1. Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease
- Author
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Simuni, Tanya, Fiske, Brian, Merchant, Kalpana, Coffey, Christopher S., Klingner, Elizabeth, Caspell-Garcia, Chelsea, Lafontant, David-Erick, Matthews, Helen, Wyse, Richard K., Brundin, Patrik, Simon, David K., Schwarzschild, Michael, Weiner, David, Adams, Jamie, Venuto, Charles, Dawson, Ted M., Baker, Liana, Kostrzebski, Melissa, Ward, Tina, and Rafaloff, Gary
- Subjects
Research ,Online First ,Comments ,Original Investigation ,Featured - Abstract
Key Points Question Do the safety, tolerability, exploratory clinical outcomes, brain penetration, and biomarker profile of nilotinib in aggregate support its development for treatment of Parkinson disease (PD)? Findings In this 6-month, multicenter, randomized placebo-controlled clinical trial of 76 participants with moderately advanced PD, nilotinib at 150-mg and 300-mg daily doses met prespecified safety and tolerability criteria. There was no evidence of symptomatic benefit of nilotinib on any measures of PD disability and there was trend toward worsening in the motor function in active treatment arms; in the cerebrospinal fluid, nilotinib level was less than 0.3% of that in the serum and failed to change dopamine metabolites levels. Meaning While nilotinib demonstrated acceptable safety and tolerability in this cohort, the low cerebrospinal fluid exposure, lack of biomarkers effects, and efficacy data trending in the negative direction indicate that further testing of nilotinib in treatment of Parkinson disease is not warranted., 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, This randomized clinical trial assesses safety and tolerability of nilotinib in participants with moderately advanced Parkinson disease.
- Published
- 2020