The Narrowing Path for Nilotinib and Other Potential Disease-Modifying Therapies for Parkinson Disease

Abstract

Nilotinib hydrochloride, an Abelson tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia, has been in the neurology news since the results of the open-label, phase 1 study in a small group of patients with advanced Parkinson disease (PD) and dementia with Lewy bodies was reported at the Society for Neuroscience in Chicago in October 2015. The extensive media coverage that followed, supported by videos of nilotinib-treated participants getting up and walking from their wheelchairs, suggested that disease modification in PD was within reach with this drug. The corresponding publication documented that, at 150 and 300 mg/d, doses lower than required for treating leukemia, nilotinib was detectable in the cerebrospinal fluid (CSF), increased CSF homovanillic acid levels, seemed to engage the target Abelson, and was relatively safe and well tolerated at 24 weeks. 1 Although the authors emphasized that "motor and cognitive outcomes suggest a possible beneficial effect on clinical outcomes," 1(p503) the accompanying editorial noted that, owing to the small sample size and lack of a control group, it was impossible to rule out a placebo effect. 2 In this issue of JAMA Neurology, Pagan and colleagues 3 present the results of a phase 2 trial of nilotinib. This was a singlecenter, double-blind, placebo-controlled study in which 75 patients were randomly allocated to placebo; nilotinib, 150 mg, taken orally once daily; or nilotinib, 300 mg, taken orally once daily for 12 months, followed by a 3-month washout. This PD cohort with more than 10 years of disease duration and a Hoehn and Yahr stage of 2.5 to 3 was treated with a mean levodopa dose of 600 mg at baseline (lower at the end of the trial because of dropouts). Pagan and colleagues 3 concluded that nilotinib was shown to be reasonably safe and capable of altering relevant biomarkers.

Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease

“…In contrast, the 2020 double-blind, placebo-controlled study reported significantly higher homovanillic acid levels in the CSF in the 150-mg nilotinib group but not in the 300-mg group at 12 months . Similar concerns regarding interpretation of the biomarker data were expressed in the Editorial that accompanied Pagan et al publication.…”

Skin Cancer May Delay Onset but Not Progression of Parkinson's Disease: A Nested Case-Control Study

“…While the number of cases undergoing immune modulation, chemotherapy, and/or radiation in our sample is anticipated to be low due to the predominant cancer subtype, we cannot discount the possibility that some may have undergone treatment and that such treatment influenced the outcome. Although data from a phase 2 clinical trial of nilotinib in PD showed some concerns regarding safety and questionable preliminary evidence of efficacy, the role of immune modulators as a disease-modifying strategy in PD continues to be a topic under active investigation (28,29). Due to multiple dopaminergic dose changes between clinic visits, we could not evaluate the effect of medications and cancer.…”

Drug reprofiling history and potential therapies against Parkinson’s disease

“…Nilotinib has been shown to attenuate exogenously expressed SNCA levels in mice and reduce SNCA-induced nigral degeneration ( Wong and Krainc, 2017 ). However, because there was no placebo group in this study and significant baseline differences between the two small groups, it was impossible to comment on any potential clinical benefits of the medicine ( Espay et al, 2020 ). Despite the promising results of preclinical research and the fact that another trial (NILO-PD) is now underway in the United States, there is no convincing evidence of nilotinib’s efficacy in PD patients ( Stoker et al, 2018 ).…”