Understanding the Nilotinib trials

Original article: Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease. A Phase 2 Randomized Clinical Trial JAMA Neurology: 2019

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The takeaway

The results of a Phase II trial on the safety of nilotinib in people with Parkinson’s has shown ambiguous biochemical results and a greater number of adverse events in the treated groups.

Why is it important?

Ultimately, it is necessary to responsibly evaluate the potential harms and benefits for all involved before considering any future trial, with input from patients and other key stakeholders, clinicians and scientists.



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Impact Opinion

Given the excitement generated around the original pilot study in 2015-16, the results of this Phase II clinical study of Nilotinib are disappointing. To be fair, the study was not powered to evaluate efficacy, but there is limited evidence in the results to indicate that Nilotinib is having any impact on Parkinson’s. Critically, it would appear that very little of the drug is actually getting into the brain (less than 1% of levels of Nilotinib in the blood), so it appears that Nilotinib is not really an ideal assessment of this class of drug in Parkinson’s. It will be important to wait for the results of the clinical trials of other Nilotinib-like drugs that have been designed to penetrate the brain (such as K-0706 and IkT-148009).


Nilotinib is a drug used to manage chronic myeloid leukemia, a form of blood cancer that affects immune cells. One of its effects of interest for Parkinson’s however is that it has been shown to reduce levels of harmful alpha-synuclein, the protein which forms pathological clumps and damages neurons. Indeed, a number of studies from independent laboratories have supported the case for repurposing it, and testing its potential for disease modification.

In 2015, the results of a small Phase I trial addressing the safety of nilotinib (see PM summary link below) in 12 people with Parkinson’s were presented. Although claimed to be generally safe, issues around potentially harmful effects on heart function were raised. It is important to note here that nilotinib has a black box warning at higher doses: this is the strictest warning for an FDA approved drug and indicates a proven health hazard associated with nilotinib. In addition, as it was not placebo controlled, the suggested benefits the authors reported could not be definitively attributed to the drug itself.

Based on the body of evidence supporting the case for nilotinib’s disease modifying potential, it was then cautiously put to a proper test in two Phase II placebo controlled trials, to determine if it is safe and well tolerated by people with Parkinson’s, and whether it could potentially treat symptoms. Both studies tested the effects of two different daily doses of nilotinib (150mg and 300mg) and compared these to placebo, in three separate groups, each consisting of 25 people with Parkinson’s.

 The results of the multicentre NILO-PD study led out of Northwestern University, which recruited people with Parkinson’s from 25 centres in the US were announced in late 2019, ahead of formal publication, in order to keep the Parkinson’s community informed. As no clinical benefit after 6 months of treatment was observed, there was no support for a future larger trial (see CPT article link below). Importantly, due to earlier indications of potential effects on the heart, strict criteria were used to exclude anyone with a history of cardiac problems. Given that heart disease is more common as people age, and the average of diagnosis is 64 yrs of age, the question of whether nilotinib is suitable for the wider Parkinson’s population was not definitively answered, largely because safety concerns raised by the earlier study.  

The details

The results of the single centre PD NILOTINIB study run out of Georgetown University have now been published. After 1 year of treatment with nilotinib, the authors reported a number of findings based on analyzing cerebrospinal fluid (CSF) – a solution that bathes the brain, obtained by spinal tap. Higher level of dopamine breakdown products were seen in both nilotinib groups compared to placebo. But given that the nilotinib treated patients were on higher doses of levodopa to begin with, it is unclear that the observed difference was due to nilotinib and not because of the higher doses of dopaminergic medications these individuals were already taking. Levels of alpha synuclein were reported to be lowered by nilotinib, but in the group receiving the lower dose of nilotinib, which is hard to explain. The sample sizes were small, so some of the statistical effects appeared to be affected by a small number (2) of individuals, whose biochemical markers improved. However, as the baseline biochemical markers of each individual entering the study were not measured, it is not possible to tell whether any observed differences between the groups actually reflect improvements for individual participants before and after treatment.

Importantly, more serious adverse events, including falls, were seen in the nilotinib treated groups compared to placebo. Two nilotinib treated individuals had to be withdrawn from the study due to cardiac abnormalities including heart attack, which were attributed to a pre-existing heart condition and undisclosed medication use. Otherwise, no significant differences in cardiovascular outcomes were reported.

Next steps

Although the authors concluded that nilotinib is safe and well tolerated, others in the clinical and scientific community are raising questions about whether another trial of nilotinib should be pursued. Key stakeholder input will be important.

Related work and trials

Pagan et al. (2019). Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease. A Phase 2 Randomized Clinical Trial. JAMA Neurology. DOI: 10.1001/jamaneurol.2019.4200


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