ALS Alert Newsletter | December

New Drug Shows Promise in
Clinical Trial

Dexpramipexole may help slow the progression of ALS.

The results of a small Phase II safety trial of a drug called dexpramipexole indicate that the drug may slow the progression of ALS in patients who have had symptoms for less than two years.

Pramipexole is an anti-Parkinson's drug that works as a dopamine agonist. Dopamine agonists help the brain compensate for the loss of the neurotransmitter dopamine that occurs with the death of dopamine neurons during the course of the disease. Loss of these cells causes the tremors and motor problems seen in Parkinson’s disease. Although pramipexole and other dopamine agonists, along with precursors of dopamine like L-dopa, can improve Parkinson’s symptoms, they are symptomatic treatments, and were not thought to alter the course of the disease.

However, a number of researchers had observed that pramipexole and some other dopamine agonists also seemed to slow the progression of Parkinson’s disease, suggesting a protective effect above and beyond a symptomatic improvement in motor symptoms. This neuroprotective effect, seen in preclinical studies, is less potent than its activity as a dopamine agonist. Pramipexole is a very high-affinity dopamine agonist, and its use as a lower potency neuroprotectant was limited by its dopamine related side effects. Pramipexole was only one version of the drug, however. When chemists synthesized the drug, they automatically produced pramipexole and its mirror image, dexpramipexole, in equal quantities. Thinking that only pramipexole was biologically active, the mirror image compound was not used.

James Bennett M.D. at the University of Virginia, who had been involved in both the original clinical studies with pramipexole and preclinical studies with both pramipexole and dexpramipexole, found that dexpramipexole was equally neuroprotective despite its much lower dopamine receptor affinity. Perhaps, Professor Bennett reasoned, since dexpramipexole had the neuroprotective properties of pramipexole without significant dopamine agonist potential, dexpramipexole might be a good candidate to treat a chronic neurodegenerative disorder. He decided to look at ALS, which has little in the way of effective treatment and a rapid course.

It turns out that it was a good candidate, and ALS was a good disease to begin to study its potential. A paper published this November in Nature Medicine found that dexpramipexole significantly slowed the progression of ALS in patients whose symptoms had begun in the previous two years. The results were from a small Phase II safety trial, and the results need to be replicated in larger Phase III clinical trials before the drug is available for patient use.

“We’re really excited about these results. Everyone from academic investigators to those of us on the industrial side are fully cognizant of all of the pitfalls of relatively small Phase II clinical trials, but we’re all very excited because it’s the first drug that has shown any evidence of efficacy in slowing both aspects of the progression of disease – mortality and function,” said Valentin Gribkoff, a researcher and former Chief Science Officer at Knopp Biosciences and senior author on the Nature Medicine paper.

A closer look at dexpramipexole.

Researchers at Knopp Biosciences, who had licensed the drug from the University of Virginia scientists, randomized 102 patients with recent-onset ALS into two different groups as part of a Phase II clinical trial to analyze the safety and tolerability of dexpramipexole. In the first part of the trial, which lasted 12 weeks, the patients received either a placebo or a daily dose of 50 mg, 150 mg, or 300 mg dexpramipexole. They observed a dose-dependent reduction in the rate of decline, as measured by the ALSFRS-R, the most widely accepted functional rating scale for ALS. Relative to placebo, the 300 mg/day highest dose group declined at a median rate that was half that observed in the placebo group.

After the first 12 weeks, all study participants were placed on a placebo for four weeks before starting the second part of the trial to ensure that all the dexpramipexole had cleared their bodies. This step allowed the researchers to essentially conduct two clinical trials in one by using the same study participants in both parts of the trial. Since researchers didn’t have to enroll two sets of patients, this greatly speeded up the progression of dexpramipexole through the clinical trial process.

In part two of the trial, the 92 remaining study participants were re-randomized into two different groups: 50 mg daily of dexpramipexole, and 300 mg daily of the drug for 24 weeks. A total of 71 people completed all 24 weeks of treatment. Patients on the 300 mg/day dose of dexpramipexole showed the least decline in functioning as measured by the ALS revised functional rating scale, and had lower mortality. The most common side effect was a reduction in white blood cells.

How the drug works.

Researchers believe that both dexpramipexole and its mirror image pramipexole help protect neurons by improving the functioning of the mitochondria, which function as the power plant for the cell by providing needed energy. Studies of pramipexole and dexpramipexole found high concentrations of the drug in the mitochondria of neurons, and these compounds are believed to help prevent mitochondrial damage. In addition, and perhaps more importantly, the drug appears to increase the efficiency of energy production by stressed mitochondria, and energy insufficiency may be one important avenue by which motor neurons become ‘at risk’ during the course of the disease. “While it might not be the primary cause of many chronic neurodegenerative diseases, mitochondrial dysfunction might be the final common pathway for neuronal death in ALS, Parkinson’s disease, and a number of other conditions,” Gribkoff said.

Mouse and human studies have shown that mitochondria in motor neurons become damaged in both the sporadic and familial forms of ALS. A drug that helps prevent mitochondrial damage or restore mitochondrial function could therefore be useful to ALS patients.

Biogen-Idec, which licensed the drug from Knopp in 2010, and Knopp Biosciences have recently begun Phase III clinical trials for dexpramipexole. “The drug shows significant promise,” Gribkoff said. “It is well-tolerated and if it continues to prove effective, I think it may be a significant addition to the repertoire of ALS clinicians, but we’ll have to wait and see.”

Although the results of the dexpramipexole study were known in 2009, the study still had to go through the peer review process to be verified and evaluated. By successfully completing peer review, the scientists are much more confident that their results are valid.

The results of a clinical trial of olexisome, another potential ALS drug targeting mitochondria were published in mid-December. Led by the European drug company Trophos, the study failed to find that olexisome slowed disease progression. Despite this setback, scientists remain optimistic that dexpramipexole may be a promising potential treatment.

"The Trophos study doesn't rule out this pathway as important in ALS. A negative trial does not necessarily mean the target is wrong. There are many reasons drug studies fail and it is important to explore those for all ALS trials," noted Merit Cudkowicz, a researcher at Massachusetts General Hospital, co-chair of the Northeast ALS Consortium (NEALS), and first author of the Nature Medicine paper. "The two drugs work in different methods. We also do not know if olexisome improved mitchondrial function in the Central Nervous System in people. There is currently no known way to measure mitochondrial dysfunction people with ALS patients. The preclinical data and the phase II dexpramipexole data in people with ALS encouraged us to proceed to phase III clinical testing."

The development of good biomarkers to help guide drug discovery would be a huge help, Cudkowicz said.

NEALS is an organization comprised of over 100 research institutions across North American, Ireland, and Israel committed to ALS research. Together, these sites function as an academic research consortium, perform clinical trials, and provide other services to the ALS community.  The Packard Center is a member of NEALS and Jeffrey Rothstein, the Packard Center's director, serves as its Scientific Advisory Board Chair.

–– Carrie Arnold