family history.

"Treating children with SMA brings new responsibilities and unique dilemmas. Doctors will need to take greater care than ever before in following patients through standardized assessments and guiding families in decision making," Dr van der Ploeg concludes.

Three coauthors hold patents on adeno-associated virus 9 delivery and/or development of oligonucleotides to treat SMA, and one coauthor holds a patent on altering SMN splicing. Some of the authors work for the sponsoring companies: Biogen/Ionis Pharmaceuticals for nusinersen and AveXis for the gene therapy. The editorialist has disclosed no relevant financial relationships.

N Engl J Med. 2017;377(18)1713-17221732, 1786-1787. Finkel article, Mendell article, Editorial

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