‘New dawn’ for spinal muscular atrophy treatment
medwireNews: Nusinersen has shown promise as a treatment for infantile-onset spinal muscular atrophy, improving muscle function and nerve activity, show phase II study findings published in The Lancet.
The drug, a uniformly modified 2’-O-methoxyethyl phosphorothioate antisense oligonucleotide, has been designed to promote exon 7 inclusion in the survival motor neuron 2 (SMN2) gene to enhance functional SMN protein production in patients with spinal muscular atrophy who have deficient levels due to deletions or mutations in the SMN1 gene.
Injected into the spinal fluid of 20 babies aged 3 weeks to 7 months via lumbar puncture, nusinersen improved muscle skills in 16, most often for grasping, ability to kick, and sitting, with improvements in some infants also seen for head control, rolling, crawling, and walking.
The first four infants received an initial drug dose of 6 mg for their first three doses before escalation to a higher dose of 12 mg every 4 months thereafter. The remaining 16 infants received the higher dose for the entire trial. At the time of the interim analysis, the 6–12 mg group had been monitored for 9–32 months and had received four to nine doses, while the 12 mg group had been monitored for 2–27 months and received two to eight doses.
Scores on the Hammersmith Infant Neurological Exam–Part 2 improved significantly from baseline for both groups combined and for the 12 mg group. And motor function, assessed using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders increased by an average 11.5 points, with 14 of 18 infants assessed showing improvement.
The researchers note that in 12 of 14 infants in the 12 mg group, the average increase was 15.2 points, which compares favorably with a typical 1.27-point decline per year previously reported for untreated infants. Also, seven of 13 participants with two SMN2 gene copies achieved a score above 40, out of a possible 64, which they stress is “rarely observed” in such infants.
Lead author Richard Finkel (Nemours Children’s Hospital, Orlando, Florida, USA) said in a press statement that the improvement in muscle function was “remarkable,” but he cautioned: “While our results are promising this drug does not represent a cure.”
He highlighted that “the drug did not restore normal levels of muscle function.” But there was evidence of an increase in electrically excitable muscle, with enhanced peroneal and ulnar nerve compound motor action potential amplitude over time, potentially representing improved function of remaining motor neurons.
Seventy-seven serious adverse events were reported in 16 infants, in line with expectations for the disease, and three infants died. But there were no safety concerns associated with the drug, except forone case each of mild transient neutropenia and vomiting considered possibly related to nusinersen treatment.
The study also confirmed the drug mechanism, with autopsies from the three infants showing uptake of nusinersen into motor neurons throughout the spinal cord and increases in the percentage of SMN2 transcripts containing exon 7, and SMN protein levels.
The effects of treatment on survival and need for permanent ventilation could not be calculated as most of the infants were surviving without permanent ventilation at the time of analysis.
Thomas Gillingwater (University of Edinburgh, UK) says in a related commentary that the findings are “a first step forward, indeed a new dawn, in developing safe and effective therapy options for spinal muscular atrophy that are urgently required.”
A large phase III randomized trial of nusinersen is already underway, and based on the positive safety findings from the current study will incorporate a more frequent dosing regimen.
By Lucy Piper
medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016