Objective: To assess the imaging and clinical effects of CEP-1347 after treatment discontinuation  in the Parkinson Research Examination of CEP-1347 Trial (PRECEPT), a multi-center randomized controlled trial including 806 early Parkinson disease (PD) patients not requiring dopaminergic therapies.

Background: CEP-1347 extends survival of neurons in multiple in vitro and in vivo non-clinical models of PD and Huntington disease (HD). PRECEPT subjects were randomized (1:1:1:1) to CEP-1347 (20, 50, 100 mg) or placebo daily and followed for 21 months when treatment was discontinued because of clinical futility. CEP-1347 did not affect UPDRS and was safe and well tolerated, but SPECT dopamine transporter (DAT) imaging showed treatment-related worsening.  

Methods: For the 87% subjects who consented to be followed after treatment was discontinued, additional DAT imaging and clinical assessments were obtained approximately 4 and 6 years after baseline by investigators at the Institute for Neurodegenerative Disorders (New Haven, CT) who remained unaware of original treatment assignment and prior imaging results.

Results: Subjects assigned originally to active CEP-1347 showed no difference in reduction in DAT binding at 4 years (p=0.75) or 6 years (p=0.92) compared with placebo subjects. UPDRS change over the entire follow-up period was not significantly different among the original treatment groups.

Conclusions: The initial trend of DAT uptake decline among subjects assigned to CEP-1347 in the PRECEPT trial relative to those assigned to placebo disappeared over the ensuing 2-4 years of observation, indicating that the impact of treatment was transient and likely due to reversible pharmacological mechanisms.  CEP-1347 remains a clinically suitable disease-modifying candidate for neurodegenerative diseases, such as HD.

References: Parkinson Study Group PRECEPT Investigators. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson’s disease. Neurology 69:1480-1490, 2007

Apostol BL, Simmons DA, Zuccato C,  Illes K, Pallos J, Casale M, Conforti P, Ramos C, Roarke M, Kathuria S, Cattaneo E, Marsh JL, Thompson LM. CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice. Molecular and Cellular Neuroscience 39: 8-29, 2008

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MDS Abstracts - https://www.mdsabstracts.org/abstract/long-term-dopamine-transporter-imaging-and-clinical-effects-of-the-mixed-lineage-kinase-inhibitor-cep-1347-in-the-precept-parkinson-trial/