Nature Medicine publishes dexpramipexole Phase 2 ALS study results

Knopp Biosciences LLC today announced the publication in Nature Medicine of comprehensive results from the Phase 2 study of dexpramipexole, a small-molecule modulator of mitochondrial bioenergetics, in people with amyotrophic lateral sclerosis (ALS). Dexpramipexole is currently in Phase 3 development under an exclusive worldwide license with Biogen Idec.

“In this well-controlled Phase 2 study, we detected an apparent clinically significant, dose-dependent effect on both function and mortality - an exciting milestone. This is the first time we've seen data suggesting benefits on both function and mortality from a drug candidate in ALS.”

"Results from this Phase 2 study demonstrate why we're so enthusiastic about the rapid advance of dexpramipexole to a Phase 3 trial," said Merit Cudkowicz, M.D., primary author of the Nature Medicine manuscript and director of the MDA ALS Clinic at Massachusetts General Hospital and the Northeast ALS Consortium. Dr. Cudkowicz was the Principal Investigator for the Phase 2 study of dexpramipexole in ALS. "In this well-controlled Phase 2 study, we detected an apparent clinically significant, dose-dependent effect on both function and mortality - an exciting milestone. This is the first time we've seen data suggesting benefits on both function and mortality from a drug candidate in ALS."

The Phase 2 clinical trial, designed by Knopp and its principal investigators and conducted at 20 U.S. sites, involved a novel design for an ALS trial in which the same subjects were randomized twice, essentially creating two separate, double-blind studies over which treatment effects could be observed on safety, functional decline, and mortality. In Part 1 of the study, 102 subjects received daily divided doses of 50 mg, 150 mg, or 300 mg of dexpramipexole or placebo for 12 weeks. In Part 2, 92 continuing subjects received placebo during a 30-day, single-blind washout period, followed by re-randomization to divided daily doses of either 50 mg or 300 mg for 24 weeks.

The Nature Medicine article details treatment effects across both parts of the study, including mortality effects. During the 12 weeks of Part 1, there were no deaths. During the 30-day placebo washout period, there were three deaths, limited to patients who had received placebo or low-dose treatment (50 mg) during Part 1. During the 24-week double-blind active treatment period in Part 2, there were 12 deaths, with nine deaths involving patients receiving the low dose (50 mg) and three deaths involving patients receiving the high dose (300 mg). This represented a 68% reduction in the hazard of mortality for the 300 mg group over the 24 weeks of Part 2.

The article also describes treatment effects on measures of disease progression in both parts of the study, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), a widely used and validated measure of function.

The trend in function favoring the 300 mg group was sustained in Part 2 of the study, with a 20.5 percent attenuation in the rate of decline compared to the active control group receiving 50 mg.

A significant effect was seen in a Combined Assessment of Function and Survival (CAFS), a joint-rank test that analyzes functional outcomes while accounting for in-study mortality. In this pre-specified test in Part 2 of the Phase 2 study, the mean CAFS score for the 300 mg group was 27 percent higher (more favorable outcomes) than for the 50 mg group.

Dexpramipexole demonstrated favorable safety and tolerability profiles in this Phase 2 trial, supporting further investigation in a Phase 3 trial. Adverse events noted in the trial included falls, muscle weakness, post-lumbar puncture syndrome, and headache, with no trend in differences in frequency among dose groups. Infrequent, reversible neutropenia was observed in both parts of the study among subjects in the 300 mg group.