[Stitcher]

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

The Parkinson Study Group PRECEPT Investigators*

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@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.

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[jeanb]

I was in this study -- as were others in this forum. I was on the 10mg dose

Glad to finally read the report.

[burckle]

Yes. Thanks Carolyn. I was on the study also.

Lloyd

[ZucchiniFlower]

Thanks to all. But were you tested for LRRK2 mutations prior to the study? Specifically the G2019S? It doesn't make a lot of sense to choose patients with different pathology and genes, especially for a targeted drug like this one.

"The G2019S substitution is situated in the mitogen-activated kinase kinase kinase domain of Lrrk2, within the hinge region of the highly conserved activation segment: Asp-Phe-Gly (DFG).[3] Based on in silico modeling using a series of homologous mixed-lineage kinases as templates, we hypothesize that the mutant form may modulate kinase activity or alter substrate specificity (Fig 2). Notably, Lrrk2 I2012T, G2019S, and I2020T substitutions, which cluster in this domain, also create potential novel targets for phosphorylation. Although the signaling or secondary messenger phosphorylation cascade has yet to be elucidated, we propose Lrrk2 kinase activity may promote -synuclein pathology either directly or indirectly via a protective response. Work in Drosophila melanogaster suggests -synuclein phosphorylation at amino acid S129 may be a critical event in neurotoxicity.[20][21] It remains to be shown whether -synuclein phosphorylation is a direct or downstream target of Lrrk2 mitogen-activated kinase kinase kinase activity; nonetheless, we postulate that Lrrk2 substrates play a crucial role in PD pathogenesis, and the amount of these substrates within the cell may have a major impact on G2019S disease parameters such as age of onset.

Interestingly, phase II/III neuroprotectant therapy for PD[22] with a mixed-lineage mitogen-activated kinase kinase kinase inhibitor (CEP-1347)[23] was initiated by the Parkinson Study Group, but recently was terminated due to ineffectiveness in the interim evaluation. In future clinical studies of mixed-lineage kinase inhibitors, it may be useful to stratify PD patients based on the presence of the G2019S carrier state. "

From:

Lrrk2 and Lewy body disease

http://www3.interscience.wiley.com/c...5245/HTMLSTART