乌鸦传媒

The chronic myeloid leukemia drug nilotinib (Tasigna) improved biomarkers and cognitive outcomes in people with dementia with Lewy bodies (DLB), a small phase II trial showed.

In a study of 43 DLB patients, 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, reported Raymond Scott Turner, MD, PhD, of Georgetown University School of Medicine in Washington, D.C.

Cognition, 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 versus placebo, Turner said in a late-breaking presentation at the Clinical Trials on Alzheimer's Disease annual meeting in Madrid.

Scores on the ADAS-Cog14 range from 0 to 90 points; scores on the MDS-UPDRS part I range from 0 to 52 points.

No effects were seen in MDS-UPDRS motor scores. Other cognitive results, including Montreal Cognitive Assessment scores, trended favorably but were not statistically significant. Psychiatric features, irritability, and cognitive fluctuations were worse with placebo compared with nilotinib, Turner noted.

Nilotinib also significantly increased brain dopamine (P=0.004) and significantly reduced the ratio of p-tau181 to amyloid-beta 42 in cerebrospinal fluid (P=0.034).

"We're looking at repositioning or repurposing tyrosine kinase inhibitors for neurodegenerative diseases, including Lewy body dementia," Turner said. "Due to its promotion of autophagy and perhaps other potential targets, nilotinib may be useful in neurodegenerative diseases."

DLB progressively leads to cognitive impairment and reduced independent function, observed Akanni Clarke, PhD, of the neuroscience division at the National Institute on Aging.

"It is critically important that we evaluate candidate interventions that show promise to target and ameliorate this devastating disease," Clarke told 乌鸦传媒. "As a repurposed drug candidate built on solid preliminary data for DLB, nilotinib is one option that shows such promise in the early stages of investigation."

Nilotinib inhibits Abelson tyrosine kinase (), a protein linked to pathways associated with alpha-synucleinopathies like DLB or Parkinson's disease. Earlier evidence from researchers at Georgetown reported that nilotinib altered dopamine metabolites, alpha-synuclein oligomers, and tau in people with Parkinson's disease. Other researchers found, however, that nilotinib did not produce biological or clinically meaningful effects that would benefit people with Parkinson's.

The current study was based on previous evidence in DLB, Parkinson's, and Alzheimer's disease, Turner said. The was designed to test nilotinib 200 mg in 60 people with DLB over 6 months.

Due to the COVID-19 pandemic, the trial was delayed for 2 years and only 43 patients were enrolled. A third were women, and mean age was 73 years.

Participants were randomized 1:1 into the nilotinib or placebo groups. The drug was taken orally once daily for 6 months, and was followed by 1-month washout.

Nilotinib was safe and well-tolerated, Turner noted. There were 37 adverse events in the nilotinib group and 74 in the placebo group (P=0.54). Notably, there were only six falls in the nilotinib group compared with 21 falls in the placebo group -- a 70% reduction, he pointed out. Improvement in cognition may help reduce falls, he noted.

The overall findings "suggest that perhaps we need to investigate this pathway, and perhaps this drug, in Parkinson's, Alzheimer's, and Lewy body dementia," Turner said. Nilotinib is now generic in the U.S., "but there's room for novel patented molecules," he added.

Comment