Nilotinib is a potential oral treatment for Parkinson’s disease (PD).
Nilotinib, developed and marketed by Novartis under the brand name Tasigna, is used to treat people with a blood cancer called Philadelphia chromosome positive chronic myeloid leukemia (CML). It was approved by the U.S Food and Drug Administration (FDA) in 2010 for this form of leukemia, and has been similarly authorized in the European Union since 2007.
How nilotinib works
Nilotinib is a type of biological therapy called a protein tyrosine kinase inhibitor (TKI). Tyrosine kinases are enzymes that act as chemical messengers, which can stimulate cancer cell growth.
In Parkinson’s disease, nilotinib may work to eliminate toxic proteins that build in the brain by activating a mechanism in brain cells that serves as a sort of garbage disposal unit.
Nilotinib in clinical trials
Researchers with Georgetown University Medical Center (GUMC) conducted a Phase 1 clinical trial (NCT02281474) that evaluated the effects of nilotinib in 11 patients with Parkinson’s and Lewy body dementia.
Results from this study, which ended in 2015, suggested that the medication can safely treat both motor and cognitive problems in patients with moderately advanced Parkinson’s and mild to severe cognitive impairment.
The six-month trial reported positive outcomes in all 11 nilotinib-treated patients, with 10 people showing significant clinical improvement. Disease biomarkers in the cerebrospinal fluid were also evaluated, and positive changes were found for alpha-synuclein (α-synuclein), amyloid beta-40/42 (Abeta-40/42), dopamime, and tau protein, a sign of toxic protein clearance from the brain.
Trial results also showed an increase in dopamine production in several patients, and that treatment discontinuation led to a deterioration in cognitive and motor skills even with levodopa use. Given at lower doses than for cancer patients (150 or 300 mg once daily), nilotinib seemed to improve symptoms over the 24-week treatment period, without causing serious adverse reactions.
Based on these findings, GUMC researchers opened a Phase 2 clinical trial (NCT02954978) in January 2017, evaluating nilotinib’s safety and tolerability at two doses — 150 mg or 300 mg capsules taken once a day — against a placebo for 12 months in 75 adults with moderate to severe Parkinson’s disease. Novartis supported this trial, providing both nilotinib and a placebo.
Patients enrolled, ages 40 to 90, had the option of continuing or beginning treatment in a 15-month extension study after finishing the main trial. In total, 63 patients moved into the longer-term study, and were randomized to treatment at either dose.
Main trial findings, reported in 2019, showed safety and reasonable tolerability at both doses after 12 months, with side effects largely mild to moderate in severity, including falls, and musculoskeletal, respiratory, and skin conditions.
An exploratory analysis of disease-relevant biomarkers found that patients given nilotinib had lower levels of two toxic proteins considered hallmarks of Parkinson’s: a 20% decrease in alpha-synuclein and 30% reduction in tau, and a more than 50% increase in dopamine levels in the brain.
Extension study findings, reported in 2021 at the annual American Association of Neurology (AAN) meeting, continued to show safety and tolerability at both doses, with no adverse events thought related to treatment. Evidence of greater benefit was seen at nilotinib’s 300 mg daily dose.
According to these 27-month results, a worsening in motor and non-motor aspects of daily living — as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) I-II — stopped in people at the 300 mg dose after about 15 months, and these scores remained stable or slightly improved through to the extension study’s end. For those on the 150 mg daily dose, these scores continued to worsen. Patient-reported quality of life was also superior on the high dose compared with lower-dose patients.
No change was evident in measures of cognitive abilities between these two groups, and no statistically significant difference in UPDRS-III scores — assessing motor symptoms — was seen between the high- and low-dose groups during “on” periods with levodopa.
Those who started on treatment later in the extension study, likely the main trial’s placebo group (although not defined as such in the AAN abstract), showed that nilotinib at 150 mg daily failed to prevent a significant worsening of combined UPDRS II and III scores, or in the total UPDRS I-III score, compared with patients at a later date given the 300 mg dose.
GUMC researchers, based on total Phase 2 findings, recommended that a larger study of treatment efficacy at the 300 mg daily dose be conducted in Parkinson’s patients.
Updated: April 20, 2021
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