Amsterdam, NL, July 12, 2016 - Parkinson's disease (PD) is the second most common neurodegenerative disorder that causes a range of motor and non-motor symptoms. During the course of the disease, dopamine (DA)-producing neurons are lost and bundles of proteins known as Lewy bodies (LBs) form in the brain. A study reported in the Journal of Parkinson's Disease provided molecular evidence that the FDA-approved leukemia drug nilotinib may restore brain dopamine and reduce toxic proteins associated with LB formation in PD and dementia patients.
Researchers from Georgetown University Medical Center conducted a small phase 1 study that included only 12 patients, primarily intended to evaluate whether patients could tolerate the drug. The results showed unanticipated improvements in clinical outcomes and motor function.
"This is the first study to treat subjects with advanced PD with a tyrosine kinase inhibitor," explained lead investigator Charbel Moussa, MD, PhD, of the Department of Neurology, National Parkinson's Foundation Center for Excellence, Georgetown University Medical Center (GUMC), Washington DC. "This study suggests that low doses of nilotinib appear to be relatively safe in a small cohort of participants with advanced PD or dementia with Lewy bodies (DLB), and although the data are supportive of additional trials, caution must be used in any future studies. 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."
Autophagy, a "housecleaning" process that removes various entities from inside cells, may be impaired in PD and DLB patients. Nilotinib is an Abelson tyrosine kinase inhibitor (Abl-TKI) that induces autophagy to destroy cancer cells. The researchers had found previously that this drug could penetrate the blood brain barrier and degrade the protein bundles, which are primarily composed of α-synuclein. Based on this observation, they conducted a small proof-of-concept, non-placebo-controlled clinical trial.
Twelve patients with late-stage PD 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.
"Patients progressively improved in motor and cognitive functions as long as they were on the drug -- despite the decreased use of dopamine replacement therapies in those participants with Parkinson's and dementia with Lewy bodies," stated the study's lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherapeutics Program and director of the Movement Disorders Program at MedStar Georgetown University Hospital.
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 nilotinib treatment; and
- The levels of cell death markers (NSE, S100B and tau) were significantly reduced in 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," Dr. Moussa said. "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."
He added, "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."
In an accompanying commentary, Richard K Wyse, MD, The Cure Parkinson's Trust, London, UK, Patrik Brundin, MD, PhD, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA, and Todd B Sherer, PhD, Michael J Fox Foundation for Parkinson's Research, New York, New York, USA, put these findings into perspective and address some of the limitations of this small but innovative study. "The current paper by Pagan et al. substantiates a new direction, addressing a molecular pathway not previously targeted in a clinical trial in this context, for potential disease modification in PD and DLB. However, this study is just a first step and a major concerted effort is needed to determine whether there is still hope that can match the hype for nilotinib in alpha-synucleinopathies."