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

Address correspondence and reprint requests to Dr. Ira Shoulson, Department of Neurology, University of Rochester Medical Center, 1351 Mt Hope Ave, Ste 218, Rochester, NY 14620 Ira.shoulson{at}ctcc.rochester.edu

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 ß-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 ß-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.

GLOSSARY: DAT = dopamine transporter; DMC = data-monitoring committee; JNK = c-Jun N-terminal kinase; MLK = mixed lineage kinase; PD = Parkinson disease; PRECEPT = Parkinson Research Examination of CEP-1347 Trial; PSG = Parkinson Study Group; trkA = tyrosine kinase; UPDRS = Unified Parkinson's Disease Rating Scale.

Supplemental data at www.neurology.org

Editorial, see page 1476

e-Pub ahead of print at www.neurology.org.

*See appendix for full listing of authors of this report.

This study was supported by Cephalon, Inc. (Frazer, PA), and H. Lundbeck A/S (Copenhagen-Valby, Denmark). This study was also supported in part by GCRC-NIH/NCRR grant M01-RR000052 at the Johns Hopkins School of Medicine.

Disclosure: Authors of this report from the Parkinson Study Group (PSG) received grant support from the sponsors through their academic institutions (appendix), but they neither had equity interests in nor received any personal remuneration from the sponsoring companies since initiation of the study. Some authors of the report are employees of the sponsor and are so designated in the appendix. The PSG maintained the database and carried out independent analysis of the data.

This study was presented in abstract form as a late-breaking science report on April 5, 2006, at the 58th Annual Meeting of the American Academy of Neurology (Neurology 2006;67:185).

The study was registered on clinicaltrials.gov with ID NCT00040404.

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