Nilotinib

Hair Repigmentation Induced by Nilotinib

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A 51-year-old man with chronic myeloid leukemia visited the oncology clinic for routine follow-up. Treatment with nilotinib, a tyrosine kinase inhibitor, had been initiated 18 months earlier. During that time, the patient had noticed, much to his delight, the gradual repigmentation of his gray hair (Panel A, photo obtained approximately 1 year before the initiation of nilotinib) to its original color. During the same period, he had not started any other new medications and had used no hair-coloring products. On physical examination, his previously gray hair was noted to have become brown (Panel B). No other changes in his hair, skin, or mucosal pigmentation were observed. Molecular testing showed a deep molecular response. A diagnosis of medication-induced hair repigmentation due to the use of a tyrosine kinase inhibitor was made. Given the response of the leukemia to treatment with nilotinib, it was continued, and the patient’s hair remained brown.

Cancer Drug Shows Early Promise for Parkinson’s Disease

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A drug used to treat leukemia has shown initial signs of promise for advanced cases of Parkinson’s disease, researchers are reporting.

Experts stressed that the study was small, and primarily designed to see whether the drug — called nilotinib (brand name Tasigna) — is even safe for Parkinson’s patients.

It did appear “relatively safe” among the dozen patients studied, said Dr. Charbel Moussa, the senior researcher on the work.

One patient had to withdraw from the study because of heart complications. But the drug was “well tolerated” in the remaining patients, according to Moussa, an assistant professor of neurology at Georgetown University Medical Center, in Washington, D.C.

Plus, he said, there were hints of benefit.

The researchers found signs that the drug boosted the brain’s production of dopamine, a chemical that helps regulate movement. It also appeared to reduce certain “toxic proteins” that build up in the brains of people with Parkinson’s.

On top of that, the patients typically showed some improvement in both physical symptoms and problems with memory and thinking, the findings showed.

“I think this is a very promising beginning,” Moussa said.

But he also emphasized how much remains to be seen.

“We have to be very cautious about the safety profile of this drug in Parkinson’s patients,” Moussa said. “We also need to clarify the symptom areas that it may benefit, [and] how and when should this drug be used.”

That cautious tone was echoed by James Beck, vice president of scientific affairs for the Parkinson’s Disease Foundation.

“It’s still the early days,” said Beck, who wasn’t involved in the research.

He pointed to a number of issues that make it difficult to know how nilotinib could fit into Parkinson’s treatment, if at all.

For one, the study included only people who were in advanced stages of Parkinson’s and had some degree of dementia, including memory loss and thinking problems.

And since the study was designed only as an early “proof of concept,” it lacked the rigors that are used in later-stage trials: There was no comparison group given a placebo (inactive treatment), Beck said, and all of the study patients (and researchers) knew they were on the drug.

Moussa acknowledged those limitations. He said his team is planning two trials that will put nilotinib to a tougher test — where patients will be randomly assigned to take either the drug or a placebo.

One study, Moussa said, will include patients with moderate-stage Parkinson’s. The other will focus on people with mild to moderate Alzheimer’s disease — since there is evidence the drug could affect dementia symptoms.

Nearly one million Americans and up to 10 million people worldwide have Parkinson’s, according to the Parkinson’s Disease Foundation.

It is a chronic, progressive movement disorder that causes tremors, stiffness in the limbs, slowed movement and problems with balance and coordination. Most people also have symptoms that are unrelated to movement, according to the foundation. For some, those include memory issues, fuzzy thinking or even full-blown dementia.

No one is sure exactly what causes Parkinson’s, but it involves the death of certain brain cells — including ones that produce dopamine, which help regulate movement.

For the past 50 years, the mainstay of Parkinson’s treatment has been levodopa, a drug that boosts brain dopamine levels.

“But what we’ve all been waiting for,” Beck said, “is a treatment that can actually alter the course of Parkinson’s.”

According to Moussa, nilotinib “gets more to the roots” of Parkinson’s.

The drug belongs to a group of cancer agents called tyrosine kinase inhibitors, which block certain proteins that fuel cancer growth.

Lab research has shown that small amounts of nilotinib can reach the brain, and help cells shed toxic proteins without killing the cell itself, Moussa said.

“The drug acts like a switch,” he explained. “It turns on the ‘garbage disposal mechanism’ in the cell, so it can get rid of toxic proteins.”

For the current study, Moussa’s team had 12 patients take low doses of nilotinib every day for six months. One patient had to withdraw after one month because he had a heart attack.

Nilotinib carries a boxed warning about potentially risky changes in heart rhythm. That’s a concern, Beck said, because Parkinson’s patients are generally older and often have other conditions that can raise their risk of heart problems.

He also said the improvements in patients’ symptoms are “difficult to interpret.”

The improvements happened quickly — within a month, Beck pointed out. That, he said, suggests a “symptomatic benefit” only, due to higher dopamine levels, rather than any shift in the course of the disease.

With nilotinib already on the market, some patients and doctors might be tempted to try it without more evidence, Moussa acknowledged. But he cautioned against that.

“We should not rush to conclusions,” he said.

The study was supported by government and philanthropic funds. Moussa is listed as an inventor on a Georgetown University patent application related to the use of tyrosine kinase inhibitors for treating Parkinson’s and other neurodegenerative diseases.

Where We Stand with a Cancer Drug for Parkinson’s

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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 on Tuesday, August 2 at 12 p.m. ET.

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.

Clinical Experience to Date With Nilotinib in Gastrointestinal Stromal Tumors

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Nilotinib, a novel tyrosine kinase inhibitor (TKI) that inhibits BCR-ABL, the stem cell factor receptor (KIT), and platelet-derived growth factor receptor-alpha (PDGFRα), is approved for the treatment of patients with newly diagnosed Philadelphia chromosome–positive chronic myelogenous leukemia (CML) and those with CML that is imatinib-resistant or -intolerant. Due to its potent inhibition of KIT and PDGFRα—the two tyrosine kinases that are the central oncogenic mechanisms of gastrointestinal stromal tumors (GIST)—nilotinib also has been investigated for potential efficacy and safety in patients with GIST who have progressed on other approved treatments. Initial results have been encouraging, as nilotinib has demonstrated clinical efficacy and safety in a phase I trial as either a single agent or in combination with imatinib, as well as in heavily pretreated patients with GIST in a compassionate use program. In addition, the phase III trial of nilotinib versus best supportive care (with or without a TKI at the investigator’s discretion) indicated that nilotinib may have efficacy in some third-line patients. Furthermore, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST g1 trial), a phase III randomized, open-label study comparing the safety and efficacy of imatinib versus nilotinib in the first-line treatment of patients with GIST, is currently under way. Other studies with nilotinib either have been initiated or are in development. Based on published and accruing clinical data, nilotinib shows potential as a new drug in the clinician’s armamentarium for the management of GIST.

source: science direct