Nilotinib, a drug that regulators have approved for the treatment of leukemia, has shown promise in a small clinical trial of people with Parkinson’s disease.

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The main purpose of the trial was to assess the repurposed drug’s safety and tolerability and how it behaves in the body in people with moderately severe Parkinson’s disease.

A secondary goal was to investigate the impact of nilotinib on certain substances that scientists think could be useful biomarkers for tracking disease progress and the effectiveness of therapies.

These biomarkers include products of dopamine metabolism and levels of alpha-synuclein and tau — two proteins that build up in the brain in Parkinson’s disease. Doctors can measure the biomarkers by sampling cerebrospinal fluid through a lumbar puncture.

The trial investigators, from Georgetown University Medical Center (GUMC) in Washington DC, also tracked changes in motor and nonmotor Parkinson’s symptoms at various stages during the 15-month trial.

They describe the methods and findings in a recent JAMA Neurology study paper.

“Determining the safety of nilotinib in people with Parkinson’s was our primary objective,” says senior study author Charbel Moussa, who is an associate professor of neurology at GUMC and director of its Translational Neurotherapeutics Program.

Parkinson’s symptoms and hallmarks

Parkinson’s disease arises when brain cells that produce dopamine, a chemical messenger that helps to control movement, stop working and die.

The disease gives rise to motor, or movement-related, symptoms and nonmotor symptoms.

Motor symptoms include tremor, slowness, stiffness, and balance difficulties. Nonmotor symptoms of Parkinson’s disease include depression, memory problems, emotional changes, and constipation.

Because Parkinson’s is a lifelong, relentless, progressive disease, the symptoms gradually worsen over time.

No two people with Parkinson’s will have exactly the same symptoms, and it is difficult to predict which symptoms will emerge and when and how rapidly they will progress in individuals.

According to the Parkinson’s Foundation, around 60,000 people receive a diagnosis of Parkinson’s per year in the United States, where nearly 1 million are living with the disease.

Parkinson’s usually affects people after the age of 60 and is more common in males than females. As the symptoms progress, they can interfere with daily living and the ability to lead an independent life.

One of the biological hallmarks of Parkinson’s disease is the accumulation of badly-folded alpha-synuclein protein in the affected areas of the brain. Pathologists can see these clumps in postmortem brain tissue of people with Parkinson’s disease.

The potential of nilotinib

The Food and Drug Administration (FDA) have approved nilotinib for the treatment of a particular type of myeloid leukemia in children.

Moussa and colleagues are interested in the potential for repurposing the drug for use in the treatment of Parkinson’s disease.

In their study paper, they cite research reports of how low doses of nilotinib entered the brain and reduced alpha-synuclein and tau proteins in animal models of neurodegeneration.

In addition, they refer to another study that found “that nilotinib may increase dopamine metabolism and potentially treat motor and nonmotor symptoms of [Parkinson’s disease].”

For the new trial, the team randomly assigned 75 participants of average age 68.4 years with moderately advanced Parkinson’s disease to three groups.

One group received 150 milligrams (mg), and another received 300 mg of nilotinib per day. The third group received a placebo. These are lower doses than the twice-daily 300 mg dose that cancer patients receive.

The participants took the daily oral dose of drug or placebo for 12 months. After this, they underwent a “washout” period with no nilotinib or placebo for 3 months.

Neither the participants nor the administrators knew which individuals received the placebo and which received the active drug until the end of each participant’s trial period. The purpose of this double-blinding is to prevent bias in reporting the results.

Nilotinib ‘reasonably safe’

The results showed that doses of 150 mg and 300 mg of nilotinib “were reasonably safe.” However, people in the two nilotinib groups experienced more severe side effects than those in the placebo group.

Nilotinib blocks Abl tyrosine kinase, which is a protein essential for cell functioning. Because of this, the FDA require nilotinib to carry a black box warning about the risk of sudden death due to this effect. However, this warning relates to the higher doses in leukemia treatment and not to the lower doses that the investigators used in the Parkinson’s disease trial.

“Our study shows that at these lower doses,” Moussa notes, “nilotinib does not seem to cause Abl inhibition, suggesting it shouldn’t have the same safety concerns that are potentially associated with Abl inhibition as might be the case at higher doses.”

When they examined the potential biomarkers, the team found that participants who took nilotinib had lower levels of alpha-synuclein and tau.

“Individually, these are very important findings, but taken together, it means that the clearance of these neurotoxic proteins may not solely depend on Abl inhibition — other tyrosine kinases or alternate mechanisms may be involved,” Moussa explains.

He and his colleagues also found higher levels of dopamine metabolites — typically more than 50% — in participants who took nilotinib. This would suggest that because the drug cleared away the toxic proteins, their brains were able to make better use of their own dopamine.

Impact on motor, nonmotor symptoms

Other results suggest that nilotinib was able to slow the progression of nonmotor symptoms compared with the placebo. The symptoms became progressively worse over the study period in the placebo group.

When they looked at effects on motor symptoms, the researchers found that all groups improved after 6 months of taking their doses. However, at the 12- and 15-month exam, those taking the 300 mg dose and placebo appeared to remain stable, whereas those on the 150 mg nilotinib dose improved over the 15 months.

Dr. Fernando L. Pagan was the principal trial investigator and first author of the study. He is also professor of neurology at GUMC and medical director of its Translational Neurotherapeutics Program.

He says that they saw overall improvements in motor symptoms in the participants who took nilotinib compared with the placebo group. The nilotinib groups also scored higher on quality of life measures during the trial.

He adds that researchers need to carry out more extensive studies in more diverse populations to confirm these results.

“These are important observations suggesting that nilotinib stabilized the disease – a potential disease-modifying effect that we haven’t observed with any other agents.”

Prof. Fernando L. Pagan