A small phase I study provides molecular evidence that an FDA-approved drug for leukemia significantly increased brain dopamine and low toxic proteins linked to illness development in patients along with Parkinson’s illness or dementia along with Lewy bodies. Dopamine is the brain chemical (neurotransmitter) lost as a result of death of dopamine-creating neurons in these neurodegenerative diseases.
Researchers from Georgetown University Medical Focus (GUMC), say the findings, described in the Journal of Parkinson’s Disease, support improved clinical outcomes observed and initial reported at the Society for Neuroscience annual meeting in October 2015.
The study tested nilotinib taken day-to-day for 6 months. A a lot smaller sized dose of nilotinib (150 or 300 mg as soon as daily) was used compared to the dose for chronic myelogenous leukemia (300-400 mg two times daily). Twelve patients were enrolled in the clinical trial — one patient withdrew as a result of an side event. Researchers say the drug appears to be safe and well tolerated in the remaining 11 participants that completed the study.
In addition to safety, the researchers additionally examined biological markers in the blood and cerebral spinal fluid also as cognitive, motor and non-motor improvement. They located considerable signs that nilotinib could give incentive for patients along with these neurodegenerative diseases.
“These outcomes have to be enjoyed along with caution and further validated in bigger placebo controlled trials, due to the fact that this study was small, the patients were quite various from each other, and there was no placebo,” says the study’s senior investigator, Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherpeutics Program.
Among the biomarker findings were that:
•The degree of the dopamine metabolite homovanillic acid — an indicator that dopamine is being created — progressively doubled, even along with the loss of the majority of dopamine neurons. the majority of study participants were able to avoid using, or reduce their usage of, dopamine substitute therapies;
•The degree of the Parkinson’s related oxidative tension marker DJ-1 — an indicator that dopamine-creating neurons are dying — was low much more compared to 50 percent after niltonib treatment; and
•The levels of cell death markers (NSE, S100B and tau) were significantly low in cerebrospinal fluid (CSF) suggesting low neuronal cell death.
In addition, Moussa adds that it appears nilotinib attenuated the loss of CSF alpha-synuclein, a toxic healthy protein that accumulates within neurons, resulting in low CSF levels in the two Parkinson’s illness and dementia along with Lewy bodies.
The researchers additionally said that every one of 11 patients that tolerated the drug reported meaningful clinical improvements. every one of patients were at mid-advanced stages of Parkinsonism and they every one of had mild to significant cognitive impairment.
“Patients gradually improved in motor and cognitive functions as long as they were on the drug — despite the decreased usage of dopamine substitute therapies in those participants along with Parkinson’s and dementia along with Lewy bodies,” says the study’s lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherpeutics Regimen and director of the Movement Disorders Regimen at MedStar Georgetown University Hospital.
But 3 months after withdrawal of the drug, participants returned to the exact same low cognitive and motor state they had prior to the study began, Pagan adds.
Some major adverse effects were reported including one patient that withdrew at week four of treatment as a result of heart attack and 3 incidents of urinary tract infection or pneumonia. The researchers say these incidents are not uncommon in this patient population, and added studies are called for to figure out if the side events are related to usage of nilotinib.
“Long-term safety of nilotinib is a priority, so it is essential that further studies be conducted to figure out the safest and the majority of efficient dose in Parkinson’s, says Pagan.
The researchers made the clinical trial to translate several notable observations in the laboratory. The preclinical studies, led by Moussa, showed that nilotinib, a tyrosine kinase inhibitor, effectively penetrates the blood-brain barrier and destroys toxic proteins that build up in Parkinson’s illness and dementia by turning on the “garbage disposal machinery” inside neurons.
Their published studies additionally showed nilotinib raises the levels of the dopamine neurotransmitter — the chemical lost as a result of neuronal destruction as a result of toxic healthy protein accumulation — and boosts motor and cognitive outcomes in Parkinson’s and Alzheimer’s illness pet models.
“Our chance is to clarify the incentives of nilotinib to patients in a a lot bigger and well controlled study. This was a quite promising start,” Moussa says. “If these data hold out in further studies, nilotinib would certainly be the crucial treatment for Parkinsonism because the discovery of Levodopa almost 50 years ago.”
He adds, “Additionally, if we can easily validate nilotinib effects on cognition in upcoming bigger and placebo controlled trials, this drug could come to be among the initial treatments for dementia along with Lewy bodies, which has actually no cure, and possibly others dementias.”
Two randomized, placebo-controlled phase II clinical trials are planned for summer/fall in Parkinson’s and Alzheimer’s diseases. The Translational Neurotherpeutics Regimen is additionally preparing a small trial in ALS (Lou Gherig’s disease).
According to Novartis, the cost (as of Oct. 2015) of nilotinib for the treatment of CML was regarding $10,360 a month for 800 mg daily. The dose used in this study was reduced — 150 and 300 mg daily.
Source:
Georgetown University Medical Center
