Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial

Abstract

Importance: There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD).

Objectives: To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers.

Design, setting, and participants: This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure).

Interventions: Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation.

Main outcomes and measures: The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers.

Results: At baseline, mean (SD) participants' age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P < .01). There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between groups (P = .17). Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3%. There was no evidence of treatment-related alteration of dopamine metabolites in the CSF.

Conclusions and relevance: While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD.

Trial registration: ClinicalTrials.gov Identifier: NCT03205488.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Simuni reports grants from National Institute of Neurological Disorders and Stroke, the Michael J Fox Foundation, Parkinson’s Foundation, Biogen, Roche, Neuroderm, Sanofi, Sun Pharma, AbbVie, IMPAX, and Prevail and other support from Acadia, AbbVie, Accorda, Adamas, Allergan,Amneal, Aptinyx, Denali, General Electric, Kyowa, Neuroderm, Neurocrine, Sanofi, Sinopia, Sunovion, Roche, Takeda, Voyager, and US World Meds during the conduct of the study. Dr Merchant reports personal fees from Vincere Biosciences, Sinopia Biosciences, Carraway Therapeutics, Nitrome Biosciences, Angel Investors, and Nura Bio; is an adviser to and has received grants from the Michael J Fox Foundation; and is a stock holder of other pharmaceutical companies outside the submitted work. Dr Venuto reports personal fees and nonfinancial support from Michael J Fox Foundation via Northwestern University during the conduct of the study and outside the submitted work. Dr Simon reports personal fees from Michael J Fox Foundation during the conduct of the study; personal fees from Biogen, Halloran Consulting Group, and Chase Therapeutics; grants and personal fees from Lysosomal Therapeutics Inc; and grants from Voyager Therapeutics, BioElectron Technology, and Neuraly outside the submitted work. Dr Weiner is an adviser to the Michael J Fox Foundation. Dr Dawson reports grants from the Michael J Fox Foundation and the National Institute of Stroke and Neurological Disorders during the conduct of the study; grants and personal fees from Sun Pharma Advanced Research Company; personal fees from Inhibikase Therapeutics and Neuraly Inc; and grants, personal fees, and nonfinancial support from Valted Seq Inc outside the submitted work; in addition, Dr Dawson has a patent, Biomarkers for Neurodegenerative Disorders, pending. Michael Schwarzschild reports personal fees from the Michael J. Fox Foundation for Parkinson’s Research during the conduct of the study; personal fees from Prevail Therapeutics, nQ Medical, and Eli Lilly and Co; other support from Acorda Therapeutics; and nonfinancial support from Denali outside the submitted work. Dr Brundin reports other support from Axial Biotherapeutics, Acousort AB, Gilead, Moderna Inc, and Inovia; personal fees from CuraSen, Fujifilm-Cellular Dynamics International, IOS Press Partners, LifeSci Capital LLCt, and Living Cell Technologies LTD; grants and personal fees from Lundbeck A/S; and grants from Roche outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants in NILO-PD Study

ECG indicates electrocardiogram.

Figure 2.. Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III ON and OFF Scores Over Time

Figure 3.. Cerebrospinal Fluid (CSF) Levels of Dopamine, Its Metabolites, and the Relationship Between Nilotinib CSF Concentrations and Dopamine Turnover Indices

DOPAC indicates 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid.