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

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 Aß40 was reduced at 6 months and Aß42 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.

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial.

Importance: This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease. Objectives: To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease. Design, Setting, and Participants: This was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease. Interventions: Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period. Main Outcomes and Measures: It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes. Results: Of the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (-0.04 pg/mL; 90% CI, -0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (-10.04 pg/mL; 90% CI, -17.41 to -2.67 pg/mL; P = .01) and nilotinib 300-mg (-12.05 pg/mL; 90% CI, -19.21 to -4.90 pg/mL; P = .01) groups. Conclusions and Relevance: In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease. Trial Registration: ClinicalTrials.gov identifier: NCT02954978.

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease.

Nilotinib is a broad-based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c-Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood-brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open-label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose-independent manner and 200 mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha-synuclein and appears to reduce CSF oligomeric: total alpha-synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha-synuclein.