Newly published data confirm that in a two-part phase 2 clinical trial, the experimental therapy dexpramipexole showed dose-related slowing of symptom progression and increased survival time in people with amyotrophic lateral sclerosis (ALS).

The findings were published online Nov. 20, 2011, in Nature Medicine by principal investigator Merit Cudkowicz (director of the MDA/ALS Center at Massachusetts General Hospital in Boston and a member of MDA’s Medical Advisory Committee) and colleagues.

Based on trial results, dexpramipexole seems to be unique in that it both improves survival and slows symptom progression, the investigators note in their report.

“To our knowledge, no other drug has shown a clinically significant effect in the decline of [function] in a properly controlled clinical trial, and no other study has shown effects on both function and mortality,” they wrote. Riluzole (Rilutek) — the only drug presently approved for treatment of ALS — modestly extends life span but doesn’t cause significant improvement in function.

Phase 2 trial data reveal safety and efficacy

In the phase 2 trial, conducted at 20 U.S. study sites, trial participants were randomly assigned to treatment and control groups twice, essentially creating two separate double-blind, placebo-controlled studies.

In the first part of the study, which lasted 12 weeks, 102 trial participants each received either 50 milligrams, 150 milligrams or 300 milligrams per day of dexpramipexole, or a placebo (fake drug).

Ninety-two participants moved on to part 2 of the trial, in which they all received placebo for 30 days (called a “washout period”). They then were randomly assigned to one of two groups, one receiving 300 milligrams of dexpramipexole per day for 24 weeks, and the other receiving 50 milligrams per day. A total of 71 people completed all 24 weeks.

Higher doses of dexpramipexole correlated with a slower rate of decline in function, based on theALSFRS-R (ALS Functional Rating Scale — Revised), a widely used and validated measure of functional ability in ALS.

In part 1 of the study, the rate of functional decline in the group receiving 300 milligrams of dexpramipexole was 31 percent lower than the rate of decline in the placebo group. In part 2, participants receiving 300 milligrams a day showed a 20.5 percent slower rate of functional decline compared to those in the 50-milligram group.

Mortality for participants in the 300-milligram group was 68 percent lower than in the 50-milligram group during the 24-week active phase in part 2 of the study.

Functional decline and mortality also were analyzed together using a Combined Assessment of Function and Survival (CAFS) test. Results indicated that the 300-milligram/day dose of dexpramipexole was significantly more effective (correlated with more favorable outcomes) than the 50-milligram/day dose.

In both parts of the study, an oral dose of dexpramipexole was found to be safe and well-tolerated when taken twice daily by trial participants. A temporary reduction in the number of white blood cells (neutropenia) was seen in a few participants and will be monitored in future trials, the investigators say.

“Results from this phase 2 study demonstrate why we’re so enthusiastic about the rapid advance of dexpramipexole to a phase 3 trial,” Cudkowicz said in a press release.

“EMPOWER,” a large-scale, global phase 3 clinical trial of dexpramipexole in ALS is under way at study sites in 28 U.S. states and 10 other countries.

Dexpramipexole: Development details

Preliminary results for this trial were reported at the April 2010 American Academy of Neurology meeting in Toronto and at the 2009 International Symposium on ALS/MND in Berlin.

Dexpramipexole, also known as (R+) pramipexole, was developed under the name KNS-760704by drug discovery and development company Knopp Biosciences (then called Knopp Neurosciences) in Pittsburgh, Pa.

The molecule’s chemical structure is the mirror image of Mirapex, a prescription drug approved for the treatment of Parkinson’s disease and restless legs syndrome. The structural difference between the two molecules results in significantly different pharmacological effects.

Dexpramipexole has demonstrated neuroprotective properties in multiple studies involving cell cultures and laboratory animals. It appears to work by improving the function and efficiency of cellular “energy factories” called mitochondria. In ALS, mitochondria experience a cell-damaging process called oxidative stress, a condition that can contribute to the death of nerve cells (motor neurons).

Knopp Biosciences and Biogen Idec in Weston, Mass., have partnered to develop dexpramipexole as an experimental treatment for ALS. (See Biogen Idec and Knopp Neurosciences Announce License Agreement for Late-Stage ALS Drug Candidate.) Biogen Idec holds an exclusive worldwide license from Knopp to develop and commercialize the drug, with Knopp providing development support.

Dexpramipexole received orphan drug status from the U.S. Food and Drug Administration in October 2007, and a “fast-track” designation in September 2009. Orphan drug status provides financial incentives for the development of drugs for rare diseases.

Meaning for people with ALS

Study investigators suggest that the favorable results from the phase 2 study of dexpramipexole “strongly support” further testing of the drug in ALS.

While these results are encouraging, they must be confirmed in a large-scale, phase 3 study. An 800-person multinational phase 3 study already is under way but is no longer recruiting new participants.

Two positive phase 3 clinical trials typically are required to receive FDA marketing approval, but in some cases a single positive study is sufficient (particularly if the trial involves a large number of trial participants, consistent results across multiple study sites and statistically significant results).

Substantial evidence of efficacy in the ongoing phase 3 study will move dexpramipexole closer to FDA approval for treatment of ALS.