Alzheimer’s disease : Nilotinib appears to aid in the clearance of accumulated beta-amyloid plaques and Tau tangles in neurons

0
138

A Georgetown University Medical Center clinical trial investigating the cancer drug nilotinib in people with Alzheimer‘s disease finds that it is safe and well-tolerated, and researchers say the drug should be tested in a larger study to further determine its safety and efficacy as a potential disease-modifying strategy.

The results of the small, phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of nilotinib (Tasigna) were published online May 29 in Annals of Neurology.

Nilotinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia.

The rationale for studying nilotinib in Alzheimer’s disease is based on laboratory and clinical research conducted by the Georgetown Translational Neurotherapeutics Program (TNP) directed by Charbel Moussa, MBBS, Ph.D.

Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in neurons in the brain – hallmarks of Alzheimer’s disease.

Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to get rid of the Tau, Abeta and other toxic proteins.

R. Scott Turner, Ph.D., MD, director of Georgetown’s Memory Disorders Program, served as principal investigator of the Alzheimer’s disease study.

“The primary goal of this study was to determine its safety and tolerability in Alzheimer’s patients,” says Turner.

“The study found that it is safe and well-tolerated, as we anticipated, and that it may have disease modifying benefits.”

After careful screening, 37 people with mild dementia due to Alzheimer’s were randomized to either the placebo or nilotinib groups for the 12-month study. A 150 mg daily dose of nilotinib or matching placebo was taken orally once daily for 26 weeks followed by a 300 mg daily dose of nilotinib or placebo for another 26 weeks.

To prevent bias the study was blinded, meaning neither the study participants nor the investigators knew if the active drug or placebo were being administered until the end of the study.

Nilotinib was safe and well-tolerated, although more adverse events, particularly mood swings (agitation and irritation), were noted at the 300 mg dose. Mood swings were significantly increased between 6 and 12 months after the dose was increased from 150 mg to 300 mg daily.

Nilotinib carries an FDA “black-box warning” because of cardiovascular issues that may lead to sudden death in cancer patients (typically treated with 600 mg daily), but no such incidents occurred in this study (maximum dose of 300 mg daily).

The amyloid burden as measured by brain imaging was reduced in the nilotinib group compared to the placebo group. Two forms of amyloid in cerebrospinal fluid were also measured.

Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to placebo. Hippocampal volume loss (on MRI scans of the brain) was attenuated at 12 months and phospho-tau-181 in spinal fluid was reduced at 6 and 12 months in the nilotinib treated group.

“The current data are in agreement with previous preclinical and other clinical studies at Georgetown suggesting nilotinib is a potential disease-modifying drug that triggers autophagy of neurotoxic proteins including Aβ40/, Aβ42, and phospho tau-181,” explains Moussa, an associate professor of neurology and senior author on the study.

“The increase in mood swings with 300 mg nilotinib is associated with dose-dependent increases of brain dopamine, suggesting that 150 mg nilotinib is the optimal dosage to investigate in a future Alzheimer study,” adds Moussa.

Turner emphasizes that “this is the first oral treatment found to lower amyloid burden in the brain.” While this has also been found with several anti-amyloid antibodies these treatments cannot be given orally. Future Alzheimer’s studies are now in the planning stage, Turner concludes.

“The results of this exploratory study repurposing nilotinib are encouraging,” says Howard Fillit, MD, Founding Executive Director and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation (ADDF), a study funder.

“We supported this research as part of a wider initiative to use the knowledge gained from cancer research to advance effective treatments for Alzheimer’s.”


Nilotinib is an oral Abl tyrosine kinase inhibitor used to treat chronic myeloid leukemia. Nilotinib induces autophagy, leading to death of rapidly dividing cells (Salomoni and Calabretta, 2009).

The drug carries a black-box warning of sudden death due to cardiac arrythmia. It also can cause myelosuppression.

Nilotinib (and another Abl kinase inhibitor cancer drug, bosutinib) has been proposed for repurposing as a disease-modifying treatment for synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Abl kinase phosphorylates α-synuclein and prevents its degradation. By inhibiting Abl, nilotinib promotes α-synuclein clearance by autophagy (Mahul-Mellier et al., 2014).

Nilotinib has been tested in preclinical models of PD and DLB. In α-synuclein-overexpressing mice, nilotinib lowered levels of α-synuclein and phosphorylated tau in brain. Treatment was reported to increase brain dopamine and improved animals’ motor skills and cognition (Hebron et al., 2013; Hebron et al., 2013; Hebron et al., 2014). Nilotinib also prevented dopaminergic cell death and behavioral deficits in the MPTP toxicity model of parkinsonism (Karuppagounder et al., 2014).

Nilotinib was reported to improve tau clearance and astrocytic function in tau P301L mice and to promote amyloid clearance in TgAPP mice (Hebron et al., 2018; Lonskaya et al., 2013). In addition, it reportedly protected against TDP-43 toxicity in mice (Heyburn et al., 2016; Wenquiang et al., 2014). Most of this work came from the same group, at Georgetown University.

FINDINGS

In November 2014, Georgetown University investigators began evaluating nilotinib in cognitively impaired patients with PD or DLB. In the first Phase 1 study, 12 participants took 150 or 300 mg nilotinib daily for six months, a dose one-half to one-fifth of that used for cancer. There was no placebo group.

Because nilotinib can cause irregular heart rhythms, people with abnormal cardiac rhythms were excluded from this and subsequent trials. The drug was generally safe and tolerable. Nilotinib crossed into the brain and was detectable in the CSF, albeit at 1 percent of plasma levels.

Treatment resulted in inhibition of tyrosine phosphorylation of Abl kinase and raised CSF levels of the dopamine metabolite homovanillic acid (HVA). In exploratory endpoints, both dose groups were reported to improve motor and non-motor symptoms assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) and PD questionnaire, and cognitive symptoms assessed by the MMSE and Scales for Outcomes in Parkinson’s disease-Cog. The gains reversed when drug was discontinued (Pagan et al., 2016).

Presentation of these data at the 2015 Society for Neuroscience conference (Nov 2015 conference news) stimulated initiation of two Phase 2, placebo-controlled studies. A single-site study at Georgetown began in January 2017. It enrolled 75 patients with PD or PD dementia to receive 150 or 300 mg nilotinib or placebo once daily for 12 months, with a three-month follow-up.

The primary outcome was safety. The nilotinib group had more serious adverse events than the placebo group. The nilotinib group had no significant improvement on exploratory motor or cognitive measures over placebo.

The 300 mg group showed a worsening of activities of daily living from baseline to 12 months on the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 2 and the Montreal Cognitive Assessment score, which was not seen in the other groups. In exploratory biomarker measurements, the 150 mg dose was reported to be associated with higher CSF concentration of a dopamine metabolite and lower CSF concentration of α-synuclein oligomers and phosphorylated tau; there was no comparison between baseline and subsequent time points (Pagan et al., 2019; editorial by Espay et al., 2019; NPR news).

The second trial started in October 2017. Called NILO-PD, it was a multicenter Phase 2a funded by the Michael J. Fox Foundation. It enrolled 76 people with moderate PD at 27 academic centers in the U.S. Participants were strictly screened for heart and other health problems. They were assigned to 150 or 300 mg nilotinib daily or placebo for six months, with two months of follow-up.

The primary outcome was safety; secondary outcomes included measures of motor and cognitive symptoms. The study finished in September 2019. In December, the study organizers announced the drug was safe in this study population, but did not improve motor or cognitive function over placebo (press release). In this trial, nilotinib concentrations in CSF were below the levels expected to inhibit Abl, and the investigators found no drug effect on dopamine biomarkers (Michael J. Fox Dec 2019 webinar).

In January 2017, the Georgetown University group began a single-center, Phase 2 safety study in Alzheimer’s disease. It enrolled 42 participants with mild to moderate AD confirmed by CSF Aβ levels. They took 150 mg nilotinib daily for six months, followed by 300 mg or matching placebo for six months. Secondary endpoints include drug levels and Abl inhibition in CSF. The expected end date is February 2020.

Another Phase 2 trial at Georgetown University is testing nilotinib in patients with DLB. Beginning in January 2019, this study compares 200 mg daily of nilotinib or placebo taken for six months, followed by a one-month washout in 60 participants.

The primary outcome is safety and tolerability; secondary outcomes are drug levels in CSF and plasma, changes in HVA in CSF, other, unspecified surrogate and exploratory biomarkers for DLB, and measures of cognition, behavior, and motor function. The trial will run through August 2023.

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.


More information: Raymond S. Turner et al. Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer’s Disease, Annals of Neurology (2020). DOI: 10.1002/ana.25775

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.