Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease
Authors: Tanya Simuni, Brian Fiske, Kalpana Merchant, Christopher S. Coffey, Elizabeth Klingner, Chelsea Caspell-Garcia, David-Erick Lafontant, Helen Matthews, Richard K. Wyse, Patrik Brundin, David K. Simon, Michael Schwarzschild, David Weiner, Jamie Adams, Charles Venuto, Ted M. Dawson, Liana Baker, Melissa Kostrzebski, Tina Ward, Gary Rafaloff, Jamie Adams, Erika Augustine, Deborah Baker, Alicia Brocht, Cindy Casaceli, Ken Eaton, Sue Henderson, Nichole McMullen, Phounsavath Muneath, Laura Trusso, Carlinda Field, Saurav Brahmachari, Liana Rosenthal, Emily Carman, Cornelia Kamp, Patrick Bolger, Claire Wegel, Holly Reynolds, Oren Levy, Amber Servi, Kelvin Chou, Angela S Stovall, Gian Pal, Kellie Keith, Kathryn Chung, Joohi Shahed, Christine Hunter, Binit Shah, Katie Sullivan, Albert Y. Hung, Grace Bwala, Meredith Spindler, Alexandria Oliver, Robert A. Hauser, Claudia Rocha, Eric Molho, Sharon Evans, Holly A. Shill, Farah Ismail, Natividad Stover, Candace Cromer, Courtney Blair, Lin Zhang, Olga Kishchenko, Matthew Swan, Laura Ramirez, Samuel Frank, Stephanie Burrows, Andrew Duker, Christina Gruenwald, Karen Blindauer, Lynn Wheeler, Lauren Seeberger, Abigail Simpson, Burton L. Scott, Lisa Gauger, Anwar Ahmed, Yvette Pitchford, Jennifer Mule, Adolfo Ramirez-Zamora, Derek B. Ridgeway, John Slevin Slevin, Renee Wagner Wagner, Vanessa Hinson, Shonna Jenkins, John L. Goudreau, Doozie Russell, Zoltan Mari, Lilliana Dumitrescu, Jason Aldred, Melissa Bixby, Mark LeDoux
Journal: JAMA Neurology (2020)

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).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.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).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.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.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.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.ClinicalTrials.gov Identifier: NCT03205488.