Why did CEP-1347 fail in the Parkinson′s trial?

HD Lighthouse Contributing Editor's Comment: 

CEP-1347 was originally tested for Parkiinson's patients and failed in clinical trials in 2005. CEP-1347 looks promising for HD based on cell and animal models of HD, but that was also true for PD. 

The authors of the study raise several possibilies for CEP-1347's failure.  The first is animal modeling in Parkinson's Disease. Since the causes of Parkinson's Disease are not fully understood, the pathologies of the disease need to be directly reproduced in animal models and that inevitably involves some assumptions which may not be accurate.  In the model used a neurotoxin was administered to cause PD like damage.  An acute insult to the brain is not the same as a progressive neurodegenerative disorder; studies in HD have shown some clear differences between older neurotoxin models of HD and the newer genetic mouse models.

In contrast, HD researchers are more accurately able to reproduce the disease in animal models since Huntington's Disease is based on one known cause, the expanded polyglutamine tract in the huntingtin's protein gene.  Transgenic mice show a progressive rather than an acute disorder.

Another issue raised by the authors is whether apoptosis is an appropriate target for treating neurological diseases.  It may be that it is too late to target programmed cell death after the onset of the disease.  If that is the case and targeting apoptosis before clinical onset would be effective, a gene test is available in HDso that early treatment could begin earlier than in PD. 

It may be that if apoptosis is blocked, cell death will occur by other other pathways.   However, in HD, even if the anti-apoptotic properties of CEP-1347 fail to modify the disease, the restoration of BDNF itself could be a significant treatment.

The authors of the commentary on the failure of CEP-1347 in Parkinson's disease suggest that, in the development of treatments for neurodegenerative disorders, it is very important that mechanisms be validated and biomarkers be used to be sure that the drug is reaching its target.  The researchers associated with the two CEP-1347 in HD studies recently covered on the Lighthouse are doing just that with careful preclinical work.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 09-21-2008

Recent clinical failures in Parkinsons disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases.

Peter Waldmeier, Donna Bozyczko-Coyne, Michael Williams,and Jeffry Vaught

Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.

Source: Biochemical Pharmacology 2006 Nov 15;72(10):1197-206.