Therapeutics

Nilotinib

Overview

Name: Nilotinib
Synonyms: Tasigna, AMN107
Chemical Name: 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Parkinson's Disease, Dementia with Lewy Bodies, Alzheimer's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2), Dementia with Lewy Bodies (Phase 2), Alzheimer's Disease (Phase 2)
Company: Novartis Pharmaceuticals Corporation
Approved for: Chronic myeloid leukemia

Background

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 prevented dopaminergic cell death and behavioral deficits in the MPTP toxicity model of parkinsonism (Karuppagounder 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). In other models, 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., 2018Lonskaya et al., 2013). In addition, it reportedly protected against TDP-43 toxicity in mice (Heyburn et al., 2016; Wenqiang et al., 2014). This preclinical work came from one group at Georgetown University.

In independent studies, nilotinib failed to lessen synuclein accumulation and cell death in mice expressing mutated α-synuclein in oligodendrocytes to model multiple systems atrophy (Lopez-Cuina et al., 2020). In a different proteinopathy model, nilotinib did not improve autophagy, pathology, survival, or motor behaviors in mice expressing mutated Huntingtin protein (Kumar et al., 2021).

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., 2019NPR news). After this trial, 63 participants entered an open-label safety and tolerability extension. Ninety percent were able to complete one year of dosing at 150 or 300 mg, with no adverse events deemed to be drug-related by the investigators (Pagan et al., 2020).

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 25 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 and tolerability; secondary outcomes included measures of motor and cognitive symptoms. The study finished in September 2019. In December 2019, the study organizers announced the drug was safe in this select study population, but did not improve motor or cognitive function over placebo (press release). According to published results, the full data show a trend toward worsening motor function in the treated groups. Nilotinib concentrations in CSF were less than 0.3 percent of plasma, and one-tenth of the levels expected to inhibit Abl. The investigators found no drug effect on dopamine biomarkers (Simuni et al., 2020).

In January 2017, the Georgetown University group began a single-center, Phase 2 safety study in Alzheimer’s disease. It enrolled 37 participants with mild to moderate AD confirmed by CSF Aβ levels or amyloid PET scan, or both. They took 150 mg nilotinib daily for six months, followed by 300 mg for six months, or matching placebo. According to published data, the total number of side effects was the same for drug and placebo, but people on the high dose experienced significantly more instances of agitation, aggression, and irritability (Turner et al., 2020; see also Tan et al., 2021). Drug concentrations in CSF reached 3.5 and 4.7 nM on the low and high doses, respectively, and did not result in detectable inhibition of Abl kinase. CSF Aβ42 was significantly reduced in the treated group compared with placebo at 12 months, and accumulation of amyloid in the frontal lobe was slowed. Tau and phospho-tau were unchanged. No differences were seen in exploratory clinical, cognitive, functional, or behavioral measures.

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 May 2023.

Nilotinib is also being tested for Huntington’s disease and cerebellar ataxia. For all nilotinib trials, see clinicaltrials.gov.

Last Updated: 05 Feb 2021

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References

News Citations

  1. Potential Parkinson’s Treatments Target α-Synuclein, Cell Replacement

Therapeutics Citations

  1. Bosutinib

Research Models Citations

  1. Tau P301L
  2. Tg-SwDI (APP-Swedish,Dutch,Iowa)

Paper Citations

  1. . Nilotinib Effects in Parkinson's disease and Dementia with Lewy bodies. J Parkinsons Dis. 2016 Jul 11;6(3):503-17. PubMed.
  2. . Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial. JAMA Neurol. 2019 Dec 16; PubMed.
  3. . The Narrowing Path for Nilotinib and Other Potential Disease-Modifying Therapies for Parkinson Disease. JAMA Neurol. 2019 Dec 16; PubMed.
  4. . Long-Term Safety and Clinical Effects of Nilotinib in Parkinson's Disease. Mov Disord. 2021 Mar;36(3):740-749. Epub 2020 Nov 20 PubMed.
  5. . Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2021 Mar 1;78(3):312-320. PubMed.
  6. . Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease. Ann Neurol. 2020 Jul;88(1):183-194. Epub 2020 May 28 PubMed.
  7. . Cardiovascular Safety of Nilotinib in Alzheimer Disease. Ann Neurol. 2021 Jan;89(1):196. Epub 2020 Nov 7 PubMed.
  8. . Targeted therapies and autophagy: new insights from chronic myeloid leukemia. Autophagy. 2009 Oct;5(7):1050-1. Epub 2009 Oct 14 PubMed.
  9. . c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson's disease. Hum Mol Genet. 2014 Jun 1;23(11):2858-79. Epub 2014 Jan 9 PubMed.
  10. . The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Sci Rep. 2014 May 2;4:4874. PubMed.
  11. . Tyrosine kinase inhibition facilitates autophagic SNCA/α-synuclein clearance. Autophagy. 2013 Aug;9(8):1249-50. Epub 2013 Jun 19 PubMed.
  12. . Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's disease models. Hum Mol Genet. 2013 Aug 15;22(16):3315-28. Epub 2013 May 10 PubMed.
  13. . Tyrosine Kinase Inhibition Regulates Early Systemic Immune Changes and Modulates the Neuroimmune Response in α-Synucleinopathy. J Clin Cell Immunol. 2014 Sep 30;5:259. PubMed.
  14. . Tau clearance improves astrocytic function and brain glutamate-glutamine cycle. J Neurol Sci. 2018 Aug 15;391:90-99. Epub 2018 Jun 12 PubMed.
  15. . Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med. 2013 Aug;5(8):1247-62. PubMed.
  16. . Tyrosine kinase inhibition reverses TDP-43 effects on synaptic protein expression, astrocytic function and amino acid dis-homeostasis. J Neurochem. 2016 Nov;139(4):610-623. Epub 2016 Sep 27 PubMed.
  17. . Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice. Hum Mol Genet. 2014 Sep 15;23(18):4960-9. Epub 2014 May 8 PubMed.
  18. . Nilotinib Fails to Prevent Synucleinopathy and Cell Loss in a Mouse Model of Multiple System Atrophy. Mov Disord. 2020 Jul;35(7):1163-1172. Epub 2020 Apr 14 PubMed.
  19. . Spatiotemporal analysis of soluble aggregates and autophagy markers in the R6/2 mouse model. Sci Rep. 2021 Jan 8;11(1):96. PubMed.

External Citations

  1. NPR news
  2. press release
  3. clinicaltrials.gov

Further Reading

Papers

  1. . Nilotinib - Differentiating the Hope from the Hype. J Parkinsons Dis. 2016 Jul 12;6(3):519-22. PubMed.
  2. . Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease. Pharmacol Res Perspect. 2019 Apr;7(2):e00470. Epub 2019 Mar 12 PubMed.
  3. . Multikinase Abl/DDR/Src Inhibition Produces Optimal Effects for Tyrosine Kinase Inhibition in Neurodegeneration. Drugs R D. 2019 Jun;19(2):149-166. PubMed.
  4. . Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20760-20769. Epub 2019 Sep 23 PubMed.
  5. . Targeting kinases in Parkinson's disease: A mechanism shared by LRRK2, neurotrophins, exenatide, urate, nilotinib and lithium. J Neurol Sci. 2019 Jul 15;402:121-130. Epub 2019 May 15 PubMed.
  6. . BMS-708163 and Nilotinib restore synaptic dysfunction in human embryonic stem cell-derived Alzheimer's disease models. Sci Rep. 2016 Sep 19;6:33427. PubMed.
  7. . Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models. Neuroscience. 2015 Sep 24;304:316-27. Epub 2015 Jul 30 PubMed.
  8. . α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment. Mol Neurodegener. 2020 Apr 16;15(1):27. PubMed.