A phase 2 placebo-controlled trial of the leukemia drug nilotinib (Tasigna, Novartis) in Parkinson disease suggests the drug is "reasonably safe," researchers conclude. Levels were detected in the cerebral spinal fluid (CSF), and there was some alteration of exploratory biomarkers.
"Taken together, our results will guide the future development of a definitive phase 3 study to evaluate the effects of nilotinib as a disease-modifying drug in Parkinson's disease," they write.
However, authors of an accompanying editorial are not impressed with these new data. "The conclusion that nilotinib is reasonably safe holds poorly to scrutiny," they argue. "With concerning signals regarding safety and discouraging preliminary evidence for disease modification, the justification for a phase 3 trial is tenuous," they add.
The study was published online in JAMA Neurology on December 16.
The authors, led by Fernando. L. Pagan, MD, and Charbel Moussa, MBBS, Georgetown University Medical Center, Washington, DC, note that nilotinib hydrochloride is a multikinase inhibitor that has been shown to reduce misfolded proteins in several models of neurodegeneration.
At low doses, nilotinib has been found to enter the brain and to degrade α-synuclein and tau in animal models, and an early clinical study has suggested that nilotinib may increase dopamine metabolism and potentially treat motor and nonmotor symptoms of Parkinson disease, they report.
The current phase 2 study was conducted to find out more about the effects of the drug in Parkinson disease, with primary focus on safety, tolerability, and pharmacokinetics. A secondary objective was to assess nilotinib's effects on CSF biomarkers of Parkinson's, and an exploratory objective was to assess nilotinib's effects on motor and nonmotor symptoms.
For the study, 75 patients with moderately severe Parkinson disease were randomly assigned to receive placebo; nilotinib 150 mg daily; or nilotinib 300 mg daily for 1 year.
Results showed that more serious adverse events were detected in the nilotinib groups ― 24% with the 150-mg dose and 48% with the 300-mg dose vs placebo (16%).
There was no significant difference in cardiovascular serious adverse events, number of falls, and total number of adverse events between all of the groups.
"It is likely that the increased number of serious adverse events, including the most common events, such as falls and hip fracture, urinary tract infection, skin diseases, pneumonia, and orthostatic hypotension, are Parkinson's-related issues that are unrelated to the study drug," the authors suggest.
However, in their editorial, Alberto J. Espay, MD, University of Cincinnati, in Ohio, and colleagues take issue with the researchers' description of nilotinib as "reasonably safe."
"Overall, serious adverse events were significantly more common with nilotinib, 300 mg, compared with placebo and there was a nonsignificant but dose-dependent increased incidence in falls in the treated groups (placebo, 39%; nilotinib, 150 mg, 54%; nilotinib, 300 mg, 61%)," they write. "The study was underpowered to assess for the occurrence of sudden cardiac death, for which the drug has a black box warning at higher daily dosages."
Some Biomarker Changes
In terms of biomarkers, the patients who received nilotinib 150 mg experienced an increase in CSF levels of the dopamine metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid. The patients who received nilotinib 300 mg showed an increase in 3,4-dihydroxyphenylacetic acid and a nonsignificant increase in HVA.
But the editorialists point out that "these results need to be interpreted in light of the nilotinib groups receiving higher daily dosages of levodopa and the potential influence of variability of timing of lumbar puncture relative to levodopa administration."
In addition, the nilotinib 150 mg group but not the nilotinib 300 mg group demonstrated a reduction of α-synuclein oligomers. A significant reduction of hyperphosphorylated tau levels was seen in both nilotinib groups.
The editorialists note: "The scatterplot of putative biomarkers, especially homovanillic acid and total and oligomeric α-synuclein, showed substantial overlap among the groups, suggesting that some of the statistical differences were driven by outliers. Hence, a repeat of the same study on a separate cohort could conceivably yield different results. The extent to which these biomarkers changed with vs without the intervention during the course of the study is unknown."
No Change in Clinical Outcomes
No significant differences were seen in overall motor and nonmotor clinical outcomes between the nilotinib groups and the placebo group.
Noting that the study was underpowered for clinical outcomes, the authors say that "it is impossible to know if the lack of a difference relates to sample size, lack of efficiency, or another factor."
But the editorialists point out that, "of concern," the nilotinib 300-mg group experienced worsening of activities of daily living from baseline to month 12, as assessed by scores on the Movement Disorders Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II, which they note is now favored by regulatory agencies for assessing disease modification over the MDS-UPDRS part III, which measures motor severity.
The 300-mg group also had significantly worse scores in the Timed Up and Go motor test and in the Montreal Cognitive Assessment over the course of the study. Such worsening was not consistently seen in the other groups, the editorialists add.
Responding to these observations in a JAMA Neurology audio interview, Moussa, the senior author of the article, stressed that with such small numbers, the study could not reliably assess clinical outcomes.
"This was on a very small scale; just one patient outlier can skew the results," he said. He also pointed out that the total UKPRS scores were not worsening overall.
The editorialists highlight some of the issues facing the continued development of nilotinib for Parkinson's. They raise the possibility that α-synuclein aggregation may not be pathogenic in all patients. "On the heels of recent negative phase 3 trials of the promising molecules isradipine and inosine, the path ahead for nilotinib is therefore a narrow and difficult one," they write.
"Neither biomarker nor clinical data from this phase 2 study adequately serve to improve selection of suitable candidates for a phase 3 study. Similarly, the use of MDS-UPDRS-II as an end point of choice looks unpromising," they add. "If the field were to support moving ahead with a phase 3 trial, biospecimen collection will be critical for post hoc analyses to evaluate the biological underpinning of potential responders, as well as to identify those who may worsen."
The study was supported by philanthropies through the Lasky and Barajas Family Fund and other private philanthropies. Nilotinib was provided by Novartis. Pagan reports receiving personal fees, grants, and/or other support from Acadia, AbbVie, Accorda, and Adamas, Teva, Medtronic, US World Meds, Sunovion, and Merz. Moussa and Georgetown University own the intellectual property on the use of nilotinib for neurodegenerative disorders.
JAMA Neurol. Published online December 16, 2019. Abstract, Editorial
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