Dexpramipexole in ALS
Seeking to Improve the Lives of Patients with ALS
Knopp is advancing dexpramipexole as a novel, oral investigational treatment for amyotrophic lateral sclerosis (ALS). ALS is a devastating disease of progressive paralysis with very limited treatment options.
In a Phase 2 study, dexpramipexole showed trends toward improvement in both survival and functional decline. A statistically significant result was observed in a prespecified exploratory endpoint, the Combined Assessment of Function and Survival (CAFS), a joint rank analysis of functional outcomes adjusted for mortality. Adverse events noted in the trial included falls, muscle weakness, post-lumbar puncture syndrome, and headache, with no dose-dependent differences in AE frequency. Infrequent, reversible neutropenia was also observed.
Following the Phase 2 program, we licensed dexpramipexole for late-stage development and commercialization to Biogen Idec, which conducted a large, global Phase 3 trial in ALS. As reported in Lancet Neurology, the Phase 3 study failed to meet its prespecified endpoints while demonstrating that dexpramipexole was generally well tolerated, with a safety profile similar to that seen in Phase 2.
A post-hoc analysis of the Phase 3 data demonstrated that significant differences existed in the populations studied in Phase 2 and Phase 3 in certain important baseline characteristics. In particular, the Phase 3 trial enrolled significantly fewer subjects with a baseline diagnosis of "definite ALS," enrolled subjects with a significantly longer duration of ALS symptoms, and included a significantly greater number of patients receiving concomitant riluzole, the only drug approved for ALS. As noted by the Phase 3 investigators in Lancet Neurology, "Based on these post-hoc analyses, subsequent research will be done to establish what effect these differences could have had on the study results."
In December 2013, Knopp presented further post-hoc analyses before the International Symposium on ALS/MND in Milan, Italy. These analyses showed that a subgroup defined by the significant inter-study differences—that is, subjects with definite ALS, short symptom duration, and receiving riluzole—experienced significantly slower disease progression, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), and also experienced a significant reduction in the hazard for mortality. We also reported that dexpramipexole treatment significantly reduced the loss of creatinine, a protein correlated with disease progression, and that this effect was greatest in those patients with the greatest clinical benefit. A portion of these data were also presented in Italy before a satellite symposium of the ALS Research Group, stimulating interest in follow-on research by a number of ALS specialists.
Knopp's pipeline consists of investigational drug products that have not been approved by the U.S. Food and Drug Administration. These investigational drug products are still undergoing clinical study to verify their safety and effectiveness.