Background: We evaluated the effects of low doses of the tyrosine kinase Abelson (Abl) inhibitor Nilotinib, on safety and pharmacokinetics in Parkinson’s disease dementia or dementia with Lewy bodies.Objectives: The primary outcomes of this study were safety and tolerability; pharmacokinetics and target engagement were secondary, while clinical outcomes were exploratory.Methods: Twelve subjects were randomized into 150 mg (n = 5) or 300 mg (n = 7) groups and received Nilotinib orally every day for 24 weeks.Results: This study shows that 150 mg and 300 mg doses of Nilotinib appear to be safe and tolerated in subjects with advanced Parkinson’s disease. Nilotinib is detectable in the cerebrospinal fluid (CSF) and seems to engage the target Abl. Motor and cognitive outcomes suggest a possible beneficial effect on clinical outcomes. The CSF levels of homovanillic acid are significantly increased between baseline and 24 weeks of treatment. Exploratory CSF biomarkers were measured.Conclusions: This small proof-of-concept study lacks a placebo group and participants were not homogenous, resulting in baseline differences between and within groups. This limits the interpretations of the biomarker and clinical data, and any conclusions should be drawn cautiously. Nonetheless, the collective observations suggest that it is warranted to evaluate the safety and efficacy of Nilotinib in larger randomized, double-blind, placebo-controlled trials.
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 PARTICIPANTSThis 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. RESULTSOf 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
Nilotinib is a broad‐based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c‐Abl) and discoidin domain receptors ( DDR 1/2). 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 (pop PK / 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.
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
Background The goal is to assess the safety, tolerability, and pharmacokinetics of nilotinib, and measure biomarkers in participants with mild to moderate dementia due to Alzheimer’s disease. We hypothesized that nilotinib is safe and detectable in cerebrospinal fluid. Nilotinib may alter disease biomarkers and potentially slow clinical decline. Method This is a single‐center, phase 2, randomized, double‐blind, placebo‐controlled study. Of 117 individuals approached, 13 declined, 51 were excluded, 51 were screened, and 37 were randomized 1:1 to placebo or nilotinib groups. The Alzheimer’s disease diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg vs matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg vs placebo for another 26 weeks. Result Of the 37 individuals enrolled, 27 were women (73%), and the mean (SD) age was 70.7 (6.48) years. Nilotinib was safe and well‐tolerated, although more adverse events, particularly mood swings, were noted at the 300 mg dose (70.6%) vs placebo (0%) groups (p<.01). In the nilotinib group, amyloid burden was reduced in the temporal (‐0.08, 90% CI, ‐0.21 to ‐0.01, p=.04) and frontal lobes (‐0.19, 90% CI, ‐2.29 to ‐0.08, p<.001) compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months (566ng/ml, 90% CI, 135 to 1018, p=.02) and Aβ42 was reduced at 12 months (73.9 ng/ml, 90% CI, 14.3 to 137.9, p=.02) in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (‐27%) at 12 months and phospho‐tau181 was reduced at 6 months (‐31.6%) and 12 months (‐39.6%) in the nilotinib group. Conclusion Nilotinib is safe and well‐tolerated, and achieves pharmacologically relevant brain concentrations. Biomarkers of Alzheimer's disease were altered in response to nilotinib treatment. These data support a larger, multi‐center, phase 3 study to determine the safety and efficacy of nilotinib in Alzheimer’s disease. ClinicalTrials.gov NCT02947893.
I read with interest the Davis-Hayes et al. 1 suggested algorithm to help guide medical retirement from sport discussion after an athlete has a single or multiple sports-related concussions (SRC). The authors are to be lauded for attempting to standardize this decision-making process. The decision to medically disqualify and retire a professional athlete from his or her chosen sport is not to be made lightly for it threatens the livelihood of not just the athlete but the entire family. Both the physician and the athlete have to make tough decisions about the athlete's future brain health in the absence of any validated biofluid (blood, CSF) or imaging biomarker for concussion and late-life neuropsychiatric sequelae of brain injury such as chronic traumatic encephalopathy, dementia pugilistica, chronic postconcussion syndrome, chronic neurocognitive impairment, posttraumatic dementia, posttraumatic cognitive impairment, posttraumatic parkinsonism, and persistent posttraumatic headaches. One size does not fit all. Risk stratification is the process of identifying the individual athlete's risk of the abovementioned late-life neuropsychiatric sequelae of brain injury after careful review of history and other clinical and imaging tests. Some professional athletes may warrant medical disqualification or denial of licensure (if combat sports) and others may be medically cleared to return to sport under supervision. Finally, the authors use the term "immediate epilepsy" interchangeably with "impact seizures." This should be avoided since impact seizures differ in their pathophysiology and prognosis from immediate epilepsy/early posttraumatic epilepsy. It would also be helpful to the readers if the authors define how they differentiate "impact seizures" from "concussive convulsions" (including fencing and other tonic postures). 1. Davis-Hayes C, Baker DR, Bottiglieri TS, et al. Medical retirement from sport after concussions: a practical guide for a difficult discussion.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.