There is tremendous value in identifying new purposes for existing drugs. Recently, Georgetown University Medical Center (GUMC) embarked on a project to do just that for Parkinson’s disease with a cancer drug called nilotinib (Tasigna). They found that the drug in people with Parkinson’s disease was reasonably safe and well tolerated. Further study with cautious optimism next.
During the study, which was published Dec 16 in JAMA Neurology, researchers found that the drug increased dopamine—the chemical lost as a result of neuronal destruction—and a decrease in neurotoxic proteins in the brain among study participants. Nilotinib is a tyrosine kinase inhibitor and halts motor and non-motor decline. The news was recently reported by George Washington University.
What is Nilotinib?
Marketed under the brand Tasigna® by Novartis, the drug was approved by the FDA for treatment of chronic myeloid leukemia back in 2007. The drug includes a “black-box warning” due to sudden death association with the inhibition of Abl tyrosine kinase, an important protein for cellular function. Nilotinib is administered in higher doses (300mg twice a day) for cancer treatment than were studied in this trial (150mg and 300mgs once per day).
A small Phase II study was conducted at Georgetown University Medical Center (GUMC). The primary goal was to ensure that the participating subjects experienced no serious safety events from nilotinib. Led by Charbel Moussa, MBBS, PhD, the research center enrolled 75 participants (average age 68.4) with moderately advanced (stage 2.5-3) Parkinson’s disease and stable symptoms participated in the trial. They were randomized to receive either placebo, 150mg or 300mg of nilotinib. Twenty-five participants were in each group.
The study was blinded, which is done to prevent bias in reporting. Hence, neither the study participants nor the study investigators were aware if the active drug or placebo was being administered till the end of the individual’s study period. The drug was taken by mouth for 12 months, followed by a 3-month washout period (no drug taken).
88% of the participants completed the study; two participants withdrew from the placebo group, three withdrew from the 150mg group (one voluntarily, two for non-compliance), and four in the 300mg group withdrew (one voluntary, one due to non-compliance and two for significant adverse events).
At lower doses, this study evidenced generally safe results, being mindful of the risks associated with Abl inhibition and sudden death. The study lead reported that no subject withdrew from the study due to tolerability.
The study team also found that participants had reduced levels of alpha-synuclein (20%) and tau (30%), two toxic proteins characteristic of those with Parkinson’s disease. These findings raised some eyebrows, as taken together, this “means that the clearance of these neurotoxic proteins may not solely depend on Abl inhibition—other tyrosine kinases or alternate mechanisms may be involved,” reported Charbel Moussa, MBBS, PhD, the senior author of the study, and director of the GUMC Translational Neurotherapeutics Program.
Of note, the drug also increased levels of dopamine metabolites (>50%), suggesting that the clearance of the toxic proteins stimulated increased utilization of the brain’s own dopamine.
The placebo group experienced worsened non-motor, quality-of-life self-reports (PDQ9) while in the nilotinib group, and it appeared to be mitigated for at least 12 months. All study groups seem to improve on motor testing (UPDRS-III) at six months—but those on placebo and 300mg remained stable at 12 and 15 months while the 150mg group improved between baseline and 15 months.
The results are definitely cause for consideration of additional research. The principal investigator Fernando Pagan, MD, commented, “We see that subjects on nilotinib performed better overall on motor testing and had a better quality-of-life measurement during the study than the placebo group. These are important observations suggesting that nilotinib stabilized the disease––a potential disease modifying effect that we haven’t observed with any other agents.”
This study clearly isn’t enough to get too excited. With significant side effects, including infection, liver function tests abnormalities, hallucinations and heart attack. Scientists and medical professionals have advised caution with over-optimistic interpretation of its effects in Parkinson’s due to the significant news reporting that’s surrounded the small and early clinical trial. For example, we include a report a Nilotinib—Differentiating the Hope from the Hype that was authored by The Cure
Fernando Pagan, MD neurology professor, Georgetown University Hospital and Medical Director GUMC Translational Neurotherapeutics
Charbel Moussa, MBBS, PhD, the senior author of the study, and director of the GUMC Translational Neurotherapeutics Program
Call to Action: These findings need to be confirmed via larger studies with more diverse participant populations. But they reveal some real promise. On the other hand, any optimism should be informed holistically by evidence of side effects, etc. TrialSite News will monitor and report on any updates.