Is Radotinib ABL to beat Nilotinib?

June 17, 2018 ~ Simon ~ 16 Comments

At the Society for Neuroscience annual meeting in 2015, the results of a small phase I clinical trial were presented and the Parkinson’s community got really excited by what they saw.

The study had investigated the use of a cancer drug called ‘Nilotinib’ (also known as Tasigna) on Parkinson’s and the initial results were rather interesting.

Two larger phase II clinical trials of Nilotinib in Parkinson’s are currently being conducted, but this week preclinical research of a new drug (called Radotinib) was published. And these new findings suggest that Nilotinib may have some impressive competition.

In today’s post, we will look at what Nilotinib and Radotinib actually do, we will review the new research, and we will discuss what the findings could mean for the Parkinson’s community.

Lots of research. Source: Thedaily

Earlier this week I wrote a post highlighting research involving a new drug (NLY01; a GLP1 receptor agonist) being developed for Parkinson’s (Click here to read that post). It was an amazing amount of work and a very impressive achievement for the research group that conducted the work.

It must have taken a long time to perform the experiments, and I figured that the researchers behind the study would probably take a well earned break.

You will understand that I was a little surprised the day after publishing the post, that I woke up to find that that same research group had published another rather remarkable amount of research… on a completely different novel drug (called Radotinib) which is also being developed for Parkinson’s!!!

Basically sums my reaction. Source: Canacopegdl

The words ‘You have to be kidding me‘ actually passed across my lips as I downloaded the new research report.

And the new drug is really interesting.

It is very similar to Nilotinib.

What is Nilotinib?

Continue reading “Is Radotinib ABL to beat Nilotinib?” →

Nilotinib: the other phase II trial

July 31, 2017July 31, 2017 ~ Simon ~ 12 Comments

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In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.

What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.

Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.

In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the ongoing Georgetown Phase II trial.

FDA-deeming-regulations

The FDA. Source: Vaporb2b

This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.

This is exciting and welcomed news.

What is Nilotinib?

What does any that mean?

Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.

Continue reading “Nilotinib: the other phase II trial” →

Phase II trial launched for Nilotinib

February 27, 2017February 28, 2017 ~ Simon ~ 4 Comments

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Big news today from Georgetown University with the announcement that they will be starting a phase II trial for the cancer drug Nilotinib.

Click here to read the press release.

In this post we will discuss what has happened thus far and what the new trial will involve.

Georgetown University (Washington DC). Source: Wallpapercave

In October 2015, researchers from Georgetown University announced the results of a small clinical trial at the Society for Neuroscience conference in Chicago.

It is no understatement to say that the results of that study got the Parkinson’s community very excited.

The study (see the abstract here) was a small clinical trial (12 subjects; 6 month study) that was aiming to determine the safety and efficacy of a cancer drug, Nilotinib (Tasigna® by Novartis), in advanced Parkinson’s Disease and Lewy body dementia patients. In addition to checking the safety of the drug, the researchers also tested cognition, motor skills and non-motor function in these patients and found 10 of the 12 patients reported meaningful clinical improvements.

In their presentation at the conference in Chicago, the investigators reported that one individual who had been confined to a wheelchair was able to walk again; while three others who could not talk before the study began were able to hold conversations. They suggested that participants who were still in the early stages of the disease responded best, as did those who had been diagnosed with Lewy body dementia.

The study involved the cancer drug Nilotinib.

What is Nilotinib?

Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). That is to say, it is a drug that can be used to treat a type of leukemia when the other drugs have failed. It was approved for this treating cancer by the FDA in 2007.

How does Nilotinib work?

The researchers behind the study suggest that Nilotinib works by turning on autophagy – the “garbage disposal machinery” inside each neuron. Autophagy is a process that clears waste and toxic proteins from inside cells, preventing them from accumulating and possibly causing the death of the cell.

The process of autophagy. Source: Wormbook

Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material.

The investigators believe that nilotinib may be helping in Parkinson’s disease, by clearing away the waste building up in cells – allowing the remaining cells to function more efficiently.

This is great, so what happened in 2016?

That’s a great question.

First, the results of the study being published (Click here to read those results). Second, the U.S. Food and Drug Administration (FDA) reviewed Georgetown’s investigational new drug application (IND) for nilotinib in Parkinson’s disease, and they informed the Georgetown University investigators that a new clinical trial could proceed.

But after that, there were whispers of issues and problems behind the scenes.

Back in August we wrote a post about the Phase II trial being delayed due to disagreements about the design of the study (Read that post by clicking here). Two separate research groups emerged from those disagreements (Georgetown University researchers themselves and a consortium including the Michael J Fox Foundation). Click here for the STAT website article outlining the background of the issues, and click here for the Michael J Fox Foundation statement regarding the situation. The Georgetown University team have a lot of leverage in this situation as they control the patent side of things (Click here to see the patent).

We are not sure what has happened since August, but the Georgetown University team has now announced that they are going to go ahead with a phase II trial to look at safety and efficacy of nilotinib in Parkinson’s disease.

What do we know about the new trial?

At the moment the details are basic:

The design of the study involves two parts:

In the first part of the study, one third of the participants receiving a low dose (150mg) of nilotinib, another third receiving a higher dose (300mg) of nilotinib and the final third will receive a placebo drug (a drug that has no bioactive effect to act as a control against the other two groups). The outcomes will be assessed clinically at six and 12 months by investigators who are blind to the treatment of each subject. These results will be compared to clinical assessments made at the start of the trial. (We are not sure if brain imaging – for example, a DATscan – will be included in the assessment, but it would be useful)

In the second part of the study, there will be a one-year open-label extension trial, in which all participants will be randomized given either the low dose (150mg) or high dose (300mg) of nilotinib. This extension is planned to start upon the completion of the first part (the placebo-controlled trial) to evaluate nilotinib’s long-term effects. (We are a little confused by this study design with regards to efficacy, but determining the safety issues of using nilotinib long term is important to establish).

We are not clear on how many subjects will be involved in the study or what the criteria for eligibility will be. All we can suggest is that if you are interested in finding out more about this new study, you can sign up here to receive more information as it becomes available.

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Summing up, this is welcomed news for the Parkinson’s community as we will finally be able to determine if nilotinib is having positive effects in Parkinson’s disease. There have been some concerns raised that the effects of the drug in the first clinical study may have been the result of removing additional Parkinsonian treatments during the study (Click here for more on this). This new study will hopefully help to clarify things.

And fingers crossed provide us with a useful new treatment for Parkinson’s disease.

The banner for today’s post was sourced from William-Jon

Nilotinib and Parkinson’s disease – an update

July 12, 2016January 9, 2017 ~ Simon ~ 4 Comments

We have previously discussed news briefings regarding a cancer drug that displayed interesting results in a pilot clinical study of Parkinson’s disease (click here to read that post). Today we will delve more deeply into the results of that particular study and consider what they mean.

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Nilotinib (Tasigna) from Novartis. Source: William-Jon

In October of last year, at the Society for Neuroscience meeting in Chicago, a presentation of data from a clinical trial got the Parkinson’s community really excited. The study was investigating the effects of a cancer drug called ‘Nilotinib’ (also known as Tasigna) on Parkinson’s disease and the initial results were rather interesting.

The results of the pilot clinical study for Nilotinib were published today in the Journal of Parkinson’s disease:

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Title: Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies
Authors: Pagan F, Hebron M, Valadez E, Tores-Yaghi Y,Huang X, Mills R, Wilmarth B, Howard H, Dunn C, Carlson A, Lawler A, Rogers S, Falconer R, Ahn J, Li Z, & Moussa C.
Journal: Journal of Parkinson’s Disease, vol. Preprint
PMID: Yet to be allocated (This article is OPEN ACCESS if you would like to read it).

The study was setup to determine safety of using Nilotinib in Parkinson’s disease dementia or dementia with Lewy bodies.

What is Nilotinib?

Nilotinib is a drug that can be used to treat a type of leukemia when the other cancer drugs have failed. It was approved for this treating cancer by the FDA in 2007.

The researchers behind the current study believe that Nilotinib works by turning on autophagy – the “garbage disposal machinery” inside brain cells. Autophagy is a process that clears waste and toxic proteins from inside cells, preventing them from accumulating and possibly causing the death of the cell.

The process of autophagy – Source: Wormbook

The researchers suggest that Nilotinib may be working in Parkinson’s disease by helping affected cells to better clear away the build up of unnecessary proteins, which helps cells to function more efficiently.

What happened in the clinical study?

Twelve people with either Parkinson’s disease dementia or dementia with Lewy bodies were randomized given either 150 mg (n = 5) or 300 mg (n = 7) daily doses of Nilotinib for 24 weeks. After the treatment period the subjects were followed up for 12 weeks. All of the subjects were considered to have mid to late stage Parkinson’s features (Hoehn and Yahr stage 3–5). One subject was withdrawn from the study at week 4 due to a heart attack and another discontinued at 5 months due to unrelated circumstances.

An important question in the study was whether Nilotinib could actually enter the brain. Various tests conducted on the subjects suggesting that the drug had no problem crossing the ‘blood brain barrier‘ and having an effect in the brain. The levels of Nilotinib in the brain peaked at 2 hrs after taking the drug and the levels of the target protein (called p-Abl) were reduced by 30% at 1 hr. This level of activity remained stable for several hours.

The motor features of Parkinson’s disease were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) and the investigators observed an average decrease of 3.4 points and 3.6 points at six months (week 24) compared to the baseline measures (scores from the start of the study) with 150 mg and 300 mg Nilotinib, respectively. A decrease in motor scores represent a reduction in Parkinson’s motor features.

The really remarkable result, however, comes from the testing of cognitive performance, which was monitored with Mini Mental Status Examination (MMSE). The researchers report an average increase of 3.85 and 3.5 points in MMSE at six months (24-week) compared to baseline, for 150 mg and 300 mg of Nilotinib, respectively. This means that the mental processing of the subjects improved across the study.

The motor and cognitive results were complemented by measures of proteins in blood and cerebrospinal fluid samples taken from the subjects. The researchers saw increases in dopamine related proteins (suggesting that more dopamine was present in the brain) and stabilization of alpha synuclein levels.

The researchers concluded that these observations warrant a larger randomized, double-blind, placebo-controlled trial to truly evaluate the safety and efficacy of Nilotinib.

Here at the SoPD, we are inclined to agree.

So what does all this mean?

The results of the study are very interesting, and the researchers should be congratulated on the outcome (and presentation of all the data in the report). As they themselves acknowledge, the study was open labelled – meaning that everyone in the study knew that they were getting the treatment – so the placebo effect could be at play here.

One intriguing note in the report was that most of the participants in the study ‘experienced increased psychotic symptoms (hallucination, paranoia, agitation) and some dyskinesia whilst on Nilotinib’ suggesting an increase in dopamine levels in the brain.

Obviously a larger, double-blind study is required to determine whether the effect of the drug in Parkinson’s disease is real. The Michael J. Fox Foundation, the Van Andel Research Institute (Michigan, USA) and the Cure Parkinson’s Trust are collaborating on the development program for a double-blind, placebo-controlled clinical trial of nilotinib, which it is hoped will begin in 2017.

The banner for today’s banner was sourced from Wikimedia

Parkinson’s disease and the cancer drug

December 11, 2015September 2, 2017 ~ Simon ~ 7 Comments

In October, 40,000 neuroscientists from all over the world gathered in Chicago for the annual Society for Neuroscience conference. It is one of the premier events on the ‘brain science’ calendar each year and only a few cities in the USA have the facilities to handle such a huge event.

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Science conference. Source: JPL

During the five day neuroscience marathon, hundreds of lecture presentations were made and thousands of research poster were exhibited. Many new and exciting findings were presented to the world for the first time, including the results of an interesting pilot study that has left everyone in the Parkinson’s research community very excited, but also scratching their heads.

The study investigators reported that one individual who had been confined to a wheelchair was able to walk again; while three others who could not talk before the study began were able to hold conversations. They suggested that participants who were still in the early stages of the disease responded best, as did those who had been diagnosed with Lewy body dementia.

So what is Nilotinib?

The process of autophagy – Source: Wormbook

Some details about the study:

The study was run at the Georgetown University Medical Center
The patients were given increasing doses of Nilotinib (150mg to 300mg/day) that were are significantly lower than the doses of Nilotinib used for CML treatment (800-1200mg/day).
The researchers took cerebrospinal fluid (CSF; the liquid surrounding the brain) and blood samples at the start of the study, 2 and 6 months into the study.
Nilotinib was detected in the CSF, indicating that it had no problem crossing the protective blood-brain-barrier – the membrane covering the brain that blocks many drugs from entering.
Participants exhibited positive changes in various cerebrospinal fluid biomarkers with statistically significant changes in an important protein called, Tau, which have been shown to increase with the onset of dementia.
The researchers found a significant reduction (>60%) in levels of α-Synuclein detected in the blood, but no change in CSF levels of α-Synuclein.
The investigators report that one individual confined to a wheelchair was able to walk again; three others who could not talk were able to hold conversations.

If the outcomes of this study are reproducible, then we here at the Science of Parkinson’s are assuming that Nilotinib is working by turning on the garbage disposal system of the remaining cells in the brain and allowing them to function better. This would suggest that there is a certain level of dysfunction in those remaining cells, which would be expected as this is a progressive disease. The study researchers reported that the small, daily dose of nilotinib turns on autophagy for about four to eight hours, and if that is enough to have such remarkable effects, then this treatment deserves more research.

The results of the study are intriguing and the participants of the study will continue to be treated and followed to see if the improvements continue.

BUT before we go getting too excited:

While these results sound extremely positive, there are several issues with this study that need to be considered before we celebrate the end of Parkinson’s disease.

Firstly, this study was an open-label trial – that means that everyone involved in the study (both researchers and subjects) knew what drug they were taking. There was also no control group or control treatment for comparative analysis in the study. Given these conditions there is always the possibility that what some of the subjects were experiencing was simply a placebo effect. Indeed the lead scientist on the project, Dr Fernando Pagan, pointed out that “It is critical to conduct larger and more comprehensive studies before determining the drug’s true impact.”

In addition, according to Novartis (the producer of the drug), the current cost of Nilotinib is about $10,360 (£6,900) per month for the daily 800mg dose used for cancer treatment. Even if the dose used in this study was only 150 to 300 mg/daily, it would still make this treatment extremely expensive.

Thirdly, Nilotinib has a number of adverse side-effects when used as an anti-cancer drug (at 800mg/day). These include headache, fatigue, nausea, vomiting, diarrhea, constipation, muscle/joint pain, skin issues, flu-like symptoms, and reduced blood cell count. It may not be the nicest of treatments to tolerate.

There are important reasons for optimism, however, with the results of this study:

In 2010, a group of researchers published a paper demonstrating the neuroprotective effects of another cancer drug very similar to Nilotinib. That drug was ‘Gleevec’

Title: Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function.
Authors: Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC,Dawson VL, Dawson TM.
Journal: Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16691-6.
PMID: 20823226

And that Gleevec publication was followed up a couple of years ago with a second study demonstrating the neuroprotective effects of another Abl-inhibitor: Nilotinib!

Title: The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease.
Authors: Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS
Journal: Sci Rep. 2014 May 2;4:4874.
PMID: 24786396

These studies provided a strong rationale for testing brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD. The phase 2 trial at Georgetown will be starting in early 2016 and we will be watching this trial very closely.