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Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial
Open accessAbstract
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. 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.
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“clinical trials showed that Nilotinib can reduce disease-related biomarkers in both AD and PD patients”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Pagan et al., 2019
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BackgroundThe Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer
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“…(Pagano et al., 2021), and anti-aggregatives), enhancement of cellular clearance mechanisms to eliminate toxic forms of aSyn (autophagy (Pagan et al., 2020; Pagan et al., 2021), lysosomal function (Mullin et al., 2020)), and modulation of neuroinflammatory processes (Athauda et al.,…”
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“After a small proofof-concept trial (n = 12) [59], a phase 2 RCT in persons with PD-MCI (MoCA score ≥22) found that nilotinib did not improve MoCA scores in the 150 mg group and significantly worsened in the 300 mg treatment group [60].”
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“Nilotinib, a small-molecule inhibitor of Bcr-Abl, had some effect on CSF and frontal cortex amyloid levels in a phase 2 clinical trial but failed to exert an effect on tau [181–183].”
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“The first was a 12-month single center study in 75 patients who were randomly assigned 1:1:1 to Nilotinib (150 or 300 mg) or placebo.(87) Nilotinib had no effect on motor function during the treatment phase or during a 3-month posttreatment follow-up period, but patients were also receiving concurrent anti-parkinsonia…”
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“Although the total number of adverse events was similar, there was a higher number of serious adverse events in patients treated with nilotinib, including four cardiovascular events [22].”
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“…patients along with favorable effects on CSF biomarkers, including brain dopamine turnover, oligomeric α ‐ syn, and hyper-phosphorylated tau [268, 269], Nilotinib demonstrated poor penetration in the brain and no relevant symptomatic benefit on measures of disability in a successive multi ‐ dose…”
Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis
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“We therefore tested the second generation TKI nilotinib, with higher selectivity for Lyn and able to cross the blood–brain barrier (BBB) [21].”
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“In the light of these findings, an autophagy inducer, Nilotinib, is currently in clinical trial for Parkinson’s [464, 465].”
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“We would argue that amyloid is a critical determinant in AD, and we should consider a multimodal approach to treating AD.”
BackgroundInfluentialNeurodegenerative diseases and cancer: sharing common mechanisms in complex interactions
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Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022?
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“oligomers, and tau in patients with PD [89].”
BackgroundCan We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?
Engelender, S., Stefanis, L., Oddo, S., & Bellucci, A. (2022) · Movement Disorders · doi:10.1002/mds.29058 · Cited by 23
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“E cacy MDS-UPDRS III Two studies reported MDS-UPDRS III scores (Pagan et al., 2020; Simuni et al., 2021).”
BackgroundInfluentialc-Abl activates RIPK3 signaling in Gaucher disease
Yañez, M. J., Campos, F., Marín, T., Klein, A. D., Futerman, A. H., Alvarez, A. R., & Zanlungo, S. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166089 · Cited by 24
Safety, target engagement, and biomarker effects of bosutinib in dementia with Lewy bodies
Pagán, F., Torres-Yaghi, Y. A., Hebron, M. L., Wilmarth, B., Turner, R. S., Matar, S., Ferrante, D., Ahn, J., & Moussa, C. (2022) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12296 · Cited by 21
Prospects for Disease Slowing in Parkinson Disease
Menozzi, E., & Schapira, A. H. V. (2024) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-022124-033653 · Cited by 23
“The treated arm showed increased levels of dopamine metabolites and reduction of a -synuclein oligomers in CSF, with a good safety and tolerability profile (42).”
Precision Medicine in Parkinson’s Disease: From Genetic Risk Signals to Personalized Therapy
Straccia, G., Colucci, F., Eleopra, R., & Cilia, R. (2022) · Brain Sciences · doi:10.3390/brainsci12101308 · Cited by 22
Satapathy, T., & Kumar, D. (2024) · Pharmacological Research - Modern Chinese Medicine · doi:10.1016/j.prmcm.2024.100499 · Cited by 20
Recent advances in understanding and treatment of Parkinson’s disease
Tarakad, A., & Jankovic, J. J. (2020) · Faculty Reviews · doi:10.12703/b/9-6 · Cited by 18
Recent Advances in the Treatment of Genetic Forms of Parkinson’s Disease: Hype or Hope?
Cavallieri, F., Cury, R. G., Guimarães, T. G., Fioravanti, V., Grisanti, S., Rossi, J., Monfrini, E., Zedde, M., Fonzo, A. D., Valzania, F., et al. (2023) · Cells · doi:10.3390/cells12050764 · Cited by 21
“placebo and oral nilotinib 150-mg or nilotinib 300-mg for 12 months followed by a 3-month washout period [62].”
BackgroundMethodWyse, R. K. H., Isaacs, T., Barker, R. A., Cookson, M., Dawson, T. M., Devos, D., Dexter, D. T., Duffen, J., Federoff, H. J., Fiske, B. K., et al. (2024) · Journal of Parkinson s Disease · doi:10.3233/jpd-230363 · Cited by 19
Therapeutic innovation in Parkinson’s disease: a 2020 update on disease-modifying approaches
Colombo, D., Pnevmatikou, P., Melloni, E., & Keywood, C. (2020) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2020.1800454 · Cited by 18
Majumdar, M., & Badwaik, H. R. (2024) · Current Drug Targets · doi:10.2174/0113894501312703240826070530 · Cited by 16
Prioritizing Parkinson’s disease risk genes in genome-wide association loci
Lange, L. M., Cerquera‐Cleves, C., Schipper, M., Panagiotaropoulou, G., Braun, A., Kraft, J., Awasthi, S., Bell, N., Posthuma, D., Ripke, S., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00933-0 · Cited by 18
O'Brien, J. T., Chouliaras, L., Sultana, J., Taylor, J., Ballard, C. G., on behalf of the RENEWAL Study Group, Aarsland, D., Blanc, F., Boeve, B. F., Brooks, D. J., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01103-7 · Cited by 17
Alteration of Autophagy and Glial Activity in Nilotinib-Treated Huntington’s Disease Patients
Anderson, K. E., Stevenson, M. E., Varghese, R. S., Hebron, M. L., Koppel, E., McCartin, M., Kuprewicz, R., Matar, S., Ferrante, D., & Moussa, C. (2022) · Metabolites · doi:10.3390/metabo12121225 · Cited by 16
“Biomarker objectives included measurement of HVA levels, HTT, neurofilaments and markers of neuro-inflammation.”
BackgroundMethodInfluentialLenka, A., & Jankovic, J. J. (2023) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2023.2177535 · Cited by 16
Min, Y., Wang, X., İş, Ö., Patel, T., Gao, J., Reddy, J. S., Quicksall, Z., Nguyen, T., Lin, S., Tutor‐New, F. Q., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42626-3 · Cited by 20
The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment
Naim, A., Farooqui, A. M., Badruddeen, B., Khan, M. I., Akhtar, J., Ahmad, A., & Islam, A. (2025) · European Journal of Neuroscience · doi:10.1111/ejn.70156 · Cited by 15
“In PD, the ABL/Src inhibitor nilotinib caused QT interval prolongation, pancreatic enzyme elevations and orthostatic hypotension, leading to the early termination of several participants and failure to meet primary efficacy endpoints (Pagan et al. 2020, 2021).”
Das, V., Miller, J. H., Goud, A. C., Annadurai, N., Sanctis, J. B. D., Hrubá, L., & Hajdúch, M. (2024) · Medicinal Research Reviews · doi:10.1002/med.22033 · Cited by 16
Seeking progress in disease modification in Parkinson disease
Lungu, C., Cedarbaum, J. M., Dawson, T. M., Dorsey, E. R., Faraco, C., Federoff, H. J., Fiske, B. K., Fox, R. J., Goldfine, A. M., Kieburtz, K. D., et al. (2021) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2021.09.006 · Cited by 15
Min, H. K., Kim, S. H., Won, J., Kim, K., Lee, J., Lee, S., & Kim, H. (2023) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.14627 · Cited by 15
Wilkes, B. J., Tobin, E. R., Arpin, D. J., Wang, W., Okun, M. S., Jaffee, M. S., McFarland, N. R., Corcos, D. M., & Vaillancourt, D. E. (2023) · npj Parkinson s Disease · doi:10.1038/s41531-023-00521-0 · Cited by 14
“Phase 2 and Phase 3 clinical trials for interventions that slow disease progression in Parkinson-ism can have several sites within one country 8,9 or multiple international sites 10 – 12 .”
Insights into the management of Lewy body dementia: a scoping review
Khan, S. A., Khan, S., Kausar, H., Shah, R. K., Luitel, A., Gautam, S., Parajuli, S. B., Rauniyar, V. K., & Khan, M. A. (2024) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000001664 · Cited by 14
“…there was a dose-related increase in the incidence of serious adverse events, and there was a trend toward increased incidence of falls in the treatment groups and both the treatment groups had an increase in CSF levels of dopamine metabolites and a decrease in CSF hyperphosphorylated tau [69] .”
BackgroundDementia with Lewy bodies: emerging drug targets and therapeutics
Pope, E. D., Cordes, L., Shi, J., Mari, Z. K., Decourt, B., & Sabbagh, M. N. (2021) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2021.1916913 · Cited by 14
“found that nilotinib can dramatically alter the course of PD in humans, with little to no harmful adverse events [22].”
BackgroundTargeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease
Peikert, K., Glaß, H., Federti, E., Mattè, A., Pelzl, L., Akgün, K., Ziemssen, T., Ordemann, R., Lang, F. J. W., Franceschi, L. D., et al. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11050392 · Cited by 14
Espay, A. J., Hauser, R. A., & Armstrong, M. J. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2019.3983 · Cited by 14
Parkinson's disease: pathogenesis and therapeutic strategies
Zhang, S., Wang, T., Peng, Y., Wang, Q., Zhang, Z., Shifeng, C. H. U., Huang, H., & Chen, N. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00445-0 · Cited by 13
Drug Repositioning and Repurposing for Disease-Modifying Effects in Parkinson’s Disease
Jeong, S. H., & Lee, P. H. (2025) · Journal of Movement Disorders · doi:10.14802/jmd.25008 · Cited by 13
“87 A single-center study with 75 participants reported increased dopamine metabolite levels in the CSF in some nilotinib-treated groups but reported no significant differences in motor or nonmotor outcomes.”
Pharmacological management of Parkinson’s disease in older people
Mouchaileh, N., & Hughes, A. J. (2020) · Journal of Pharmacy Practice and Research · doi:10.1002/jppr.1683 · Cited by 13
Yan, H., Huang, X., Xu, J., Zhang, Y., Chen, J., Xu, Z., Li, H., Wang, Z., Yang, X., Yang, B., et al. (2023) · Advanced Science · doi:10.1002/advs.202302002 · Cited by 12
A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson’s Disease
Kwon, S., Kim, S., Park, A. Y., Lee, S., Gadhe, C. G., Seo, B. A., Park, J. S., Jo, S., Oh, Y., Kweon, S. H., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01022 · Cited by 13
Lillian, A., Zuo, W., Laham, L., Hilfiker, S., & Ye, J.-H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087186 · Cited by 12
“IPX203 Extended-release Carbidopa-levodopa [72] Dopamine receptor Phase III”
BackgroundStevenson, M. E., Algarzae, N. K., & Moussa, C. (2024) · Frontiers in Dementia · doi:10.3389/frdem.2024.1458038 · Cited by 13
Skin Cancer May Delay Onset but Not Progression of Parkinson's Disease: A Nested Case-Control Study
Mahajan, A., Chirra, M., Dwivedi, A. K., Sturchio, A., Keeling, E. G., Marsili, L., & Espay, A. J. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00406 · Cited by 12
Khan, M. A., Haider, N., Singh, T., Bandopadhyay, R., Ghoneim, M. M., Alshehri, S., Taha, M., Ahmad, J., & Mishra, A. (2023) · Metabolic Brain Disease · doi:10.1007/s11011-023-01180-z · Cited by 12
Bashir, B., Vishwas, S., Gupta, G., Paudel, K. R., Dureja, H., Kumar, P., Cho, H., Sugandhi, V. V., Kumbhar, P., Disouza, J., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102693 · Cited by 11
Mutant-Huntingtin Molecular Pathways Elucidate New Targets for Drug Repurposing
Makeeva, V. S., Dyrkheeva, N. S., Lavrik, O. I., Zakian, S. M., & Malakhova, A. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316798 · Cited by 12
“…[123–125], cysteamine bitartrate [126–131], lithium citrate [132–135], laquinimod [136,137], rapamycin [138–141], minoxidil [142], felodipine [143], nilotinib [144,145], dextromethorphan [146], and INO-1001 [147] have been conducted. clozapine was tested in a double-blind randomized trial Ref.”
BackgroundChandía-Cristi, A., Gutiérrez, D. A., Dulcey, A. E., Lara, M., Vargas, L., Lin, Y.-H., Jimenez-Muñoz, P., Larenas, G., Xu, X., Wang, A. Y., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114144 · Cited by 9
Metadata
- Authors
- Pagan, F. L., Hebron, M. L., Wilmarth, B., Torres-Yaghi, Y., Lawler, A., Mundel, E. E., Yusuf, N., Starr, N. J., Anjum, M., Arellano, J., Howard, H. H., Shi, W., Mulki, S., Kurd-Misto, T., Matar, S., Liu, X., Ahn, J., & Moussa, C.
- Affiliations
- Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC
- Georgetown University Medical Center (US)
- MedStar Georgetown University Hospital (US)
- Corresponding author
- Moussa, Charbel
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2020-03-01
- Volume
- 77
- Issue
- 3
- Pages
- 309
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC6990742
- OpenAlex
- W2995537689
- Cited by
- 185
- References
- 32
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 35 · 2023: 29 · 2022: 28 · 2021: 30 · 2020: 26
- FWCI
- 14.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Neurology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- nilotinib, Parkinson's disease, disease-modifying therapy, safety and tolerability, pharmacokinetics, cerebrospinal fluid biomarkers, homovanillic acid, DOPAC, dopamine metabolism, adverse events, dose comparison, washout
- MeSH terms
- Aged, Dopamine, Double-Blind Method, Female, Humans, Male, Middle Aged, Parkinson Disease, Pyrimidines, Biomarkers, tau Proteins
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