Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease

Abstract

Objective Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)‐approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease. Methods This single‐center, phase 2, randomized, double‐blind, placebo‐controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks. Results Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well‐tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (−27%) at 12 months and phospho‐tau‐181 was reduced at 6 months and 12 months in the nilotinib group. Interpretation Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183–194

Broad kinase inhibition mitigates early neuronal dysfunction and cognitive deficits in tauopathy

“…To reduce tau hyperphosphorylation with the goal of limiting tau pathogenesis, clinical trials using small molecule kinase inhibitors have predominantly targeted either individual kinases or whole kinase families with some success (47)(48)(49)(50). Nilotinib, a multi-family kinase inhibitor, was used in a recently completed Phase II clinical trial in which it reduced hippocampal volume loss, cognitive decline, and phosphorylated tau levels in early to moderate AD patients (51). The compound targets multiple tyrosine kinase families (52), strongly supporting the therapeutic potential of broad kinase inhibitors in treating tauopathies.…”

Cardiovascular Safety of Nilotinib in Alzheimer Disease

“…1 The authors reported the cardiac safety profile of nilotinib, and demonstrated no QTc prolongation, which can be associated with risk of sudden cardiac death. 1 We caution that the risk and incidence of cardiovascular events (CVE) while on nilotinib may not have been fully accounted for in this report. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) trial, which investigated the efficacy and safety of nilotinib in the treatment of chronic myeloid leukemia, there was a dose-and duration-dependent association between nilotinib and CVE, defined as a composite of ischemic heart disease, ischemic cerebrovascular events, and peripheral vascular disease.…”

“…We read with interest the article by Turner et al on the use of nilotinib for the treatment of mild-to-moderate Alzheimer disease (AD). 1 In this phase 2 trial, nilotinib was found to reduce central nervous system amyloid burden, cerebrospinal fluid Aβ40 and Aβ42, hippocampal volume loss, and phospho-tau-181 associated with AD at 12-month follow-up. 1 The authors reported the cardiac safety profile of nilotinib, and demonstrated no QTc prolongation, which can be associated with risk of sudden cardiac death.…”

“…1 In this phase 2 trial, nilotinib was found to reduce central nervous system amyloid burden, cerebrospinal fluid Aβ40 and Aβ42, hippocampal volume loss, and phospho-tau-181 associated with AD at 12-month follow-up. 1 The authors reported the cardiac safety profile of nilotinib, and demonstrated no QTc prolongation, which can be associated with risk of sudden cardiac death. 1 We caution that the risk and incidence of cardiovascular events (CVE) while on nilotinib may not have been fully accounted for in this report.…”

“…Finally, the authors suggested that these doses may be noncardiotoxic based on previously reported lack of plasma Abelson inhibition using similarly low doses of nilotinib. 1 It is worth noting that nilotinib toxicity may result from both on-target and off-target kinase inhibition, hence may not be predicted by plasma Abelson inhibition alone. 4 In summary, low-dose nilotinib may be a promising treatment for AD; however, assessment of cardiovascular risk and detailed description of acute and long-term CVE should be considered in future phase 3 trials.…”