Six month follow up on Nilotinib trial.
 

During my 6 month follow up neuro appointment at Georgetown Medstar Hospital I inquired how the Nilotinib trial was going. One of my neurologists is involved with the trial and gave me a brief review. Nothing has been published because the trial is for 9 months but there are some very positive results appearing at 6 months. This trial has 10 "end stage" PWP (this is the term she used) and the purpose of the trial is to test the safety of Nilotinib, a drug used to tx leukemia. So far abnormal proteins and tau have been reduced in the brain. Levels have been measured in spinal fluid and cell activity has been detected in blood work. By cellular activity this means dopamine production by the cells once damaged by abnormal proteins. In fact enough dopamine was produced that Parkinson medications had to be reduced in some patients. There have also been positive cognitive changes. At least one patient who hadn't talked in years started talking. All the patients received Nilotinib no placebo group.
This trial will finish up in the fall and another trial will begin around November. This was the estimated time frame given to me today. I will be included in the next trial if they are testing mild disability PWP. She isn't sure if this next trial will include a placebo group but all patients will be giving the drug at different times in the trial.
Funding for this current trial is being done by 2 of the current patients. MJFF hasn't given any $$ and according to the neurologist isn't planning to provide any funding. GTH is looking at grants etc for funding for the next trial.
This is the first time I've been excited or had any hope concerning this disease. I'll keep everyone informed about what happens in November when, I hope, I'm entered in the new trial.
All the best to everyone,
Betsy

Thank you

Here some links: http://www.foxnews.com/health/2013/0...ia-discovered/

http://www.georgetown.edu/news/cance...ons-study.html

http://www.nature.com/srep/2014/1405...srep04874.html

I've been following this closely for over a year and have discussed the science behind the hypothesis with both neurologists and oncologists. They all thought that this could be something that would work (although, of course, we've heard that before). I was somewhat disappointed when the FDA only approved the phase I trial for mid to late stage volunteers. Once again, this is a case where the scientists believe that the earlier the intervention with the drug, the more likely it would show efficacy. I was somewhat surprised that they would tell you interim trial information prior to a formal release of data.

I have heard of some off-label attempts with alzheimers patients that did not work. Nevertheless, I hope they are able to go to a phase 2 study so we can get more information. I'm surprised that they can't just get funding from the manufacturer, Novartis, as it would seem to be to their benefit if the drug is approved for other use outside of CML (and I think now AML also).

Nilotinib trial
 

I agree with you about your surprise of trial information being released. I simply asked how the trial was going and kept asking questions as the information was forth coming. I was most excited about what appears to be dopamine production in this advanced group. Also motor improvement was noted, walking in particular. I asked about tremor but she wasn't sure said not all the patients had tremor to begin with. Who knows what will happen the last three months of the trial.
I return in November when it's anticipated the second phase of this trial will begin with all stages of PWP. I've been hearing about this trial for about 16 months from the neurologists in anticipation that if I'm eligible I could enter the trial at the appropriate time. I'm hoping it's November. I'll keep everyone posted.

i personally would never repeat interim results from a clinical trial that weren't made public, imho this dr. should not have revealed them, things can change, the results haven't been peer reviewed, plus most pd phase 1 trials succeed and phase 2 don't once the placebo affect is removed and other clinicians besides the original investigator become involved with the larger phase2 trial. if the results were that fantastic i assume they would seek to get approval asap to expand the trial or start a new one. the fear i have is that pd'ers will start bugging their dr's for this already approved drug.

sorry if i got this wrong.

Assuming the trials for nilotinib go well and in a timely fashion, how long would it take to bring this drug to market. Are we looking at maybe 3 years or more like 5? How many more trials are necessary?

This trial, conceptually, is somewhat similar to the Isradipine Steady-PD trial. In that study the FDA required a 1 year phase 2 (which was successfully completed). The phase 3 commenced the end of 2014/ beginning of 2015 and is designed as a 3 year trial. If the FDA required a similar timeline, and taking into account time for patient recruitment, data analysis, NDA submittal and FDA review, you would have a minimum of 6 years. Of course, there is interim monitoring and if the results warranted it, the trial could be stopped earlier.

I wonder if the dose is similar to the one used for leukemia. Like the rest of the chemotherapy tribe it has some rough side effects at that dose.

It's not. The standard dose for chemo is either 300mg or 400mg 2X/day. The dosage for this trial was either 150mg or 300mg once per day. This is the reason there have been much less side effects than with chemo use.

Seems like a long time to extend testing on already approved drugs if trials are positive. In the case of Nilotinib doses are much lower for PD patients. Not sure what hoops have to be jumped through to fast tract these approved drugs. First at least in the case of Nilotinib we have to wait for official published results and hope they compare to the unofficial results I was told. And I agree with ST that a lot can go wrong especially, in this case , the funding. STill I'm staying upbeat about this drug. I have to believe something out there is going to work for us to keep me going.
All the best to everyone.

It does seem like a long time. I was just comparing it to the FDA requirements for the more advanced trial of Isradipine, which is also approve; has been on the market much longer; and as a hypertension drug, is much safer than nilotinib, which is a chemotherapy drug.

I asked about side effects associated with Nilotinib the first time this trial was mentioned to me. As soon as I heard it was a chemo drug I asked about hair loss. I was told that this drug doesn't kill cells it "mops up or cleans" up cells so hair loss shouldn't be a problem especially at the lower doses given during this trial. The neurologist told me they have about a 1% patient population experiencing hair loss. During the current trial when I asked about side effects I was told that in the 10 patients the main side effect they were seeing was agitation which occurs when too much dopamine is on board. This lead to a reduction in Parkinson medications in the affected patients. I just hope all this continues over the next three months and the official published report is as encouraging as this unofficial report.
This is the only encouraging news I've heard lately concerning this disease and what is keeping me going. Just wanted to share some good news with everyone I'm as desperate as the next person for a cure or at the least stopping disease progression. We can all just hope and pray the end official report is as encouraging as the unofficial report I've been given. So far so good.
All the best to everyone.

Mechanism of Nilotinib (animal study)
 

Use of Nilotinib Cancer Drug for Treatment of Parkinson’s, Alzheimer’s, Dementia

Hum. Mol. Genet. (2013)doi: 10.1093/hmg/ddt192 First published online: May 10, 2013

Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models

Michaeline L. Hebron†, Irina Lonskaya† and Charbel E.-H. Moussa
Abstract

Parkinson’s disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of α-synuclein. The tyrosine kinase Abl is activated in neurodegeneration.Here, we show that lentiviral expression of α-synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases α-synuclein levels, in agreement with Abl activation in PD brains.

Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and ameliorates autophagic clearance of α-synuclein in transgenic and lentiviral gene transfer models. Subcellular fractionation shows accumulation of α-synuclein and hyper-phosphorylated Tau (p-Tau) in autophagic vacuoles in α-synuclein expressing brains, but nilotinib enhances protein deposition into the lysosomes.

Nilotinib is used for adult leukemia treatment and it enters the brain within US Food and Drug Administration approved doses, leading to autophagic degradation of α-synuclein, protection of SN neurons and amelioration of motor performance.

These data suggest that nilotinib may be a therapeutic strategy to degrade α-synuclein in PD and other α-synucleinopathies.
[Show]
Citation

Girija mentions tyrosine kinase inhibitors.

If we assume that:
- tyrosine kinase inhibitors are an effective treatment for PD.
- any commercial drugs will take at least five years to get to market and even then be too expensive for many.

Then it make sense to see if there are any natural substances with this property.

A quick Google gives:

- curcumin;

- genistein (found in broad (fava) beans, soybeans, coffee, kudzu).

Rick mentioned genistein back in 2012:
http://neurotalk.psychcentral.com/sh...ight=genistein

A quick sanity check:

- epidemiological results suggest that coffee consumption is negatively associated with PD.

- genistein crosses the BBB.

John

Further tyrosine kinase inhibitors activate AMPK which initiates autophagy so
gynostemma tea should help PWP!

As researchers continue to unravel the mysteries of AMPK, they have discovered four ways to boost the body’s AMPK activity:

Exercise: AMPK activity increases with regular vigorous exercise.73 This beneficial effect of exercise on AMPK, however, may vanish in the elderly.5
Calorie Restriction: When you under eat, you create increased AMPK activity as cells sense a requirement to function more efficiently in the presence of diminished energy (food) intake. However, when normal food intake resumes, AMPK activity declines.74,75
Metformin: One of the drug metformin’s most beneficial mechanisms is to activate AMPK.76 This is one way it lowers elevated glucose.77 Unfortunately, most physicians only prescribe metformin for type II diabetes, making access to this drug difficult for most people. Some people also experience digestive upset in response to metformin and cannot take it.78
Botanical Extracts: Two natural agents (the Chinese herb Gynostemma pentaphyllum79 and trans -tiliroside derived from rose hips80) have been shown to activate AMPK. Each of these agents triggers different downstream metabolic benefits, and in one study, trans-tiliroside led to an even greater glucose-lowering effect than the AMPK-activating antidiabetic drug metformin.81

With these four documented methods of boosting AMPK signaling, there is no reason for aging humans to suffer the degenerative impact caused by loss of activated AMPK.

As Gynostemma is a blood thinner be sure to talk with your MD before taking this herb.

http://www.lef.org/Magazine/2014/SS/AMPK/Page-01?p=1

Nilotinib and Parkinson
 

Since the formal report was released in Oct. 2015, the result was promising.

How about the Nilotinib tiral ii ? Does anyone kindly konw?

sami, I saw the brief abstract released at the Neuroscience conference in Chicago last Oct. However, I haven't yet seen the full report. Do you have a link to an actual published report?

I have an appointment at Georgetown Medstar UH, January 20. I'll ask about the trial but my neurologist isn't working directly with the trial and couldn't give me much information at my last visit the end of October. The doctor that was seeing me and working directly with the trial has left Georgetown and is now at the NIH. She was at GT on a fellowship. So I've lost my inside source but will see what, if anything I can find out this next appointment.

Phase ll Nilotinib Trial
 

My last appointment at Georgetown Medstar movement disorder clinic I got some Information about the second phase of the Nilotinib trial. It's scheduled to start this summer and has funding. The funding is coming from foundations not Novartis. However Novartis is being approached to give the medications used in the trial. At the present time the trial will be testing the drug on stage l and stage ll PDers. It involves a lot of planning so my neuro said it could be delayed but he emphasized the funding was there. I don't know anything about the placebo group and how that will be handled. I go back again in March and he said he would give me all the current information he has on the trial at that time.
This is all I have at this time but will keep you posted about any information I'm told at my appointments. I'll ask about the placebo groups next visit.

Michael Fox and Partners plan to Start Nilotinib Study in 2017
 

Michael Fox and Partners plan to Start Nilotinib Study in 2017!

Parkinson's Disease | Nilotinib Update: Where We Stand with a Cancer Drug for Parkinson’s

The Georgetown study results have finally been published.

Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies - IOS Press (link is at the bottom of the abstract)

Patent expiration dates:

July 4, 2023
✓
Patent use: A METHOD FOR THE TREATMENT OF LEUKEMIAS
✓
Drug substance
✓
Drug product
Generic Tasigna Availability - Drugs.com

Here is the Parkinson's patent application:

TREATING NEURAL DISEASE WITH TYROSINE KINASE INHIBITORS - GEORGETOWN UNIVERSITY

Keep in mind that these prices are for the CML dosage. The dosages that will be tested for PD are less, about a third of the amount. Also, there may be as many as 10 times more people with PD than CML. The larger market should allow Novartis to lower overall pricing, and certainly would position the insurance companies to force it. Finally, there is also some research going on now testing the drug for Alzheimer's, which, if successful, would widen the market dramatically.

In any case, we still have a long way to go before this gets an approval. Reading the actual study results leaves me at about a 50/50 chance. There definitely was some improvement with the volunteers, albeit it could be attributed to placebo. Some of the blood measure improvements may be harder to attribute to placebo. Unfortunately, it just wasn't that good of a study to draw many conclusions. My biggest concern is actually how fast the improvement came on, and then how fast it disappeared when the treatments stopped. This, along with the evidence of increased dopamine in the patients, leads me to think that the drug may have had a symptomatic impact, but not necessarily an interventional one. If that's the case, we may not want to take a somewhat dangerous cancer drug for the rest of our lives if only for symptomatic relief and not for slowing or halting progression.

It definitely will be interesting to see what more vigorous, controlled, trials will show. Particularly when the volunteers are early and mid-stage rather than the later-stage patients in the reported study

Great points Tupelo. The patent for use of Nilotinib for Parkinson's apparently was just allowed July 1, 2016 and shows use for Parkinson's, Huntington's, Alzheimer's etc. So it seems like there is a great opportunity for the owner to make a good $ which may mean that if this drug is viable it will be pushed through the system quickly! Sure Hope so!

TREATING NEURAL DISEASE WITH TYROSINE KINASE INHIBITORS - GEORGETOWN UNIVERSITY

More info nilotinib ...
 

MJFF posted a blog yesterday on nilotinib and where the research stands on its use in Parkinson’s. The blog also discusses MJFF’s collaboration with the Van Andel Research Institute and Cure Parkinson’s Trust to advance the research and understanding of nilotinib.

MJFF is hosting a webinar to discuss nilotinib and answer questions on Tuesday, August 2 at 12 p.m. ET. You can register here.

Debi

Curcumin reduces alpha-synuclein
 

Another clinical trial. Not great news for someone 13 years into PD and needs a caretaker. If I had PD, I would be taking 2 grams of curcumin daily until or if they ever come up with something a lot better than Sinemet.

Curcumin reduces alpha-synuclein induced cytotoxicity in Parkinson's disease cell model. - PubMed - NCBI

Here we show that curcumin can alleviate alphaS-induced toxicity, reduce ROS levels and protect cells against apoptosis. We also show that both intracellular overexpression of alphaS and extracellular addition of oligomeric alphaS increase ROS which induces apoptosis, suggesting that aggregated alphaS may induce similar toxic effects whether it is generated intra- or extracellulary.

http://www.hindawi.com/journals/ijcb/2012/683097/

Curcumin-glucoside, A Novel Synthetic Derivative of Curcumin, Inhibits α-Synuclein Oligomer Formation: Relevance to Parkinson's Disease (PDF Download Available)

fyi
Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD) & Prodromal PD

Georgetown Nilotinib trial scheduled tentatively for Fall.
 

My last neurology appointment in the Movement Disorder's clinic at Georgetown (GT) was within the last week. My neurologist, Dr. Bahroo, said the Nilotinib trial has been held up by the FDA as they scrutinize the data from the last trial. There is funding; he was positive about that. They are aiming for Fall but he said don't be surprised if it gets pushed to Winter. The hold up is the FDA. November is my next appointment I'll get an update then, if I don't hear from them before.

From what I'm reading it looks like there maybe two trials for Nilotinib.....GT and MJFF. More participants, more locations, more results could be good. I've been asked if I'm going to be in the GT trial. Dr. Bahroo has submitted my name and I will be contacted once they get things moving. Then I have to be screened and qualify, like everyone else. I was reading the trial results, posted by Tupelo (thank you) and there were any number of conditions that could keep someone out of the trial. Then there are those spinal taps that make me nervous (never had one) but PD makes me more nervous.

Now on to the price of Tasigna, brand name for Nilotinib. I called the Canadian pharmacy I use when I hit the Medicare gap. The price of Tasigna 150mg, 120 count, $4,539.39, approx $38.00/pill. A lot better than U.S. $10,000+++. Plus there is a referral plan that reduces the price further. I can give my pharmacy number to someone and they get a 25% discount on their first order and I get 5% credit to my account. Then people can refer others and get the credits for themselves. The pharmacy has everything written for the plan.

I'll let the forum know if I hear anything from GT before my November appointment.

Everyone take care and stay well.

Betsy