The FDA has informed Georgetown University Medical Center that it may proceed with a phase 2, randomized, double-blind, placebo-controlled study of nilotinib (Tasigna, Novartis) as a treatment for patients with mild-to-moderate Alzheimer’s disease (AD). Nilotinib is a kinase inhibitor approved for use in patients with leukemia.
The rationale for using nilotinib is based on research conducted at Georgetown and involves clearing the brain of accumulated beta-amyloid plaques and tau tangles. Both biomarkers are hallmarks of AD. Nilotinib appears to penetrate the blood–brain barrier and induce autophagy inside neurons to clear tau, beta-amyloid, and other toxic proteins.
“In a 2015 small study at Georgetown, patients with Parkinson’s and dementia with Lewy bodies were given nilotinib. As my colleagues reported, all who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers—the same biomarkers seen in Alzheimer’s,” said Scott Turner, MD, PhD, who will lead the AD investigation. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study gives an even stronger rationale.”
“By stimulating the brain’s normal autophagic process, which clears out these misfolded proteins in cells, we hope to prevent or slow the progression of Alzheimer’s,” Turner explained. “In fact, nilotinib may be a first—a broad-spectrum antineurodegenerative drug that targets all misfolded protein aggregates that accumulate in the brain of Alzheimer’s patients. By targeting both amyloid and tau, this study may point the way to a new strategy in Alzheimer’s disease treatment.”
Charbel Moussa, MD, PhD, conducted the preclinical research that led to the discovery of nilotinib for the treatment of neurodegenerative diseases.
“When used in higher doses for chronic myelogenous leukemia [CML], nilotinib forces cancer cells into autophagy or cell death,” he said. “The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study. When used in smaller doses once a day, as in this study, nilotinib turns on autophagy for about four to eight hours—long enough to clean out the cells without causing cell death. Toxic proteins that build up again will be cleared when the drug is given again the next day.”
The Alzheimer’s Drug Discovery Foundation (ADDF) has supported the study with a $2.1 million grant.
The trial is expected to begin this year and will include 42 patients, with half receiving an escalating dose of nilotinib and the other half receiving placebo. The study’s primary objectives will be to test the drug’s safety and tolerability, and to measure whether nilotinib reduces inflammation and the presence of beta-amyloid and tau in spinal fluid. The investigators will also perform cognitive and functional ability tests.