Leukemia Drug Shows Promise in Lewy Body Dementia

Nilotinib, a drug approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia, improved biomarkers and cognitive outcomes in patients with dementia with Lewy bodies (DLB) in a phase 2 randomized, double-blind, placebo-controlled trial. 

The findings align with an earlier study that showed possible disease-modifying effects of nilotinib in patients with mild cognitive impairment or Alzheimer’s disease, as previously reported by Medscape Medical News. 

“We’re looking at repositioning or repurposing tyrosine kinase inhibitors for neurodegenerative diseases,” said study investigator Raymond Scott Turner, MD, PhD, of Georgetown University School of Medicine in Washington, DC.

The data were presented at the 17th Clinical Trials on Alzheimer’s Disease (CTAD) conference.

Better Cognition, Fewer Falls

Nilotinib is a tyrosine kinase inhibitor that preferentially targets discoidin domain receptors. The drug has been shown in preclinical studies to have the capability of penetrating the blood-brain barrier and subsequently reducing beta-amyloid plaques and tau tangles.

In the phase 2 study, 43 adults with DLB were randomly assigned to receive 200 mg of oral nilotinib or matching placebo for 6 months. 

The average Montreal Cognitive Assessment (MoCA) score at screening was 19 in both groups, indicating mild to moderate dementia, and the International Parkinson and Movement Disorder Society Unified Parkinson’s Disease Rating Scale (UPDRS) Part III score was 19, indicating mild parkinsonism in both groups.

Compared with placebo, nilotinib led to an increase in cerebrospinal fluid (CSF) amyloid-beta 42 and a decrease in total alpha-synuclein, although the differences failed to reach statistical significance. 

There was also a reduction in p-tau181 and the ratio of p-tau181 to total tau in the nilotinib group compared with placebo that was “not quite significant,” Turner said. However, the ratio of p-tau181 to amyloid-beta 42 was significantly reduced with nilotinib treatment (P = .34). 

Nilotinib also led to a significant (P = .004) increase in CSF dopamine levels, “suggesting an effect on dopaminergic neurotransmission,” Turner said. 

Turning to cognitive outcomes, at 3 months, scores on Alzheimer’s Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14) improved by 2.8 points with nilotinib vs placebo (P = .037).

Nilotinib also led to a significant 0.9-point (P = .044) improvement on the MDS-UPDRS Part I (cognition), with no effect on MDS-UPDRS Part II (activities of daily living) or Part III (motor).

Other cognitive and functional scores, including those on the MoCA and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale, trended toward improvement with nilotinib. Nilotinib also reduced caregiver reported behavioral symptoms (irritability and apathy) and cognitive fluctuations compared with placebo. 

At a dose of 200 mg once daily, “all the biomarkers and all the clinical and cognitive outcomes were moving in the correct direction,” Turner reported.

Exciting New Directions, Combinations

Nilotinib was safe and well tolerated, with more adverse events noted in the placebo group (74 vs 37; P = .54). There was an increase in the levodopa equivalent daily dose in the placebo group, but no significant increase or no change in the nilotinib group, which would suggest more parkinsonism or disease progression in the placebo group. 

Notably, Turner added, there were fewer falls in the nilotinib group than the placebo group (6 vs 21) — a “70% reduction,” which could be due to improved cognition with nilotinib. 

He noted that nilotinib is now generic in the US and there are other tyrosine kinase inhibitors that are coming off patent. “The evidence would suggest that perhaps we need to investigate this pathway and perhaps this drug in both Parkinson’s, Alzheimer’s, and Lewy body dementia,” Turner concluded. 

Looking at the bigger picture, Heather M. Snyder, PhD, Alzheimer’s Association senior vice president of medical and scientific operations, said that “perhaps the most exciting and encouraging aspect of this year’s CTAD 2024 meeting has been the number of new directions and combination approaches to treating Alzheimer’s and other diseases that cause dementia that are being presented.”

This early-phase study of nilotinib in DLB is a prime example, said Snyder. 

“It will be important to do the next-phase studies in large, representative populations, and it is exciting to see the increasing diversity of the clinical trials pipeline across all the diseases that cause dementia,” Snyder stated. 

Funding for the study was provided by the National Institutes of Health. Turner has no relevant disclosures. Study investigator Charbel Moussa, MBBS, PhD, is an inventor on a patent issued to Georgetown University to use tyrosine kinase inhibitors for the treatment of neurodegenerative diseases. The university exclusively licensed this technology to KeifeRx. Moussa is a paid adviser, scientific director and shareholder of KeifeRx. Snyder have no relevant disclosures.