AAN 2011: Ataluren Reduces Decline in Ambulation in Duchenne Muscular Dystrophy

An experimental oral drug reduces the loss in ambulatory function in boys with Duchenne muscular dystrophy (DMD), according to a study presented at the 63rd Annual Meeting of the American Academy of Neurology.

Patients treated with the drug ataluren over 48 weeks declined by only 12.9 meters, versus 42.6 meters for placebo, in the distance they were able to walk in six minutes.

Based on these results, PTC Therapeutics, the company that developed ataluren, is planning to seek approval for its use in DMD from the United States Food and Drug Administration. Because of the mechanism by which the drug overcomes the effects of the mutation, it would be appropriate for only about 13% of DMD patients, according to study presenter Ted Abresch, Research Associate in Neuromuscular Disease at the University of California at Davis.

Ataluren is a new chemical entity that binds to the ribosome, the cell's protein manufacturing machinery. It interacts with messenger RNA (mRNA), allowing the ribosome to “read though” aberrant stop signals that would otherwise halt protein synthesis. One of the most common mutations causing DMD is a nonsense mutation that introduces such a stop codon in the gene for dystrophin, a muscle protein. By allowing read-through of dystrophin mRNA, ataluren increases the amount of normal dystrophin made in muscle.

To test the ability of ataluren to improve clinical features of DMD, the authors of the study randomized 174 boys with DMD to placebo, low-dose, or high-dose ataluren, taken three times per day for 48 weeks. The drug was dispensed in a sachet placed in orange juice, into which it dissolves.

Patients enrolled in the study were all boys with the target mutation. They had a mean age of 8 years (range 5 to 20 years), and 71% were taking corticosteroids, a treatment for DMD. The three groups were matched for age range, corticosteroid use, and baseline walking distance.

“Progressive loss of walking ability is a critical functional concern in boys with Duchenne muscular dystrophy, and stabilizing or slowing the decline in walking ability would represent a clinically meaningful benefit,” Abresch said.

At baseline, mean 6-minute walking distance was 360 meters. Typical distances in healthy controls would be approximately twice that, he said. Because DMD is a progressive disease, walking distance declines every year, and so would be expected to decline during the course of the study.

After treatment, 6-minute walking distance had declined by 42.6 meters in those receiving placebo, 12.9 meters in those receiving low-dose ataluren, and 41.8 meters in those receiving high-dose ataluren.

There was a positive trend in the difference between low-dose treatment and placebo (P=0.0584), while there was no treatment effect observed for the high-dose versus placebo in 6-minute walk distance.

The U-shaped dose-response curve was troubling at first, Mr. Abresch said. But the explanation may lie in the interaction of the drug with the ribosome. There are two distinct binding sites for the drug, one with low affinity, and one with high affinity, with different (but still poorly understood) effects on protein synthesis. The researchers currently believe the high dose of the drug may saturate both sites, leading to a loss of the benefit from activation of the high-affinity site alone, which is seen with the low dose of the drug.

Sub-group analysis lent some support to this hypothesis. Among those patients receiving the high dose of the drug, those with the lowest plasma levels showed the most benefit. The plasma levels in this group were similar to those in the low-dose group.

Secondary outcome measures supported the primary measure, with positive trends observed in the low-dose group on timed tests of stair climbing and descending, time for walking 10 meters, and caregiver-reported falling.

Based on these results, PTC Therapeutics is planning to apply to the FDA for approval of ataluren for treatment of DMD, Abresch said.