A cancer drug used to treat a type of leukemia appeared to improve motor and cognitive function in patients with Parkinson's disease, a small study by researchers at Georgetown University's Medical Center showed.
Notably, treatment with the drug, called nilotinib, seemed to increase natural production of dopamine, a key neurotransmitter which is typically lost as brain cells die in patients with Parkinson's. Loss of dopamine makes it increasingly difficult for Parkinson's patients to control or coordinate muscle movement, leading to the characteristic tremors.
While discovery of a drug that boosts dopamine production in the brain would be a major development in Parkinson's treatment, the study was primarily aimed at assessing safety, and tested nilotinib in only 12 patients. Researchers are planning two Phase 2 trials, set to begin later this year.
Although cautious about study results from a small, unblinded study, Charbel Moussa, research director of Georgetown's Translational Neurotherapeutics Program and a senior investigator for the trial, was optimistic about the nilotinib's potential use as Parkinson's treatment.
“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,” Moussa said in a statement.
Marketed by Novartis as Tasigna, nilotinib was approved in 2007 to treat chronic myeloid leukemia and earned $1.6 billion in sales last year. Moussa was drawn to nilotinib as a potential option for treating Parkinson's due to its ability to penetrate the blood-brain barrier in small doses and for its effect in clearing buildup of toxic proteins in the brain.
First approved in the 1970s, levodopa has become a mainstay drug for treatment of Parkinson's due to its ability to help improve patient mobility. Levodopa is converted into dopamine by enzymes in the brain, replacing some of neurotransmitters lost as the disease progresses.
But levodopa only reduces the symptoms of the disease. No drug has been discovered which halts and slows the progress of Parkinson's itself.
Additionally, levodopa and other dopamine replacement therapies have a number of disruptive side effects, including dykinesia or involuntary movements. Levodopa can also impair cognitive function while improving motor function.
Which is why Moussa is excited about the prospects of nilotinib. Among the 11 patients who finished the trial, levels of the dopamine metabolite homovanillic acid, an indicator of dopamine production, nearly doubled. (One patient withdrew from the trial after suffering a heart attack.)
Most participants were able to stop or scale back the use of levodopa or other dopamine replacement therapies while taking nilotinib.
"This increase in dopamine happened in patients despite the fact that we had to reduce the levodopa, or even some of the dopamine replacement therapy—which means the brain is making its own endogenous dopamine as a response to drug treatment," Moussa said.
Inducing the brain to make dopamine, even after the loss of the neurons typically responsible for production, would allow patients to sidestep the cost-benefit battle inherent in treatment with levodopa and other existing therapies.
Additionally, nilotinib showed signs of reducing neuronal cell death, lowering the levels of cell death biomarkers in cerebrospinal fluid of patients. The apparent increase in dopamine production coupled with the improvement in biomarkers has Moussa eager to continue studying nilotinib in mid-stage studies.
Promising, but still early
But all this promise is tempered by the small size and design of the trial, which did not include a placebo arm and was conducted open-label, meaning patients knew they were receiving the drug.
When information on the trial was first reported in October last year, David Weiner, a scientific advisory board member at the Michael J. Fox Foundation noted the dangers of reading too much into open-label studies for Parkinson's disease.
“We know historically that there’s a huge placebo effect with Parkinson’s open label trials," Weiner said in a blog post at the time. "You have to be extremely cautious with interpretation of open label trial data in Parkinson’s."
The drug was mostly well-tolerated in the 11 patients who completed the study, with three cases of urinary tract infections or pneumonia reported. Moussa said he believed the heart attack was unrelated to treatment.
Patients were dosed with either 150 milligrams or 300 milligrams of nilotinib once daily for six months, roughly 25% to 50% of the dose typically used to treat leukemia. This helped the drug penetrate the blood-brain barrier while lowering the risk of side effects, Moussa said.
Interestingly, when patients stopped taking nilotinib after the six-month trial, the observed improvement in patient’s cognitive and motor function disappeared. Moussa hopes that this post-treatment follow up helps to compensate for the lack of a placebo.
And a one-year, placebo-controlled Phase 2 trial studying nilotinib in 75 patients with mild cognitive impairment is set to begin later this summer, with another trial studying the drug in Alzheimer’s planned later on this year.
Looking ahead at those studies, Moussa thinks nilotinib has the potential to become a major new treatment option.
"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," Moussa said.
But given the constraints of study, that outlook likely represents the best-case scenario for nilotinib’s future development.