Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease

Neurology. 2007 Oct 9;69(15):1480-90. doi: 10.1212/01.wnl.0000277648.63931.c0. Epub 2007 Sep 19.

Abstract

Background: CEP-1347 inhibits mixed lineage kinases that activate apoptotic pathways implicated in the pathogenesis of Parkinson disease (PD). CEP-1347 enhances neuronal survival in a variety of nonclinical models and was found to be safe and well tolerated during 4 weeks in PD patients. We conducted the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) to assess its disease-modifying potential in early PD.

Methods: Consenting PD patients not yet requiring dopaminergic therapy (n = 806) were randomized equally to CEP-1347 in dosages of 10 mg BID, 25 mg BID, or 50 mg BID, or matching placebo, and were evaluated blindly and prospectively. The primary clinical end point was time to the development of disability requiring dopaminergic therapy. Secondary end points included changes in the Unified Parkinson's Disease Rating Scale (UPDRS) and beta-CIT SPECT imaging of striatal dopamine transporters.

Results: The study was concluded early, after an average of 21.4 months of follow-up, when a planned interim analysis demonstrated that it would be futile to continue experimental treatment. At that time, 108 of 191 subjects randomized to placebo (57%) had reached the primary end point of disability requiring dopaminergic therapy compared with active CEP-1347: 133 of 205 (65%) on 10 mg BID, 126 of 212 (59%) on 25 mg BID, and 127 of 198 (64%) on 50 mg BID. Changes in UPDRS scores and beta-CIT imaging showed similar patterns.

Conclusions: In contrast to research in animal models that predicted favorable disease-modifying outcomes, we found CEP-1347 to be an ineffective treatment in early Parkinson disease.

Trial registration: ClinicalTrials.gov NCT00040404.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / metabolism
  • Carbazoles / administration & dosage*
  • Corpus Striatum / diagnostic imaging
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Disease Progression
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Double-Blind Method
  • Enzyme Inhibitors / administration & dosage*
  • Female
  • Humans
  • Indoles / administration & dosage*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Middle Aged
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / physiopathology
  • Neuroprotective Agents / administration & dosage*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / enzymology
  • Parkinson Disease / physiopathology
  • Prospective Studies
  • Tomography, Emission-Computed, Single-Photon
  • Treatment Failure

Substances

  • Apoptosis Regulatory Proteins
  • Carbazoles
  • Dopamine Plasma Membrane Transport Proteins
  • Enzyme Inhibitors
  • Indoles
  • Neuroprotective Agents
  • 3,9-bis((ethylthio)methyl)-K-252a
  • JNK Mitogen-Activated Protein Kinases

Associated data

  • ClinicalTrials.gov/NCT00040404