A phase II trial has indicated that nilotinib, a drug typically used to treat chronic myeloid leukemia, may offer benefits for individuals with dementia with Lewy bodies (DLB). The study, involving 43 DLB patients, revealed improvements in cognitive outcomes and biomarkers following treatment with nilotinib.
Cognitive and Motor Function Improvements
Raymond Scott Turner, MD, PhD, of Georgetown University School of Medicine, presented the findings at the Clinical Trials on Alzheimer's Disease annual meeting. The results showed that nilotinib improved cognition scores by 2.8 points versus placebo (P = 0.037) on the Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14) at 3 months. Furthermore, cognition, as measured by Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part I scores, improved by 0.9 points (P = 0.044) with nilotinib compared to placebo.
While no effects were observed in MDS-UPDRS motor scores, other cognitive results, including Montreal Cognitive Assessment scores, trended favorably, though not statistically significantly. Notably, psychiatric features, irritability, and cognitive fluctuations were less pronounced with nilotinib than with placebo.
Biomarker Changes
The study also demonstrated that nilotinib significantly increased brain dopamine levels (P = 0.004) and reduced the ratio of p-tau181 to amyloid-beta 42 in cerebrospinal fluid (P = 0.034).
Repurposing Tyrosine Kinase Inhibitors
"We're looking at repositioning or repurposing tyrosine kinase inhibitors for neurodegenerative diseases, including Lewy body dementia," Turner stated. He suggested that nilotinib's promotion of autophagy and other potential targets may make it useful in treating neurodegenerative diseases.
Akanni Clarke, PhD, of the National Institute on Aging, emphasized the importance of evaluating promising interventions for DLB, noting that nilotinib, as a repurposed drug candidate, shows promise in early stages of investigation.
Mechanism of Action and Previous Research
Nilotinib inhibits Abelson tyrosine kinase (c-Abl), a protein linked to pathways associated with alpha-synucleinopathies like DLB and Parkinson's disease. Prior research from Georgetown indicated that nilotinib altered dopamine metabolites, alpha-synuclein oligomers, and tau in individuals with Parkinson's disease. However, other studies have reported that nilotinib did not produce clinically meaningful benefits for Parkinson's patients.
The current trial, designed to test nilotinib 200 mg in 60 people with DLB over 6 months, was impacted by the COVID-19 pandemic, resulting in a reduced enrollment of 43 patients. Participants were randomized 1:1 to receive nilotinib or placebo orally once daily for 6 months, followed by a 1-month washout period.
Safety and Tolerability
Nilotinib was found to be safe and well-tolerated. The nilotinib group experienced 37 adverse events, while the placebo group had 74 (P = 0.54). A notable observation was a 70% reduction in falls in the nilotinib group (6 falls) compared to the placebo group (21 falls), potentially linked to improved cognition.
Future Directions
Turner suggested that these findings warrant further investigation of this pathway and potentially this drug in Parkinson's, Alzheimer's, and Lewy body dementia. With nilotinib now available as a generic drug in the U.S., he also noted opportunities for developing novel patented molecules targeting similar pathways.
