Editor's note: Read a patient’s perspective on balancing the hype and the hope around new therapies such as this one.
A promising therapy that may slow or stop Parkinson's progression is moving forward. Today The Michael J. Fox Foundation (MJFF), the Van Andel Research Institute (VARI) in Michigan and the Cure Parkinson's Trust (CPT) in the United Kingdom announced plans to collaborate to assess the clinical use and development of cancer drug nilotinib. Among the partners' goals: planning a double-blind, placebo-controlled clinical trial of nilotinib, which MJFF hopes can begin in 2017.
The announcement came in conjunction with today's publication, in the Journal of Parkinson's Disease, of a paper on the first trial of nilotinib in people with Parkinson's disease from a team at Georgetown University. An accompanying editorial, "Nilotinib -- Differentiating the Hope from the Hype," presents the research on nilotinib and its target, c-Abl (read more on this emerging protein of interest below), as intriguing, but warns against patient use until we know more about the drug's safety and efficacy for people with Parkinson's disease. (The editorial was authored by MJFF CEO Todd Sherer, PhD; Richard Wyse, MD, director of research and development at Cure Parkinson's Trust; and Patrik Brundin, MD, PhD, director of the Van Andel Research Institute Center for Neurodegenerative Science and editor of the journal.)
"It is impossible to extract definitive safety and valid efficacy signals from a small open-label unblinded study (lacking a placebo control) in PD and dementia with Lewy bodies," the authors write. "A major concerted effort is needed to determine whether there is still hope that can match the hype for nilontinib in alpha-synucleinopathies."
Here we cover some frequently asked questions about this drug and area of research. Learn more in a special MJFF webinar, and read one patient's take on the media response to news of the first clinical trial.
What is nilotinib?
Nilotinib is a drug approved for chronic myelogenous leukemia, a cancer of the white blood cells, under the brand name Tasigna. The medication inhibits a class of certain proteins, including one called c-Abl, which is an emerging target for Parkinson's research.
What is the connection between c-Abl protein and Parkinson’s disease?
Higher levels of c-Abl are associated with Parkinson's disease. This means trouble in a few different ways:
- An MJFF-funded project showed that heightened c-Abl activity inhibits the parkin protein. Parkin, when acting normally, goes around the cell and tags unnecessary or dysfunctional proteins and mitochondria for degradation. When parkin is not working correctly (perhaps because of high c-Abl levels), bad proteins -- such as the key Parkinson's player alpha-synuclein -- and damaged mitochondria can build up into toxic clumps and harm the cell. Other cellular players that work with parkin (called substrates) also can become toxic to the cell if parkin is not functioning correctly.
- Also, last month another paper reported that deleting c-Abl from pre-clinical models reduced alpha-synuclein aggregation, while over-expressing c-Abl led to the protein clumps. The research team on that paper showed a direct link between c-Abl and alpha-synuclein, further supporting the role of c-Abl in Parkinson's disease.
- In addition to the role of c-Abl in regulating parkin and/or alpha-synuclein, some researchers have demonstrated its involvement in dopamine-signaling pathways.
To recap: scientists believe that too much c-Abl hurts cells by messing with parkin function, encouraging alpha-synuclein aggregation directly and/or impacting dopamine signaling. With the evidence mounting, c-Abl is gaining attention as a Parkinson's drug target.
What has the research told us about nilotinib?
Two studies in pre-clinical PD models from 2013 and 2014 showed protective effects of nilotinib. And several other studies in pre-clinical PD models have shown protective effects of inhibiting c-Abl. This provided impetus for testing nilotinib in patients.
The trial results published today -- from a small, open-label (all knew they were getting the drug) trial of nilotinib in people with advanced Parkinson's -- included impact on spinal fluid measures of alpha-synuclein and imaging scans of dopamine function.
The drug was well tolerated, and participants reported improvements in motor skills and cognitive function. These are encouraging results; unfortunately, researchers know that the likelihood of placebo effect is high in any open-label Parkinson's clinical study. Nonetheless, MJFF deems these findings supportive of continued, rigorous research in this area.
Should patients start taking nilotinib?
In short, no. We just don't know enough yet. Patients and clinicians are urged to wait for further safety data before considering adding the drug to their treatment regimens at this time. Much work remains to be done to validate the drug in a clinical setting, and there is not yet enough information to assert with certainty that it works in Parkinson's and, critically, that it is safe to take over the course of a lifetime.
Cancer treatments are notoriously hard on the body. While people with Parkinson's might take a significantly lower dose, we need to know the long-term effects.
Why the lower dose for PD? In cancer treatment, you try to get that tagging and degradation system working in overdrive to eat up everything in the cancer cells. In Parkinson's, we just want the tagging system to work normally, so we might not need as much drug. But we don't yet know whether a lower dose of nilotinib will actually inhibit c-Abl in the brain.
Which leads to another question: How much drug gets the system working enough to protect the cell but not so much as to harm it? We need to make sure the drug is truly treating the Parkinson's process.
"Nilotinib does not get into brain that well, so one of the questions that I have is: At the dose touted to be effective in humans, is c-Abl in brain cells being inhibited?" says Ted Dawson, MD, PhD, of Johns Hopkins University and author of the recent paper connecting c-Abl to alpha-synuclein. "And it has toxicities, so if a patient is contemplating taking nilotinib, it should really be done in the setting of a controlled clinical trial where you're appropriately monitored."
Are there other drugs similar to nilotinib?
There are other c-Abl inhibitors for cancer, but they either also come with harsh side effects or don't pass the blood-brain barrier (a requirement to stop the Parkinson's process).
So what are the next steps?
MJFF, VARI and CPT are collaborating on a therapeutic development program to assess the safety and efficacy of nilotinib in people with PD. The program includes the goal of planning of a double-blind, placebo-controlled (neither researchers nor participants know who has gotten the drug or placebo) clinical trial of nilotinib, which MJFF hopes can begin in 2017.
The partners plan to expand on early safety findings to better understand the implications of long-term use of nilotinib and to rigorously vet early-stage pre-clinical and clinical findings such as around drug penetration into the brain and the relationship between nilotinib dosing and c-Abl activity.
The sponsors of the first clinical trial also are planning a follow-up. These parallel studies will help gather more data and provide independent findings for comparison.
And the field is working on new c-Abl inhibitors that get in to the brain better with fewer risks and side effects.
How can I learn more?
Watch a special webinar on nilotinib covering the science behind this potential treatment, findings thus far, safety concerns, and next steps.
We'll continue to update the Parkinson's community on the MJFF/VARI/CPT partnership through our blog, emails and social channels.
Create a profile on Fox Trial Finder or make sure your profile is up to date to be notified if you are a likely match for this or other clinical trials in need of research volunteers.