Novel effects of TKI inhibitors in Parkinson’s disease

 

A new study has reported that nilotinib, a tyrosine kinase inhibitor (TKI), alters brain dopamine metabolism and significantly reduces plasma total alpha-synuclein in patients with Parkinson’s disease (Pagan et al. Pharm Res Perspect 2019; epublished March 12, 2019; free full text at https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1002/prp2.470).

Nilotinib (Tasigna) is a small-molecule TKI that targets breakpoint cluster/Abelson (BCR-Abl) and is approved to treat chronic myelogenous leukemia (CML) at a dose of 300-400 mg BID. Other agents in this class include imatinib (Gleevec), ponatinib (Iclusig) and bafetinib (INNO-406, a BCR-Abl/Lyn TKI).

In the CNS, c-Abl regulates neurogenesis, synapse formation and neurite outgrowth (reviewed in Wang JY. Mol Cell Biol 2014;34:1188-1197). Animal models have indicated that c-Abl overexpression may contribute to neurodegeneration, neuroinflammation and tau pathology (Schlatterer et al. J Mol Neurosci 2011;45: 445-452. Estrada et al. Curr Alzheimer Res 2011;8:643-651). Both nilotinib and INNO-406 have been shown to reduce oxidative stress and slow the progression of dopamine neuronal damage in an MPTP model of PD (Karuppagounder et al. Sci Rep 2014;4:4874. Imam et al. PLoS One 2013;8:e65129). Nilotinib was also shown to inhibit apoptotic pathways and promote autophagic clearance of SNCA/alpha-synuclein in a mouse transgenic model (Hebron et al. Autophagy 2013;9:1249-1250).

A preliminary study was conducted in 12 patients with PD or Lewy body dementia who were randomized to low-dose nilotinib (150 mg or 300 mg) for 24 weeks (Pagan et al. J Parkinsons Dis 2016;6:503-517 ; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC5008228/pdf/jpd-6-jpd160867.pdf). The mean decrease from baseline in UPDRS motor and non-motor scores (I-IV) was 7.0 and 11.1 points with nilotinib 150 mg and 300 mg at week 24; effects were reversed 12 weeks after nilotinib discontinuation. Treatment was associated with dyskinesia and psychotic symptoms (hallucination, paranoia, agitation), which required a change in the MAO-B inhibitor regimen. There was one case of myocardial infarction/left bundle block and two cases of transient QTc prolongation. (The Tasigna (nilotinib) product monograph includes warnings about QTc prolongation and sudden cardiac death.)

The new report was of a randomized single-dose study that is part of an ongoing 1-year double-blind trial of nilotinib. A total of 75 subjects received one of four doses of nilotinib (150 mg, 200 mg, 300 mg or 400 mg) or placebo. Lumbar punctures were obtained 1-4 hours post-dosing; blood samples were collected 30 minutes prior to LPs. All subjects had not received any MAO-B inhibitors for at least 6 weeks. A maximum dose of 800 mg carbidopa/levodopa equivalents was permitted.

The results showed that nilotinib entry into the brain was not dose-dependent. For the concentration of dopamine metabolites in CSF with nilotinib, DOPAC (3,4-Dihydroxyphenylacetic acid) levels were significantly increased 1 hour after dosing, with a peak at 2 hours; there was a non-significant increase in HVA (homovanillic acid). There were no changes in metabolite concentrations in the placebo group.

The concentrations of total alpha-synuclein and oligomeric alpha-synuclein in CSF were unchanged with nilotinib. There was also no significant difference in the oligomeric/total alpha-synuclein ratio in CSF. However, exploratory analyses showed a significant reduction in oligomeric alpha-synuclein in CSF with nilotinib 400 mg at 3 hours, and a reduction in the oligomeric/total alpha-synuclein ratio with nilotinib 150 and 200 mg versus placebo.

Also of interest to the pathophysiology of PD is triggering receptor on myeloid cells (TREM)-2, which regulates microglial production of reactive oxygen species that contribute to neurodegeneration, and promotes microglial phagocytosis (Sims et al. Nat Genet 2017;49:1373‐1384). In the Pagan et al. study, nilotinib 150 and 200 mg was associated with an increase in soluble TREM2 levels in CSF. Recent studies have suggested that increased TREM2 expression may have neuroprotective effects (Ren et al. Exp Neurol 2018;302:205‐213), although the authors note that this is controversial and will require further study (Konishi et al. Front Cell Neurosci 2018;12:206).

TOPICS:
Recommend to a Colleague

Related Posts

Go back to home page