Nilotinib: the other phase II trial


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.


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?

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).

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.

How does Nilotinib work?

In certain types of leukemia, a specific genetic abnormality occurs in chromosome 22. This is called the Philadelphia chromosome and it results from part of chromosome 9 and 22 actually swapping places.


Philadelphia chromosome. Source: Wikipedia

The result of this mix up is that a fusion gene on chromosome 22, which is created by shifting of the ABL1 gene from chromosome 9 (region q34) to a part of the BCR gene on chromosome 22 (region q11). This leads to a weird fusion protein called bcr-abl, and this protein undertakes various functions, but it is always turned on. And this constant activity helps to drive cancer cell growth in blood cells.

Initially a cancer wonder drug called Imatinib (also known as Gleevec – maybe you’ve heard of it) was developed to block the bcr-abl fusion protein from binding to other proteins that help to encourage the cancer growth. It competitively binds to a small region of the bcr-abl fusion protein, not allowing (or blocking) it to fulfill its function.


How Imatinib (aka Gleevec) works in cancer. Source: Wikipedia

Basically, Nilotinib is very similar to Gleevec – in shape and function. Think of Nilotinib as the new and improved version of Gleevec.

What on earth does this have to do with Parkinson’s disease?

Well, while Nilotinib and Gleevec were originally designed to target the bcr-abl fusion protein, both drugs can also be used to block the abl protein by itself.

It has been suggested that the activation of the ABL1 gene may be playing a role in neurodegenerative conditions, such as Alzheimer’s disease (Click here for the Alzheimer’s related research and click here for an early review on this topic). This idea is also supported in Parkinson’s disease, because in 2010 by a group of researchers publishing a paper demonstrating that there is increased levels of abl in the Parkinsonian brain, and by blocking the abl protein, Gleevec could effectively protect models of Parkinson’s disease.

Here is that research report:


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            (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers reported that cellular abl (or c-Abl) binds to and interacts with the Parkinson’s associated protein Parkin. But this interaction is not good: abl basically stops Parkin from having doing its job – that is, grabbing old proteins and other rubbish for disposal or recycling in a process called autophagy.

Autophagy is a process that clears waste and old 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. When Parkin is inhibited, normal autophagy does not take place and old proteins and faulty mitochondria start to pile up, making the cell sick (ultimately leading to the death of the cell).

The researchers found that cells treated with a neurotoxin (MPTP) had high levels of activated abl protein, and by blocking this abl protein they could reduce the effect of the neurotoxin (in a fashion that was dependent on Parkin being present). They also showed that genetically engineered mice with no ABL gene were more resistant to the neurotoxin than normal mice. Importantly, they provided data indicating that the inactivated form of Parkin and the activated version of abl are higher in the brains of people with Parkinson’s disease than normal controls.

Naturally the investigators concluded that “inhibition of c-abl may be a neuroprotective approach in the treatment of Parkinson’s disease”. And critically many of these findings were replicated independently by another research group shortly after this first report was published (Click here to read that second research report).

The Gleevec results were also followed up a couple of years later by a research team at Georgetown University (the same folks co-ordinating the clinical trial), but this time using the new and improved version of Gleevec, Nilotinib. And this study demonstrated another cute trick of abl-inhibiting drugs: Parkin is not the only Parkinson’s associated protein being affected.


Title: Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models.
Authors: Hebron ML, Lonskaya I, Moussa CE.
Journal: Hum Mol Genet. 2013 Aug 15;22(16):3315-28.
PMID: 23666528               (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators demonstrated that levels of activated abl protein increase with accumulation of the Parkinson’s associated protein Alpha Synuclein – accumulation of which is a characteristic feature of the Parkinsonian brain. By giving Nilotinib to mice that had been genetically engineered to produce high levels of alpha synuclein, the researchers found that they could reduce the negative effects of the accumulating protein. They also demonstrated that the positive effect of Nilotinib treatment was produced (in part) by the activation of the garbage disposal system (autophagy) and removal of the accumulating alpha synuclein.

In another experiment in that report, when they modelled the accumulation of alpha synuclein in dopamine neurons, the researchers found that Nilotinib treatment could protect the dopamine cells from dying and corrected dopamine levels back to normal. And this research group also demonstrated elevated levels of abl in the Parkinsonian brain when compared to normal controls. They concluded that the “data suggest that Nilotinib may be a therapeutic strategy to degrade alpha synuclein in Parkinson’s disease and other alpha synucleinopathies”.

Importantly, these results have been replicated by independent research groups. Firstly by a Swiss group that found that abl binds and interacts with alpha synuclein:

Title: c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease.
Authors: Mahul-Mellier AL, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, Lamontanara AJ, Bisquertt A, Eliezer D, Masliah E, Halliday G, Hantschel O, Lashuel HA.
Journal: Hum Mol Genet. 2014 Jun 1;23(11):2858-79.
PMID: 24412932             (This article is OPEN ACCESS if you would like to read it)

These Swiss researchers also reported raised levels of abl in the brains of people with Parkinson’s disease, AND their results supported the findings that Nilotinib encourages degradation of alpha synuclein protein. Interestingly, they also found that Nilotinib reduced levels of abl protein itself (via the autophagy pathway).

Two birds with one drug?

The second research group to independently reproduce the Nilotinib results was the group behind the original Gleevec results:


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              (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers found that Nilotinib treatment protected dopamine neurons in a model of Parkinson’s disease and restored normal dopamine levels in the brain. They also found that administration of Nilotinib reduces abl activation and the levels of the Parkin interacting protein PARIS (PARkin Interacting Substrate). High levels of PARIS in normal mice can result in the loss of dopamine cells, and this effect can be rescued by an over production of Parkin (I have discussed PARIS in a previous post – click here to read that post). Interestingly, these researchers suggested that Nilotinib was having this effect in a way that was independent of Parkin, as Nilotinib treatment had no effect on Parkin levels in their hands.

All of these studies provided a strong rationale for testing brain permeable abl inhibitors as potential therapeutic agents for the treatment of Parkinson’s disease (For those seeking more information about the research of Nilotinib and other acl inhibitors in Parkinson’s disease models – click here for a good review).

And it was tested in people with Parkinson’s disease?

Yes, and you may have heard about the results as they caused some excitement.

The Georgetown researchers – led by Dr Charbel Moussa and Dr Fernando Pagan undertook the clinical study.


Georgetown researchers Dr Charbel Moussa and Dr Fernando Pagan. Source: Georgetown

They reported the results in the Journal of Parkinson’s disease:


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).

Twelve people with either Parkinson’s disease dementia or dementia with Lewy bodies were randomised 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 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 stabilisation of alpha synuclein levels.

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

This all sounds great. What happened next?

I have to be careful what I write here.

There were disputes over how the follow up studies should be structured and designed. These disagreements led to further issues. There is a very good article on the STAT website that tries to explain what happened (Click here to read that article and click here for the Michael J Fox Foundation statement regarding the situation).

The Georgetown University team have a lot of leverage in the situation as they control the patent side of things (Click here to see the patent). And they were the first of the two parties to initiate a phase II trial back in February of this year (Click here to read more on this).


Georgetown University (Washington DC). Source: Wallpapercave

The Georgetown trial (named ‘PD Nilotinib’ – Click here for the details of trial NCT02954978) 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.

In the second part of the study, there will be a one-year open-label extension trial, in which all participants will be randomised 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.

The Georgetown study will recruit 75 subjects and will be completed in July 2020. The investigators are looking for participants aged 40-90 years, with a Hoehn and Yahr staging of 2.5 – 3 (a relatively advanced level of Parkinson’s), and medically stable on 800mg Levodopa daily (for at least 4 weeks). 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.

So what was announced this week?

The initiation of a second phase II clinical trial for Nilotinib in Parkinson’s disease.

According to the press release, the trial (named ‘NILO-PD’ – Click here for the details of trial NCT03205488) will be co-ordinated by Professor Tanya Simuni, head of the division of movement disorders at the Feinburg School of Medicine at Northwestern University. The study will be carried out at 25 different clinical sites across the USA through the Parkinson Study Group, which is the largest not-for-profit network of Parkinson’s disease centres in North America.

Starting in September 2017, a first cohort (group) of 75 people with moderate to advanced Parkinson’s disease will be randomly assigned to receive either a daily dose of 150 mg of Nilotinib, 300 mg of Nilotinib or placebo.

The treatment will be given everyday for six months, during which the participants will be closely monitored. Following the treatment phase there will be an 8 week follow up period (during which all treatments are stopped), in order to determine Nilotinib’s safety and tolerability. Trial participants will be tested on their motor and cognitive abilities, and they will give sampled (i.e., blood and spinal fluid) for biological testing. All of these tests will provide the investigators with data with which to evaluate the potential impact of Nilotinib on Parkinson’s symptoms and the disease progression.

If the drug is shown to be safe in this first cohort, a second trial is planned to be immediate initiated which would test Nilotinib in a second cohort of 60 people with early Parkinson’s disease. These subjects would be given the highest tolerated daily dose of Niltotinib (based on the results of the first study) or a placebo for 12 months. The same measurements (eg. biological samples) would be applied to this study as well.


The Michael J. Fox Foundation for Parkinson’s Research has collaborated with the Van Andel Research Institute (Grand Rapids, Michigan), and The Cure Parkinson’s Trust (London, UK), on this second phase II clinical trial for Nilotinib in Parkinson’s disease. Partial funding for the trial has been generously provided through an anonymous leadership gift from a family living with Parkinson’s disease, as well as contributions from the Demoucelle Parkinson Charity (Belgium) and The Parkinson Alliance (Kingston, New Jersey).

The results of the trial will be known on October 2020.

And what’s the difference between the two studies?

The two studies share many features such as the same doses of oral capsule Nilotinib to be used. But they do differ in their basic design:

  • The first part of the Georgetown study will run double-blinded for 12 months, and then all participants will be placed on the Nilotinib in an open-label fashion for another 12 months.
  • The NILO-PD study will have a double-blinded 6 month safety test on advanced Parkinson’s disease, and then switch to a double-blinded 12 month efficacy trial on people with recently diagnosed Parkinson’s disease.

While my opinion accounts for nothing and is rarely given, I lean towards the second trial as a better test of efficacy. I like the length of the Georgetown study, but prefer the double blind nature of the NILO-PD study (though I worry about the placebo effect in both of these studies – see my comment below). I also would like to see some brain imaging results in these studies – it is expensive, but it would be a useful definitive measure of dopamine function in the brain.

What does it all mean?

The initiation of a second phase II clinical trial for the cancer drug Nilotinib in people with PD should be warmly welcomed by the Parkinson’s disease community. The initial results suggest that this drug may represents an exciting step forward for this condition, if it behaves the same way in humans as it has in animal models of Parkinson’s disease. The disagreements and arguments regarding this move forward should be forgotten or at least set aside until definitive results indicate whether the drug is effective or not.

If the drug is found to be effective, there will no doubt be a flood of abl-inhibitor drugs rushing to clinical trial in drug-repurposing studies, including Bafetinib which has already demonstrated beneficial effects in preclinical models of Parkinson’s disease (Click here to read more about that study). One interesting angle on this story, however, is written in wording of the Georgetown Nilotinib patent. The document is littered with the words “…a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is not Gleevec and wherein the tyrosine kinase inhibitor crosses the blood brain barrier…”. This careful editing suggests that either Gleevec is off-patent for neurodegenerative conditions (unlikely), or else the pharmaceutical company Novartis is quietly waiting to see what becomes of all this activity.

If the drug is not found to be effective in the clinical trials, there will a host of commentaries to medical research journals similar to one that I have previously discussed (click here to read that post). There will be a lot to be said of this saga regardless of which way the trials go. The worst case scenario, however, will be if the results of one trial says ‘yes’ and the other says ‘no’. And there is a real possibility of this occurring that has nothing to do with the efficacy of the actual drug.

One of my major concerns going into these trials is the placebo effect. Given the hype surrounding this drug, there is a very real possibility that participants involved in the studies will start to believe that they are receiving Nilotinib (both studies start out double blind) and they will begin experiencing amazing benefits that are not pharmacologically real. Control subjects experiencing these imaginary beneficial effects ruin clinical trials. And we have seen this before in the world of Parkinson’s research (Click here to read more), and we have not really done anything with regards to clinical trial design to counter the strong placebo effect (which is so exaggerated in Parkinson’s disease research).

It will be interesting to see where all of this activity ends up. In a good place, I pray.

Stay tuned.

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

12 thoughts on “Nilotinib: the other phase II trial

  1. Good review. I tried to enroll in the GU study but didn’t meet criteria mentioned. Which is probably a good thing. (I live about 2 miles away from Georgetown.)


    1. Hi Don,
      It’s a nice part of the world old Georgetown. Shame they did not take you for the study, but a lot of other research going on in that neck of the woods. It will be interesting to see how these particular trials turn out though. Hopefully if they are both going well we’ll know some results before 2020.
      Kind regards,


  2. Excellent review. As someone actively involved in the NILO-PD trial, you coverage of the distinction between the two trials was quite accurate. Regarding the original dispute, the information reported in the press was partially accurate, and also had many inaccuracies (which is typical in these situations). However, as you stated very well, it’s time to forget that and move forward with the research. That’s all the PD community really cares about at this time.


      1. Thanks Simon. I’m a member of the investigator steering committee for the NILO-PD trial (I’m actually the one who came up with the name…haha). Unfortunately for me, the IRB has ruled me ineligible for the trial due to their feeling there would be a conflict of interest. I had always intended to participate, but now I’ll have to watch and wait……..


    1. How do you guys estimate the treatment will pan out if and when the drug is approved for slowing down Parkinson’s? Do you estimate that it is going to be a one time course over a period of a few months or a year, or annual courses lasting a few months, or do you believe that this will need to be a daily medication for life?

      I’m an engineer here and so pardon my thought process. If this drug opens up certain pathways that increase lysosomal activity that will automatically clean up protein aggregates in the brain, then after some time one is left with very little or no protein aggregation, correct? I’d like to think of this as a small speck of rust causes more rust. however when you treat the rust the rust doesn’t spread

      Excellent article guys. One is really hopeful that this is a game changer for early stage Parkinson’s at least and that payers will be willing to pay for this.


  3. there is so much more to this story and I wish investigators would reach deeper in to the background. Like who now owns the patient rights for Tasigna since georgetown sold it. Why is Georgetown sending so many people away? To stretch out the length of there trial? Also what Generic brand company are getting ready to buy the rights ? If georgetown wins the patient and hs sold the rights who will financially benefit from the trial. Who is supplying the drug for the trial? Where dose the mj fox foundation now sit with the trial. with patients pending around the world who really is in charge. Also who is following up on many of us who are taking the drug off script to see how we are doing? So many questions I would like answered.


    1. Hi PJ,
      Thanks for your comment.
      With regards to your question on ‘who now owns the patient rights for Tasigna since Georgetown sold it’ – I was not aware that Georgetown had sold the patent rights. I would be interested to learn more about this though. All I know is that Dr. Charbel Moussa of Georgetown University has several pending patents, but they are all limited to “nilotinib (Tasigna), bosutinib, and a combination thereof” (May 2, 2013 – They do not include other kinase inhibitors such as Imatinib (Gleevec –, Dasatinib, Ponatinib, and Bafetinib (INNO-406 – Some of these other kinase inhibitors are not as specific to c-Abl, and Imatinib and Ponatinib appear to have less brain penetration which may explain the focus on Nilotinib & Bosutinib (for a good review on the topic of c-Abl inhibitors and PD –, but I do think that there is certainly scope for other c-Abl inhibitors to be tested in PD.
      Dr. Moussa also has another patent (also filed May 2, 2013) for inhibiting toxic protein aggregation in subjects with an alpha-synucleinopathy by administering nilotinib at a dosage of about 5 mg/kg or less( But again, this patent is limited to just Nilotinib. So, while I am no patent expert, there is certainly space for others to move in this area (and they may well be moving already, if only provisionally).
      Georgetown rejecting people for their trial may be due to their tight criteria for participant selection (see Their inclusion criteria includes: People between the age of >40 years (so no really young onset), Hoehn and Yahr stage of 2.5 – 3 (which is a mid-stage of disease course, say 5-7 years post diagnosis). And their exclusion criteria include: any history of cardiac conditions (which can cut a few people out of contention), Hypokalemia and Hypomagnesaemia (blood potassium and magnesium levels are too low), treatment with Anticoagulants (warfarin, etc). In order to determine if the drug actually works (everything to this point has been open label), they will be wanting to target it towards the individuals that they believe have the best chance of benefiting from it. They certainly wouldn’t be sending people away to stretch out the length of their trial – they have no interest in that nor the financial resources.
      To my knowledge there are no generics looking to produce Nilotinib yet as the first patents relating to it do not expire until 2023 ( Yes, there are a lot of fake/caveat emptor sources of the drug online, but no generics yet. And with regards to who is supplying the drug for the trial, that is Novartis (though the exact arrangements with Georgetown has not been disclosed). The Michael J Fox foundation are funding the second trial mentioned in this post, I do not know who is funding the Georgetown trial, which launched in February (
      I have been contacted by numerous individuals who are taking c-Abl inhibitors off-licence and I have suggested to several of them that some kind of monitoring system is required (otherwise 1. how can they know whether the drug is benefitting them or not; 2. precious information is being lost). It is a similar situation with Exenatide/Byduren. It would be EXTREMELY useful if the PD community set up a Clinicrowd-style resource ( for this sort of activity. If people are going to go off licence with these sorts of drugs, any data they can collect should be made available for analysis, no?
      Thanks for the interesting set of questions.
      I hope this helps.
      Kind regards,


  4. Hi! Great article! Someone very, very close to me has Progressive Supranuclear Palsy (PSP) considered a pure taupathy. The Georgetown team mentioned that Nilotinib might work on PSP as well. I don’t see how it would work if it doesn’t target tau. Any insight?


  5. Hi! Thanks for this article! Someone very, very close to me has Progressive Supranuclear Palsy (PSP), considered a pure taupathy. The Georgetown team mentioned Nilotinib might help PSP but I don’t understand how since it doesn’t target yay. Any insight?


    1. I read somewhere that nilotinib also helped to remove tau protein from the brain of patients participating in that small clinical trial in the USA. I also read that in Alzheimer’s two types of tau accumulate whereas in PSP only one. Researchers are now conducting clinical trials in PSP as the progress of the disease is easier to track than in Alzheimer’s. They believe that if it works in PSP it will work in Alzheimer’s. The ultimate goal is to develop new treatments for Alzheimer’s disease because that’s where the money is.


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