Synonyms: RPPX, Dexpramipexole, KNS-760704 , BIIB 050
Chemical Name: (R)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Discontinued)
Company: Biogen, Knopp Biosciences LLC, Virginia Commonwealth University
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).
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
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|Virginia Commonwealth University||NCT01388478||
- Bozik ME, Mather JL, Kramer WG, Gribkoff VK, Ingersoll EW. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J Clin Pharmacol. 2011 Aug;51(8):1177-85. Epub 2010 Oct 19 PubMed.
- Rudnicki SA, Berry JD, Ingersoll E, Archibald D, Cudkowicz ME, Kerr DA, Dong Y. Dexpramipexole effects on functional decline and survival in subjects with amyotrophic lateral sclerosis in a Phase II study: subgroup analysis of demographic and clinical characteristics. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan;14(1):44-51. Epub 2012 Sep 17 PubMed.
- Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, Hardiman O, Bozik ME, Ingersoll EW, Archibald D, Meyers AL, Dong Y, Farwell WR, Kerr DA, EMPOWER investigators. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol. 2013 Nov;12(11):1059-67. Epub 2013 Sep 23 PubMed.
- Abramova NA, Cassarino DS, Khan SM, Painter TW, Bennett JP. Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma. J Neurosci Res. 2002 Feb 15;67(4):494-500. PubMed.
- Ferrari-Toninelli G, Maccarinelli G, Uberti D, Buerger E, Memo M. Mitochondria-targeted antioxidant effects of S(-) and R(+) pramipexole. BMC Pharmacol. 2010 Feb 5;10:2. PubMed.
- Alavian KN, Dworetzky SI, Bonanni L, Zhang P, Sacchetti S, Mariggio MA, Onofrj M, Thomas A, Li H, Mangold JE, Signore AP, Demarco U, Demady DR, Nabili P, Lazrove E, Smith PJ, Gribkoff VK, Jonas EA. Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. Brain Res. 2012 Mar 29;1446:1-11. Epub 2012 Jan 28 PubMed.
- Boscolo A, Starr JA, Sanchez V, Lunardi N, DiGruccio MR, Ori C, Erisir A, Trimmer P, Bennett J, Jevtovic-Todorovic V. The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: the importance of free oxygen radicals and mitochondrial integrity. Neurobiol Dis. 2012 Mar;45(3):1031-41. Epub 2011 Dec 14 PubMed.
- Corcia P, Gordon PH. Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole. Ther Clin Risk Manag. 2012;8:359-66. PubMed.
- Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, Moore DH, Schoenfeld D, Mather JL, Archibald D, Sullivan M, Amburgey C, Moritz J, Gribkoff VK. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med. 2011 Dec;17(12):1652-6. PubMed.