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 has also been reported to increase toxicity of α-synuclein in Neuro2A cells (Shaker et al, 2013) and to induce apoptosis and autophagic cell death in cultured liver cells (Eteläinen et al., 2022).

Additional targets of nilotinib are the discoidin domain receptor (DDR) tyrosine kinases, which have been implicated in cancer, fibrotic disorders, and inflammatory diseases. DDR1 is claimed to be elevated in AD brain. In models of protein toxicity, DDR1 or DDR2 knockdown reduced levels of α-synuclein, tau, and Aβ, and inflammation (Hebron et al., 2017). Inhibition of DDR2 may account for some aspects of nilotinib’s cardiac toxicity (Carracedo et al., 2022).

Nilotinib has been tested in preclinical models of PD and DLB. In the MPTP toxicity model of parkinsonism, nilotinib prevented dopaminergic cell death and behavioral deficits (Karuppagounder et al., 2014). 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., 2018; Lonskaya et al., 2013). In addition, it reportedly protected against TDP-43 toxicity in mice (Heyburn et al., 2016; Wenqiang et al., 2014). Much of 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). The drug did inhibit microglia-mediated dopaminergic death induced by LPS injection in an inflammatory model of PD (Wu et al., 2021).

In AD models, nilotinib prevented degeneration of dopamine neurons and improved memory performance in Tg2576 mice (La Barbera et al., 2021; see also Nobili et al., 2021). It also improved mitochondrial function and energetics in astroglia isolated from 3xTg AD mice (Adlimoghaddam 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., 2019; NPR 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., 2021). An analysis of CSF miRNA expression in trial participants found changes in pathways related to angiogenesis, extracellular matrix, and autophagy over one year on placebo, some of which were modified by nilotinib (Fowler et al., 2021). A continuation of this study reported that nilotinib treatment reduced miRNAs involved in inflammation, vascular fibrosis, and DDR1 kinase expression, and changed others related to autophagy and dopamine metabolism, compared to placebo (Stevenson et al., 2023). DDR1 kinase activity in CSF rose over time in placebo-, but not in nilotinib-treated patients.

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., 2021).

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 tested nilotinib in patients with DLB. Beginning in July 2019, this study planned to compare 200 mg daily of nilotinib or placebo taken for six months, followed by a one-month washout in 60 participants. The primary outcome was safety and tolerability; secondary outcomes were drug levels in CSF and plasma, changes in HVA in CSF, amyloid burden by PET, and other, unspecified surrogate and exploratory biomarkers for DLB, as well as measures of cognition, behavior, and motor function. The trial finished in December 2023, and results were presented at the October 2024 CTAD conference in Madrid. Due to the COVID pandemic, only 43 people enrolled, fewer than expected. No one dropped out due to side effects, and there were no serious adverse events related to drug. Overall, the treated group had fewer adverse events, including falls, than placebo. In exploratory endpoints, nilotinib improved the ADAS-Cog14 and the MDS-UPDRS cognition scale. Treatment did not change motor function, but reduced measures of irritability and apathy, and cognitive fluctuations.

The Georgetown investigators founded the company KeifeRx. In December 2021, KeifeRx registered a Phase 3 clinical trial for a new, low-dose formulation of nilotinib in AD. In 50 centers across the U.S., the study is to enroll 1,275 patients diagnosed with early AD, defined as a CDR of 0.5 or 1, MMSE scores between 20 and 27, and PET or CSF evidence of brain amyloid. The study will test 84 or 112 mg daily of the company’s Nilotinib BE against placebo for three years. The primary outcome is CDR-SB after 18 months. Secondary outcomes include ADAS-Cog14, MMSE, ADCS-ADL-MCI, and ADCOMS. Substudies will analyze CSF and imaging biomarkers at baseline and 18 months. The study was planned to run from February 2022 to June 2026, but according to clinicaltrials.gov has not started recruiting. Nilotinib no longer appears on the company’s pipeline.

A Phase 1 in Huntington’s disease began in 2018; its current status is unknown. A Phase 2 study in cerebellar ataxia was completed in Korea in August 2020. For all nilotinib trials, see clinicaltrials.gov.