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.

Conflict of interest statement

C.M. 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. C.M., 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 LLC), from which C.M. receives consulting fees and Georgetown University, C.M., and F.L.P. receive equities and Y.T.‐Y. is an advisor. An individual and institutional conflict management plan (CMP) determines that C.M. can design a study as the (inventor) person who discovered the potential effects of nilotinib in neurodegenerative diseases (thus conceived of the study), can serve as a corresponding principal investigator (PI) and senior author but cannot serve as a clinical PI of any nilotinib clinical study. C.M. must not determine participants' eligibility and must not consent participants. C.M. does not perform primary clinical data analysis and all primary CSF biomarkers analyzed in C.M. laboratory and Georgetown University by blinded investigators must be validated by an external and independent organization using comparable technologies and methods (see Acknowledgments). All investigators must be blinded to treatments until all data are analyzed per group and unblinded by an externally independent DSMB (see Acknowledgments). An external independent study monitor follows study progress and adherence to the protocol. Study visits, scheduled events, and adherence to study protocol are verified by independent nurses and staff of the CRU (see Acknowledgments), which is a Translational Science Awards Program (CTSA). No other authors have any related conflicts of interest. C.M. discovered the potential use of nilotinib in preclinical models and conceived of this phase 2 clinical study and contributed with R.S.T. to the protocol and study design based on his understanding of nilotinib mechanisms of action in preclinical models, especially in relation to nilotinib effects on CNS biomarkers in AD, hence, he is a corresponding and senior author. In adherence with the CMP, C.M. did not provide any scientific or statistical analysis (J.A., R.S.T., and M.L.H.) of the data and the other authors who performed the experiments (R.S.T., G.E., F.B., and X.L.) have analyzed the data with other members (M.L.H., X.J., S.M., M.A., M.S., and S.M.) of the study team who managed the data (S.M., D.F., W.S., M.L.H., M.A., M.S.) and prepared the figures and performed statistical analysis (J.A. and M.L.H.). C.M. was not the clinical principal investigator (PI) who (R.S.T.) executed the protocol and monitored patients (N.J.S., A.L., N.Y., A.L.M., M.A., and Y.T.‐Y.). All safety, biomarkers, and clinical data were unblinded by the DMSB and analyzed by S.M., D.F., M.A., M.L.H., W.S., and S.M., and figures and tables were prepared by M.L.H. and J.A. by the study team. C.M. contributed to manuscript drafting and all authors contributed to the interpretation of the data and approved the final version of manuscript.

© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Figures

FIGURE 1

CONSORT Flow Diagram. Phase 2, randomized, double‐blind, placebo‐controlled study to evaluate nilotinib effects on safety, tolerability, pharmacokinetics, biomarkers, and potential clinical outcomes in Alzheimer's disease. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

Quantitative Regional Analysis of (A) standardized regions of interests displayed on fused positron emission tomography (PET) computed tomography (CT) images. Representative PET CT images at baseline and at 12 months of amyloid deposition in the reference cerebellum, frontal, and temporal lobes in participants who (B) received placebo or (C) nilotinib. The graph shows reduction in standardized uptake value ratio (SUVR) from baseline to 12 months in: (D) frontal lobe, (E) temporal lobe, and (F) whole brain (composite) in nilotinib versus placebo groups. *p < 0.05, **p < 0.01 within the group or as indicated between groups.

FIGURE 3

Graphs represent, (A) volumetric hippocampal volume and CSF levels of (B) Aβ40, (C) Aβ42, (D) Aβ42/Aβ40 ratio, (E) total tau, (F) phospho‐tau‐181, and (G) ratio of ptau‐181/total tau. The level of dopamine metabolites (H) homovanillic acid (HVA) and (I) 3,4‐hydroxyphenylacetic acid (DOPAC). Graphs represent the mean difference in (J) Abelson phosphorylation at tyrosine 412, (K) pan‐tyrosine phosphorylation of Abelson, and (L) the ratio of Abelson phosphorylation (activation) at tyrosine 412/pan‐tyrosine in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) treated with nilotinib versus placebo. *p < 0.05, **p < 0.01, and ***p < 0.001 within the group or as indicated between groups (% change is included only with nonsignificant differences).

FIGURE 4

Graphs represent exploratory clinical outcomes and their 95% confidence interval between the placebo and nilotinib‐treated groups in (A) Mini‐Mental Status Examination (MMSE), (B) Alzheimer Disease Assessment Scale–cognitive subscale (ADAS‐Cog), (C) ADAS‐Cog subscale 13 (Maze) or time to complete task, (D) Global Clinical Dementia Rating–Sum of Boxes (CDR‐SOB), (E) Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS‐ADL), and (F) severity and frequency of behavioral symptoms as measured by Neuropsychiatric Inventory (NPI). *p < 0.05.