CML Drug Nilotinib Shows Early Effects in Alzheimer's Disease

Nancy A. Melville

October 20, 2020

Nilotinib (Tasigna), approved by the US Food and Drug Administration (FDA) for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), shows safety and suggestion of possible disease-modifying effects in the treatment of Alzheimer's disease, in a new study.

"Nilotinib is significantly different from other therapies that are being developed for Alzheimer's disease because it is the first oral drug that is not an antibody that significantly lowers the level of amyloid in the central nervous system," senior author Charbel Moussa, MBBS, PhD, told Medscape Medical News.

"It is also unique because a lot of safety data already exists demonstrating the safety profile of this drug in leukemia [using 600 mg daily], and the Alzheimer's disease trial results indicate that even a quarter of this dose [150 mg daily] is a potential therapy for Alzheimer's disease," said Moussa, an associate professor of neurology and director of the Translational Neurotherapeutics Program in the Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, in Washington, DC.

The findings were presented as part of the American Neurological Association's ANA 2020 Virtual Annual Meeting.

Commenting on the study, Eric McDade, DO, who moderated the session, said the findings, though preliminary, show intriguing effects surprisingly early in the course of treatment.

"These very preliminary results are encouraging in that there was evidence of changes in both amyloid and tau CSF biomarkers in those treated with nilotinib," he told Medscape Medical News.

"Given the proposed mechanism of action of this drug, it would not have been fully predicted over the relatively short treatment period that these biomarkers would show changes," said McDade, an associate professor of neurology at the Washington University School of Medicine, in St Louis, Missouri.

"However, the common caveat of this study requiring replication, particularly given the very small numbers, certainly applies here."

Nilotinib, a tyrosine kinase inhibitor that preferentially targets discoidin domain receptors (DDRs), 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.

To determine the drug's safety and tolerability in Alzheimer's disease, Moussa and colleagues enrolled 37 patients with mild dementia due to Alzheimer's disease between January 2017 and October 2018 and randomized them in the double-blind study to treatment with nilotinib 150 mg daily (n = 17) or a matching oral placebo (n = 20) for 26 weeks, followed by a 300-mg daily dose of nilotinib or placebo for an additional 26 weeks.

The patients were a mean age of 70.7 and 73% were women.

Reductions in AD Biomarkers

In terms of disease biomarkers, those in the nilotinib group showed significantly greater reductions in amyloid burden in the temporal lobe (–0.08; 95% CI, –0.21 to 0.01; P =.04) as well as the frontal lobe (–0.19; 95% CI, –2.29 to 0.08; P < .001), compared with the placebo group.

In addition, greater reductions in cerebrospinal fluid amyloid beta 40 were observed at 6 months (566 ng/mL; 90% CI, 135 to 1018; P = .02) as was amyloid beta 42 (52.1 ng/mL; 90% CI, –1.0 to 121.8; P = .07) with nilotinib.

Amyloid beta 42 was further reduced at 12 months (73.9 ng/mL; 90% CI, 14.3 to 137.9; P = .02) compared with placebo.

Furthermore, MRI showed hippocampal volume loss was attenuated (–27%) at 12 months. And reductions in phospho-tau181 were observed with nilotinib at 6 months (–3.07; CI 90%, –5.92 to 1.18; P = .02) and 12 months (–4.75; CI 90%, –8.03 to 1.76; P = .01).

"Significantly, this drug appears to target multiple pathologies, including CSF p-tau and CSF amyloid and amyloid burden via PET and dopamine metabolism," Moussa said.

The effects appear to be the result of the drug "turning on a 'garbage disposal machine' [activates autophagy] rather than targeting a single toxic protein like an antibody," Moussa explained.

He noted that the study was too small to determine differences in measures of clinical and cognitive decline, however, some encouraging exploratory outcomes offer clues and should help to guide the design of larger and longer studies of nilotinib in Alzheimer's disease, he noted.

They include a one-point change, albeit nonsignificant, in the Mini-Mental State Examination (MMSE) score in the nilotinib group versus placebo, a difference in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale 13 (maze) that was significant at 6 months between the nilotinib and placebo groups, and differences of 10 to 13 seconds to finish the task, with more errors in the placebo group compared with no change in the nilotinib group.

The changes could be clinically meaningful due to the effects of increased CNS dopamine levels on executive functioning, Moussa explained.

Nilotinib, he said, "might enhance executive functioning in Alzheimer's disease due to reduction of amyloid burden [via PET] in the frontal lobe of the brain [as well as] enhancement of dopamine transmission that mediates executive functioning, which is severely affected in different stages of Alzheimer's disease."

No differences between the groups were observed in measures of disease progression; however, intervention at an earlier disease stage (MMSE 22-30) and longer treatment duration may provide better opportunities to affect clinical decline, Moussa said.

Although nilotinib was determined to be safe and well-tolerated, a notable adverse effect was mood swings of irritability and agitation, reported in as many as 70% of patients in the 300-mg dose group versus none with placebo (P = .001).

However, no mood swings or behavioral changes were reported between baseline and 6 months in the 150-mg group, suggesting that 150 mg should be the optimal dose in ongoing studies in Alzheimer's disease, Moussa said.

Black Box Warning for Cardiovascular Risk

Notably, nilotinib carries a black box warning from the FDA regarding risk of QT prolongation and sudden death observed with the higher 600-mg daily dose for patients with CML, observed in 0.3% of patients.

Due to the risk, patients with QTc prolongation or other cardiovascular diseases were excluded from the current trial, and there were no reports of the cardiac effects, Moussa said.

"Cumulatively, in both Alzheimer's disease and Parkinson's disease trials, more than 2000 patient visits up to 27 months did not show any cardiac effects or QT prolongation, suggesting that a dose up to 300 mg is safe," he said.

"Importantly, in leukemia, nilotinib may cause cardiac effects [clinically] due to inhibition of the tyrosine kinase Abelson [biologically], but we show no evidence of Abelson inhibition in both Alzheimer's disease and Parkinson's disease patients using lower doses of 150 to 300 mg daily," Moussa said.  

Of note, nilotinib engages DDR-1 with 20-times more potency and selectivity than Abelson, Moussa further explained.

"Thus, lower doses of nilotinib, 150 mg or 300 mg, inhibit DDR-1, which is activated in Alzheimer's and Parkinson's disease brains, but not Abelson, thereby avoiding cardiac effects," he explained, adding that "more studies need to be done to demonstrate nilotinib safety."

The research team is currently preparing for a large, multicenter phase 3 trial of 800 to 1000 patients to study nilotinib's safety and efficacy in early Alzheimer's disease, with recruitment expected to start in mid-2021.

This study was also published in the July issue of the Annals of Neurology.

The study was supported by a grant from the Alzheimer's Drug Discovery Foundation. Moussa is an inventor on several US and international Georgetown University patents to use nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. Moussa, his laboratory, and Georgetown University previously received some income from licensing of the technology to Axovant Science. Georgetown University spun out the technology (April 2020) to a start‐up company (KeifeRX), from which Moussa receives consulting fees. McDade has no disclosures to report.

ANA2020. Abstract 535. Presented October 9, 2020.

Ann Neurol 2020;88:183-194. Full text

For more Medscape Neurology news, join us on Facebook and Twitter.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.