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Tyrosine kinase inhibitors (TKIs) have changed the treatment paradigm for patients with chronic myelogenous leukemia (CML), and new research suggests one of the agents could potentially do the same for patients with Parkinson's disease. Researchers found that nilotinib (marketed as Tasigna by Novartis)-approved by the U.S. Food and Drug Administration for the treatment of patients with CML (OT 7/10/10 issue)-improved cognition, motor skills, and non-motor function for patients with Parkinson's disease and Lewy body dementia. Complete data from the Phase I clinical trial were presented at the Annual Meeting of the Society for Neuroscience in October (Program 12, Poster 1).

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"When used in higher doses for CML, nilotinib forces cancer cells into autophagy-a biological process that leads to the death of tumor cells," study coauthor Charbel Moussa, MD, PhD, Director of Georgetown's Laboratory of Dementia and Parkinsonism, explained in a news release. "The dose used in CML treatment is significantly higher than what we used in our Parkinson's study.


"It appears that in smaller doses once a day, nilotinib turns on autophagy for about four to eight hours-long enough to clean out the cells without causing cell death. Then proteins that build up again will be cleared when the drug is given again the next day."


The observed efficacy in cognition, motor skills, and non-motor function improvement (such as constipation) for many patients was the most dramatic result, the researchers reported, according to the news release. One individual confined to a wheelchair was able to walk again; three others who could not talk were able to hold conversations.


Study Details

The study included 11 patients with advanced Parkinson's disease, Parkinson's disease with dementia, or Lewy body dementia, who received 150 to 300 mg nilotinib daily for six months. All patients benefited from the drug, and 10 had clinically meaningful improvements. Patients also showed positive changes in relevant cerebrospinal fluid biomarkers of Parkinson's, including alpha-synuclein ([alpha]-synuclein), amyloid beta-40/42 (Abeta-40/42), and dopamine, with statistically significant changes in total Tau and p-Tau. Prior studies show that [alpha]-synuclein and Abeta 40/42 in cerebrospinal fluid are decreased as Parkinson's worsens, while Tau and p-Tau are increased in cerebrospinal fluid with the onset of dementia.


"The changes in Tau, p-Tau, [alpha]-synuclein and Abeta-40 and 42 in spinal fluid suggest the clearance of toxic proteins in the brain," another study coauthor Fernando Pagan, MD, a Georgetown University Medical Center Associate Professor of Neurology and Director of the Movement Disorders Program at MedStar Georgetown University Hospital, said, also in a news release.


"To my knowledge, this study represents the first time a therapy appears to reverse-to a greater or lesser degree depending on stage of disease-cognitive and motor decline in patients with these neurodegenerative disorders," Pagan added. "But it is critical to conduct larger and more comprehensive studies before determining the drug's true impact."


No serious side effects were reported and the drug was well tolerated by the patients on the trial.


Why Try a Cancer Drug?

Moussa's preclinical research led him to think about using cancer drugs to treat neurological disorders. He was looking for an FDA-approved drug that could penetrate the blood-brain barrier and turn on the "garbage disposal machinery" inside neurons to clear toxic intracellular proteins and prevent their accumulation within, or secretion outside of, brain cells, he noted. Moussa is an inventor on a Georgetown University patent application for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative disease.


At the end of this study patients were given the option to continue taking nilotinib (provided by Novartis) as part of an expanded access study. Moussa and other Georgetown researchers are now planning larger clinical trials with nilotinib for patients with Parkinson's and other similar diseases including Alzheimer's disease, likely to begin in 2016.