CHICAGO — The tyrosine kinase inhibitor nilotinib (Tasigna, Novartis), approved in the United States for acute myelogenous leukemia (CML), has shown early promise in patients with Parkinson's disease (PD) with dementia (PDD) and Lewy body dementia (LBD).
In an open-label phase 1 study, nilotinib, given at doses considerably lower than that used for CML, led to statistically significant changes in relevant biomarkers of neurodegeneration in cerebrospinal fluid.
The drug also produced marked improvement in cognition and motor function in 11 of 12 patients who completed the 6-month study, with 10 patients reporting meaningful clinical improvements, the researchers say.
Fernando Pagan, MD, associate professor of neurology at Georgetown University Medical Center (GUMC), and director of the Movement Disorders Program at MedStar Georgetown University Hospital, Washington, DC, presented the findings at the Society for Neuroscience (SfN) 2015 Annual Meeting.
"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," Dr Pagan said in a statement from the university. "But it is critical to conduct larger and more comprehensive studies before determining the drug's true impact," he cautioned.
The 12 patients had advanced PD, PDD, and LBD and no prolonged corrected QT interval, myelosuppression, or other medical conditions. They were treated with nilotinib starting at 150 mg/day and increasing to 300 mg/day over 6 months. (In patients with CML, nilotinib is given at a dose of 800 to 1200 mg/day).
Some patients saw dramatic improvement in symptoms; one individual who had to use a wheelchair was able to walk again, and three others who could not talk were able to hold conversations. Those with earlier-stage disease responded best, as did those diagnosed with LBD, the researchers say.
Treatment with nilotinib also led to significant declines in several cerebrospinal fluid (CSF) biomarkers of neurodegeneration, including tau, pTau, α-synuclein, and amyloid β, suggesting "clearance of toxic proteins in the brain," Dr Pagan said. Nilotinib also increased CSF concentrations of several neurorestorative biomarkers.
"We are very pleased with the safety profile in this patient population, and it's really exciting to see a disease-modifying effect," Charbel Moussa, MD, PhD, who directs the GUMC Laboratory of Dementia and Parkinsonism, noted in an interview with Medscape Medical News.
"Nilotinib gets into the brain, has direct target engagement in the brain, and triggers autophagy, and that leads to degradation of intracellular proteins that we think are the main culprits in neurodegeneration, but also β-amyloid plaque, which is extracellular," said Dr Moussa, who did the preclinical work that led to the phase 1 clinical study.
Nilotinib had good penetration in the CSF — 0.5% to 1.5% — which is higher than the penetration seen with dopamine drugs, the researchers note. And "strikingly," Dr Moussa said, "we see an increase in the neurotransmitter dopamine" during nilotinib treatment such that doses of L-dopa and other dopamine-sparing drugs had to be lowered or stopped.
However, stopping nilotinib led to cognitive and motor decline despite restarting L-dopa therapies. Patients in the study can continue taking nilotinib provided by Novartis as part of an expanded-access study.
The researchers urge caution in interpreting the phase 1 results because the study was designed to test safety, not efficacy, and lacked a control group. Also, nilotinib was not compared with a placebo or other medications used to treat PD in the study.
Constantino Iadecola, MD, director, Brain and Mind Research Institute at Weill Cornell Medical College in New York City, also urged caution in interpreting the results from this early study.
It's "exciting" data, but from a "nonrandomized, nonblinded, non–placebo-controlled study that looked at 12 patients," he noted in an interview with Medscape Medical News. "The patients were selected very carefully, and we don't know all the criteria for selection. More quantitative assessment of the data is needed. I would encourage the media not to blow it up out of proportion."
The cost also has to be considered, as low-dose nilotinib would likely have to be taken daily and continuously for continued benefit in PD. "In Manhattan, a 150-mg pill is $93 per pill, which means $100 a day essentially. It's not like in cancer, where you take it for a period of time and then stop," Dr Iadecola noted.
Dr Moussa and colleagues are now planning a double-blind, placebo-controlled phase 2 clinical trial testing nilotinib in patients with PD and other neurodegenerative diseases, including Alzheimer's disease. The study is likely to begin in 2016, he said.
The phase 1 study received philanthropic funding and was supported by the Georgetown-Howard Universities Center for Clinical and Translational Science. Dr 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. Dr Pagan has disclosed no relevant financial relationships.
Society for Neuroscience (SfN) 2015 Annual Meeting. Abstract 12.01. Presented October 18, 2015.
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