SMA Antisense Drug Shows Safety, Tolerability in Phase 1 Trial

An experimental drug designed to treat the underlying molecular defect in spinal muscular atrophy (SMA) has shown encouraging results in a phase 1 trial.

The drug, ISIS-SMNRx, is being developed and tested by California-based biotechnology company Isis Pharmaceuticals. Laboratory development of this antisense-based drug was supported by MDA through a grant to molecular biologist Adrian Krainer at Cold Spring Harbor Laboratory (N.Y.).

The early-stage trial in children with SMA showed that ISIS-SMNRx had no safety concerns, was well-tolerated at all dose levels and reached appropriate concentrations in the spinal fluid and blood plasma. Although the trial was not designed to test efficacy, indications of improved muscle function were observed in trial participants who received the highest dose level of the drug.

Results were announced late Wednesday, March 20, 2013, at the 65th annual meeting of the American Academy of Neurology in San Diego, by Claudia Chiriboga, an associate professor of clinical neurology and pediatrics at Columbia University Medical Center.

Open-label trial tested safety and tolerability

Twenty-eight medically stable children with SMA between the ages of 2 and 14 were given a single injection of ISIS-SMNRx into the fluid around the spinal cord.

The phase 1 trial was designed to assess the safety and tolerability of the drug and the procedure, and to see what levels the drug would reach in the spinal fluid and blood. Some measurements of motor function and electrophysiological tests of nerve function also were included in the trial.

Trial participants were divided into four groups, each of which received an increasing dose of ISIS-SMNRx. All participants completed the trial, which was open label, meaning there was no placebo group. All participants received the drug, and the investigators were aware of the dosage being given.

No safety issues identified

A summary of the results follows:

  • ISIS-SMNRx was well-tolerated at all dose levels, with no safety or tolerability concerns identified.
  • The spinal fluid injection procedure was shown to be feasible in children with SMA.
  • Concentrations of the drug in the spinal fluid and blood plasma were correlated with the dose administered — higher doses of the drug resulted in higher concentrations.
  • Children receiving the highest dosage level of the drug showed clinically significant improvements on a scale that measures motor function (the Hammersmith Motor Function Scale — Expanded), although the investigators note that these results must be interpreted with caution because there was no placebo group and a small number of trial participants.

Drug designed to boost production of full-length SMN

SMA is caused by a deficiency of the SMN(survival motor neuron) protein, resulting from mutations in both copies of a gene known as SMN1. Without sufficient SMN protein, spinal motor neurons, which control muscle activity, are lost, leading to varying levels of weakness.

Luckily, a gene known as SMN2 also carries instructions for making the SMN protein. However, most of the protein made from the SMN2 gene is a shortened, nonfunctional version of SMN because of a slight difference in the DNA of SMN2 compared to SMN1.

ISIS-SMNRx is based on an "antisense" molecule that changes the way cells process the SMN2 gene’s instructions so that a full-length, fully functional SMN protein can be made.

Next steps

A multiple-dose, phase 1b/2a study with additional endpoints and longer follow-up time is ongoing and will provide more data on safety and efficacy.

Phase 2/3 trials in infants and children with SMA are being planned.

For more information

To learn more about ISIS-SMNRx and antisense in SMA, see:

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