Background

Dexpramipexole is an (R)-(+) optical enantiomer of pramipexole, a marketed dopamine agonist by Boehringer Ingelheim that is used in many countries around the world for the treatment of Parkinson's disease and restless leg syndrome. R-pramipexole has a lower affinity for dopamine receptors than pramipexole, and thus it can be administered and studied at a wider dose range. The compound originated at Virginia Commonwealth University. Besides modulating dopamine receptors, it has been variously described to act as an antioxidant, apoptosis inhibitor, and free radical scavenger. R-pramipexole is thought to protect neurons through effects on microglia and to improve free radical-induced cognitive impairment following general anesthesia in rats (e.g. Abramova et al., 2002; Ferrari-Torinelli et al., 2010; Alavian et al., 2012; Boscolo et al., 2012). Preclinical studies reported dexpramipexole to be orally bioavailable and to reach high central nervous system concentrations relative to plasma, raising interest in this compound for the treatment of several different neurodegenerative diseases (Bozik et al., 2011).

Findings

Biogen Idec conducted four Phase 1 studies to assess safety, tolerability, pharmacokinetics, food effects, metabolism and drug-drug interactions of single and multiple doses of dexpramipexole in healthy volunteers in the United States and Japan. Single doses of 50, 150, or 300 mg, and multiple doses of 50, 100, or 150 mg twice daily over several days were found to be safe and well tolerated. Dexpramipexole was rapidly absorbed and eliminated in urine without generating toxic metabolites (e.g. NCT01449578, NCT01424176, NCT01597310, NCT01536249, NCT01424163, see also Bozik et al., 2011).

In 2009, the U.S. Food and Drug Administration granted fast-track designation to dexpramipexole for amyotrophic lateral sclerosis (ALS). Knopp Neurosciences conducted a Phase 2 trial of dexpramipexole in 102 ALS patients (see Rudnicki et al., 2010).  Biogen Idec subsequently evaluated the compound in a multinational Phase 3 program for this indication; however, in January 2013 top-line results of the pivotal Phase 3 trial EMPOWER showed that it had missed the co-primary endpoint of function and survival, as well as key secondary endpoints and analyses in patient subpopulations. The trial had administered 150 mg of dexpramipexole twice daily for up to 18 months in 943 patients with ALS. Subsequently, Biogen Idec ended development of dexpramipexole (Cudcowicz et al., 2013).

In July 2011, an investigator-initiated Phase 2 trial at the University of Kansas began evaluating R-pramipexole in 20 patients with Alzheimer's disease. Sponsored by Virginia Commonwealth University and the Alzheimer’s Drug Discovery Foundation, this safety and efficacy trial aims to assess oxidative injury to cells in the blood and spinal fluid by measuring levels of isoprostane, a biomarker for oxidative stress, and by measuring brain glucose metabolism with FDG-PET before and after treatment. The trial admisters ascending doses of 100 to 300 mg/day for a total six months of treatment. The trial, NCT01388478, is set to run until 2014.

Clinical Trial Timeline