Myeloid Leukemia Drug Disappoints in Parkinson's Disease

December 16, 2020

Despite showing neuroprotective effects in preclinical models of Parkinson's disease, the tyrosine kinase inhibitor nilotinib does not appear to have a future for this indication, new results suggest.

"While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low cerebral spinal fluid exposure and lack of biomarkers effects combined with the efficacy data trending in the negative direction led us to conclude that nilotinib is not suitable for further testing in Parkinson's disease," the investigators, led by Tanya Simuni, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, write.

The study results were published online December 14 in JAMA Neurology and first reported earlier this year at the American Academy of Neurology 2020 Science Highlights. 

Worsening Function

Noting that nilotinib, an approved therapy for chronic myeloid leukemia, works predominantly via Bcr-Abelson tyrosine kinase (c-Abl) inhibition, the investigators note that the current findings do not refute the hypothesis that c-Abl inhibition is a potentially important therapeutic target in Parkinson's disease, and there are a number of novel molecules targeting the c-Abl pathway in development with a better therapeutic profile.

"While results of these studies are highly anticipated, ideally, next-generation studies will select participants based on the demonstration of susceptibility to the targeted mechanism of action, which will require further biomarker development," they note.  

The current trial was conducted at 25 US sites in patients aged 40-79 years with a diagnosis of Parkinson's for more than 5 years, Hoehn and Yahr stage 2.5 or 3, and a stable regimen of medications that included levodopa.

Of 125 patients screened, 39% were excluded mainly because of comorbid conditions associated with increased risk of nilotinib adverse events, with 76 patients being randomized to placebo, 150 mg to nilotinib, or 300 mg to nilotinib once daily orally for 6 months, followed by 2 months of off-drug evaluation.

Results showed that nilotinib had an acceptable safety profile in this cohort. However, the researchers point out that these tolerability outcomes apply to participants selected based on stringent inclusion/exclusion criteria "and are not generalizable to the Parkinson's population at large because the study excluded participants with comorbid conditions that increase the likelihood of nilotinib-related adverse events."

In terms of efficacy, there was no evidence of symptomatic benefit of nilotinib on any measures of Parkinson's disease disability and there was trend toward worsening motor function in the active treatment groups, with both doses showing worse MDS-UPDRS-3 ON scores compared with placebo.

Potential in Alzheimer's?

In addition, the study revealed the drug had a CSF-to-serum ratio of 0.19% to 0.26%, with a CSF concentration one-tenth of the reported cellular potency of nilotinib for c-Abl inhibition, indicating that, at doses within the safe therapeutic range, there would be minimal c-Abl inhibition in the brain.

There was also no evidence of treatment-related alteration of dopamine metabolites in the CSF.

The authors note the findings regarding safety, tolerability, and lack of the symptomatic effect of nilotinib are in-line with a previous phase 2 study by Pagan et al, although a smaller open-label study had suggested some possible benefit.  

"In aggregate, results of both (phase 2) studies highlight limitations of open-label studies of symptomatic effects in Parkinson's disease," they conclude.

However, another, albeit small, randomized study has recently reported possible benefits of nilotinib in Alzheimer's disease with a proposed mechanism of targeting discoidin domain receptors.

Simuni has reported receiving grants from the National Institute of Neurological Disorders and Stroke, Michael J. Fox Foundation, Parkinson's Foundation, Biogen, Roche, Neuroderm, Sanofi, Sun Pharma, AbbVie, IMPAX, and Prevail, and other support from Acadia, AbbVie, Acorda, Adamas, Allergan, Amneal, Aptinyx, Denali, General Electric, Kyowa, Neuroderm, Neurocrine, Sanofi, Sinopia, Sunovion, Roche, Takeda, Voyager, and US World Meds during the conduct of the study. Nilotinib and matching placebo were provided by the drug manufacturer, Novartis.

JAMA Neurol. Published online December 14, 2020. Abstract

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