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doi: 10.1097/01.NT.0000384108.10957.21
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Investigators reported that for ALS patients, dexpramipexole produced a dose-dependent slowing of decline in function over three months in a double-blind trial, and a trend toward improved survival over six months in a randomized, open-label extension.

TORONTO—So far, the only approved treatment for amyotrophic lateral sclerosis (ALS) is riluzole. But riluzole may have company one day soon, if encouraging findings from a phase 2 trial are borne out in larger trials. The results of the phase 2 trial were announced here at the AAN annual meeting in April.

The drug, dexpramipexole, produced a dose-dependent slowing of decline in function over three months in a double-blind trial, and a trend toward improved survival over six months in a randomized, open-label extension. Knopp Neurosciences Inc., of Pittsburgh, PA, sponsored the trial.

“I'm excited about this,” said lead investigator Merit Cudkowicz, MD, professor of neurology at Harvard Medical School and Massachusetts General Hospital. “I haven't seen another phase 2 trial in people with ALS with this kind of data.”

Dexpramipexole is the mirror-image molecule, that is, an enantiomer, of the dopamine agonist pramipexole, used in Parkinson disease. The switch from a left-to a right-handed molecule removes virtually all the dopaminergic effect, and the drug is not acting on the dopaminergic system, it is believed. Preclinical work indicates dexpramipexole has neuroprotective properties, probably due to its ability to prevent mitochondria from developing leaky membranes when under stress.

Results from an open-label trial in ALS patients, published in 2008, indicated it was safe, and provided a hint of efficacy at slowing decline on the revised ALS Functional Rating Scale (ALSFRS-R), the standard measure of disability in ALS.

With those encouraging results, Dr. Cudkowicz and colleagues from the Northeast ALS Consortium, a nationwide ALS clinical trials group, planned the phase 2 study. The primary objective, she said, was to confirm safety at a range of doses, and determine if there was still an efficacy signal with double-blind treatment.

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The consortium enrolled 102 newly diagnosed ALS patients, randomized to placebo or one of three doses of dexpramipexole, 50 mg, 150 mg, or 300 mg per day, for 12 weeks of treatment. This phase of the trial included a four-week single-blind washout within it, to determine if there were any adverse effects that would disappear on drug withdrawal. After the first 12 weeks, the second phase of the trial began, in which patients were re-randomized to either 50 mg or 300 mg of dexpramipexole daily for an additional 24 weeks.

“It was done this way to maximize a patient's chances of being on the drug, and safety was the primary outcome variable in the trial,” Dr. Cudkowicz explained.

The only significant safety signal from active treatment during the first phase of the trial appeared to be a drop in white blood cell count, and one patient stopped taking the drug because of it.

As their disease progresses, ALS patients decline on the ALSFRS-R, about 1 point a month on average, Dr. Cudkowicz said. Treatment failure, defined as a 6-point decline in the scale over 12 weeks, was seen in 33 percent of patients on placebo, 35 percent of patients on 50 mg, 15 percent on 150 mg, and 8 percent on 300 mg. The trend was significant (p=0.014).

A similar result was seen for decline in pulmonary function. Treatment failure, defined as a 20 percent decline in forced vital capacity from baseline, was seen in 30 percent, 13 percent, 12 percent, and 4 percent of patients in the four groups, respectively (p=0.028). Overall, patients in the high-dose group experienced a 30-to 40-percent slowing in their disease progression compared to placebo.

“The drug is safe,” Dr. Cudkowicz said, “and there is a dose-dependent slowing of decline in function. We happened to see an efficacy effect, although we didn't go in thinking we would. The nice thing is the dose dependency — it makes it a little more believable that the results aren't just due to chance. But it's still only a phase 2 study.”

High-dose dexpramipexole slowed functional decline in the second phase of the trial by 20 percent, and showed a trend toward reducing mortality compared to low-dose treatment (p=0.071).

“Everyone in the ALS research field has been generally enthusiastic about the results so far,” Dr. Cudkowicz said, “but no one thinks this is enough. These results support moving forward to a phase 3 study.”

That trial is in the planning stages, with the drug's patent owner, Knopp Neurosciences, currently in discussions with potential partners. The hope is to do an international trial with 700 patients, and to begin before the end of the year.

Part of what made this study so valuable, according to Orla Hardiman, MD, was the focus on dose-ranging. “Previous trials in ALS have not had this, for the most part, so you didn't know why the drug failed,” she said. Dr. Hardiman is director of neurology and senior lecturer at the Beaumont Hospital and Royal College of Surgeons in Dublin, Ireland. “The results are very exciting,” especially since there is nothing else but riluzole to offer ALS patients, she said.

Dr. Cudkowicz pointed out that in ALS drug development, dose-ranging studies are often bypassed, which has been a weakness of previous drug trials. “I think the biggest challenge is that this kind of smaller and shorter study”— a true phase 2 trial —“is often skipped in ALS, because people thought you couldn't see efficacy in this short a time. The tendency has been to leap right to 300-patient studies for 12 months.” Negative results have then been inconclusive, she said, because there was never an attempt to see the effect of different doses.

“We are learning from the prior mistakes. Our study suggests maybe you can see efficacy in a shorter time, although we won't know that for sure until we do the phase 3 trial.”



©2010 American Academy of Neurology