MedicalResearch.com Interview with:
Charbel Moussa MD. PhD
Assistant Professor of Neurology
Director- Laboratory for Dementia and Parkinsonism
Clinical Research Director- National Parkinson’s Foundation Center for Excellence
Translational Neurotherapeutics Program
Department of Neurology
Georgetown University Medical Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: We conducted a pilot open label proof-of-concept study to evaluate the safety and tolerability of Nilotinib in participants with advanced Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB). Our primary objective is to demonstrate that low oral daily doses of 150mg or 300mg Nilotinib (compared to 600-800mg in cancer) are safe and tolerated.
Our secondary objectives are that Nilotinib will cross the blood brain barier and may inhibit cerebral spinal fluid Abl. Based on preclinical data we also hypothesized that Nilotinib will increase DA levels. Motor and cognitive functions were also measured as exploratory clinical outcomes. Other exploratory outcomes are that Nilotinib may alter PD-related CSF biomarkers DJ-1 and α-synuclein. As most participants in this study had dementia we also explored the effects of Nilotinib on Alzheimer’s Disease-related CSF biomarkers, including Aβ40 and Aβ42, total tau and phosphorylated tau (p-tau).
MedicalResearch.com: What are the main findings?
Response: Twelve patients with late-stage Parkinson’s disease or DLB randomized into two groups were given either 150 mg or 300 mg of nilotinib daily for six months, significantly lower than the 600-800 mg doses used in leukemia treatment. Careful safety monitoring included physical and neurological exams, EKGs, and extensive blood chemistry testing. Blood and cerebrospinal fluid (CSF) were collected at the beginning of the study and again after 8 and 24 weeks. Nilotinib uptake was measured at various intervals after dosing, and a variety of biomarkers associated with PD and neurodegeneration were assessed.
In addition, motor symptoms were monitored using the Unified Parkinson Disease Rating Scale (UPDRS). The researchers observed improvements in all participants at 24 weeks, with the effects reversing by the 36-week follow up visits, after treatment had concluded.
Among the biomarker findings were that:
• The level of the dopamine metabolite homovanillic acid — an indicator that dopamine is being produced — steadily doubled, even with the loss of most dopamine neurons. Most study participants were able to stop using, or reduce their use of, dopamine replacement therapies;
• The level of the Parkinson’s related oxidative stress marker DJ-1 — an indicator that dopamine-producing neurons are dying — was reduced more than 50 percent after niltonib treatment; and
• The levels of cell death markers (NSE, S100B and tau) were significantly reduced in cerebrospinal fluid (CSF) suggesting reduced neuronal cell death.
“Our hope is to clarify the benefits of nilotinib to patients in a much larger and well controlled study. This was a very promising start,” “If these data hold out in further studies, Nilotinib would be the most important treatment for Parkinsonism since the discovery of Levodopa almost 50 years ago.”
Additionally, if we can validate nilotinib effects on cognition in upcoming larger and placebo controlled trials, this drug could become one of the first treatments for dementia with Lewy bodies, which has no cure, and possibly other dementias.”
MedicalResearch.com: What should readers take away from your report?
Response: This is a highly promising start that may change the course of Parkinson’s disease research. This is just the beginning and more trials are needed.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The data give a clear signal to move forward with more definitive trials to determine an appropriate therapeutic dose and evaluate Nilotinib effects in larger, randomized, double-blinded, placebo-controlled trials.
MedicalResearch.com: Is there anything else you would like to add?
Response: Georgetown University is preparing for phase II double blind placebo controlled studies in Parkinson’s disease and Alzheimer’s Disease.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Fernando Pagan, Michaeline Hebron, Ellen H. Valadez, Yasar Tores-Yaghi, Xu Huang, Reversa R. Mills, Barbara M. Wilmarth, Hellen Howard, Connell Dunn, Alexis Carlson, Abigail Lawler, Sean L. Rogers, Ramsey (Drew) Falconer, Jaeil Ahn, Zhaoxia Li, Charbel Moussa. Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies.
Journal of Parkinson’s Disease, 2016; 1 DOI: 10.3233/JPD-160867
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