Those of you who are following clinical trials for repurposed drugs that offer potential to slow or halt the progression of PD will no doubt recall the highly favorable reports from the Phase I trial of Nilotinib that was done at Georgetown University and was reported on in October of 2015. You will also likely remember the ensuing flap that occured between GU and MJFF's CEO Todd Sherer over the fact that the trial had no Placebo, was small, was not double blinded. Determined to "separate Hope from Hype" (or Hype from Hope), I forget the details . . MJFF decided to fund their own Phase II Trial and Georgetown has done their own Phase II trial independently. Two precious years elapsed before the two trials were started.
I am a trial participant (#71) for the GU trial and just returned from Wash D.C. yesterday. All participants have completed the first year and 3 month washout and are now taking Nilotinib. The entire research team, left Friday for Nice, France for the annual International Congress of Parkinson's Disease and Movement Disorders conference which is being held (next week). I understand they will be reporting the information below (which I got from material published about the conference by the conference organization).
It is quite promising. I believe that everyone of our group of 75 has elected to continue on 150 / 300 MG of the drug for another year. It would appear (to us) that the drug is slowing (halting ?) the progression of symptoms.
- - - - - - - - - - - - Reported Information from conference material - - - - - -
LBA 15 Nilotinib safety and clinical effects on "ON" disability in Parkinson's disease patients F. Pagan, M. Hebron, B. Wilmarth, Y. Torres-Yaghi, A. Lawler, E. Mundel, N. Yusuf, N. Starr, M. Anjum, J. Arellano, H. Howard, W. Shi, S. Mulki, T. Kurd-Misto, S. Matar, X. Liu, J. Ahn, C. Moussa (Washington, DC, USA)
Objective: This study evaluated Nilotinib effects on top of the clinical standard of care at 6 and 12 months. Background: Parkinson’s disease (PD) involves motor and non-motor symptoms and loss of brain dopamine neurons. Nilotinib is a brain-penetrant tyrosine kinase inhibitor that may alter brain dopamine metabolism.
Method: A phase II randomized, double-blind, placebo-controlled evaluation of the impact of Nilotinib on safety, tolerability and clinical effects in PD. Seventy-five mid-stage PD participants (H&Y 2.5-3) were randomized 1:1:1 into placebo, 150mg or 300mg Nilotinib once daily for 12 months.
Results: Participants well-tolerated Nilotinib and no hematological, hepatic and other systems disorders were observed. Cardiovascular events were seen in all groups. Prior to randomization all participants were stabilized on either Levodopa and/or dopamine agonists and were tested ON time. As expected, all 3 groups were stable at 6 months, indicating the effects of PD medications. However, the placebo group significantly declined on UPDRS II (2.39 points, p=0.007), total UPDRS I-III (4.78 points, p=0.031) and UPDRS I-IV (4.47 points, p=0.038) at 6-12 months but Nilotinib groups remained stable. Similarly, all groups were stable on PDQ39 SI and the emotional well-being subscale at 6 months but the placebo group significantly declined (8.17 points, p=0.001 and 1.7 points, p=0.03, respectively) at 6-12 months, while Nilotinib groups remained stable.
Conclusion: Nilotinib is well tolerated and appears to be safe in PD patients. Nilotinib appears to stop the decline in motor and non-motor functions when the effects of PD medications wear off six months after treatment. Nilotinib may have a significant impact on the care and management of PD patients, leading to delay or elimination of dose adjustment, thus avoiding various side effects associated with PD medications.
PLEASE, IF YOU ARE CURRENTLY IN EITHER THE FOX OR GU TRIAL (OR CURRENTLY ARE TAKING NILOTINIB INDEPENDENTLY, WOULD YOU PRIVATE MESSAGE ME YOUR EMAIL SO WE CAN SHARE FUTURE INFORMATION. ALSO MY EMAIL IS frank.mundo@gmail.com
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FMundo
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Glad to be a participant (even though I just learned I've been in the "placebo group" for the last 15 months (and my deterioration during that time has helped show the effectiveness of Nilotinib. Never-the-less, I am on the drug now, no side effects.
How long before FDA approval? Will neurologists/MDSs be willing to prescribe it? Thank you!
It takes people like you, Marc, and WinnieThePoo, willing to participate in clinical trials for the benefit of thousands of PwP. For that, we are grateful!!
I really have no idea how long it will take to become FDA approved. The average time for repurposed drugs is 6.5 years for repurposed drugs, 10-15 years fir :from scratch. Nilotinib has been FDA approved for Leukemia since 2007, has been used with thousands of patients for long periods of time, thus falling in former category. However there are risks (cardio-vascular) and EKG's and blood tests must accompany initial use. Getting a prescription from an MD is legal now (off label prescription). I did that and also purchased the product. With product in hand and reading the 'black box" warnings I decided that I might be better served having physicians with experience at hand, especially considering the fact that only 11 PwP's had taken the drug in Phase I.
Hello, has the research of Nilotinib ceased? I read it does not penetrate the brain well but wouldn't they have assessed that prior to phase 2? Cardiovascular problems with it? Thank you
Mjff and Cpt have stopped but Georgetown want to push forward. Both trials failed due to poor brain penetration. Seems stupid to waste more money on another trial.
I suspect that they are referring to "palpitations" or minor chest pain. This was inquired about at monthly clinical visits. EKG's were taken, blood extracted and a cerebral punch or two (whether you wanted one or not).
During the Phase I trial one person had a heart attack, which apparently was due to an undetected pre-existing condition. The EKG is monitoted closely with focus on your QTi which has to be within a certain range. There are cardio-vascular concerns with this drug that may disqualify it for some people.
GU staff report that the 150mg group are doing the best of the three groups. A lower dose seems most desireable, based on trial results.
I know of one case where insurance picked up the tab (including the co-pay). Keep in mind that we pay three or four times the cost paid in other countries.
My husband’s neurologist is/was in Nice for the conference. I look forward to asking him about it. He is very “switched on”. Thank you for your report. We all live in hope.
One 150mg capsule a day taken 1 hour before eating or two hours after. The dose is 25% or less that given to CML (Leukemia) patients. People I have known who are taking Nilotinib have significantly reduced their use of dopamine replacement drugs. Trial participants are asked to keep their use of these drugs as they were before starting the trial. It is my understanding that more dopamine is produced by your neurons when you take nilotinib.
I share your sentiments for Big Pharma. We have one of the "best governments that money can buy." You can buy drugs in Canada.... but only three months worth. Wonder where that law came from?
" It is my understanding that more dopamine is produced by your neurons when you take nilotinib...."
Unfortunately no. More dopamine is not produced by this drug. The mice model study suggested that it was "protective" of existing neurons, i.e., as a c-Abl inhibitor, nilotinib, protects dopaminergic neurons (in mice).
However, we also know that over time degradation of signaling mechanisms and dopaminegeric neurons also takes place in the human brain. Therefore, the real question becomes whether or not nilotinib can slow that process down for most PD patients if given early enough...and over a significant period of time.
Let's hope they jump to a head to head Phase 3 with all c-Abl inhibitors. Doubt it. It would be too progressive to think that far out of the narrow CT box.
FMundo said: "People I have known who are taking Nilotinib have significantly reduced their use of dopamine replacement drugs."
sharoncrayn said: "More dopamine is not produced by [taking] this drug."
My recollection is that nilotinib provides a boost to the autophagy process, thus helping the dopaminergic neurons to dispose of alpha synuclein. It seems to me that more-healthy neurons could well produce more dopamine.
Thanks for your comment, but you are not addressing his quote that is relevant to my post. Here is his quote that I addressed in case you forgot:
..." It is my understanding that more dopamine is produced by your neurons when you take nilotinib...."
Your quote from him is a purely subjective assessment by him which doesn't address the real issue. He has the right certainly to post post subjective assessments from his or other's personal observations. But I addressed something very specific.
Just be careful about drawing your own conclusions and expanding them into a unverifiable theory. We have an overabundance of theories about PD. Basing your theory on whether or not it disposes of a-synuclein is a stretch. How much for how long? Anyone's guess.
Instead of being antagonistic, read the mice study. I am simply repeating their conclusion, which I find reasonable given the parameters of the study and their use of the drug.
The drug was protective; not generative. Nothing suggests otherwise.
I have no qualms stating I have no theories about PD.
Sorry I responded to your comment. I'll know better next time.
Here is information dated August, 2015 "Nilotinib adverse events in CML population"
Nilotinib AEs (adverse events) in CML population:
The percentages below were taken from a randomized trial of nilotinib 300mg BID in newly diagnosed Ph+ CML
patients (N=279)—taken from the Tasigna 2017 package insert.
The most common (>10%) non-hematologic adverse drug reactions were rash, pruritis, headache, nausea,fatigue, alopecia, myalgia, and upper abdominal pain.
and asthenia were observed less commonly (≤10% and>5%). These have been of mild to moderate severity, manageable and generally did not require dose reduction.
The most common hematologic adverse drug reactions (all grades) were myelosuppression including:
thrombocytopenia (18%), neutropenia (15%) and anemia (8%).
QTc prolongation:
- Increase in QTc greater than 60msec from baseline was observed in 1 participant (0.4%)
- No participants had an absolute QTc of greater than 500msec while on study drug
Cardiac and Arterial Vascular Occlusive Events occurred in 9.3%:
The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the
possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
My comments: It would appear to me (as a layman) the most troubling issue here is
"Cardiac and Arterial Vascular Occlusive Events occurred in 9.3%." To this I add the fact that the dosage recommended by GU as ideal is 25% to 50% of that given to CML patients. Consider that with the fact that 100% of PD patients suffer with declining life quality and eventually expire from complications brought on by Parkinson's.
Should neurologists, consider enabling their patients to slow or stop the progression of PD by prescribing Tasigna for their patients (who wish to assume the risks for above - with monthly EKG's and blood test monitoring)?
If we wait ten years for FDA approval of nilotinib many of the readers here will be pushing up daisies.
That sudden death quote was a little surprising to see, well maybe shocking might be a better word if I understood what they were saying correctly. I'm not sure I got the math right, but are they saying that 17 people died from Nilotinib? I must have figured that incorrectly!
16,98 call it 17. That's how I read it. I'd say those are pretty good odds wouldn't you?
An important factor not taken into account by judging outcomes using CML patient data is the fact that I'll bet that people who have PD are, as a group, considerably older and probably more fragile than those who have CML. They often have complications, respiratory problems and orthostatic hypertension).
We should be cautious in making too many inferences from CML patients because the autonomic system is, in many cases not working optimally for PD patients. Blood pressure can be low. It may be that people with moderate or advanced PD should not take Tasigna. I don't know, I'm not a doctor.
I will note, however, that the Phase I participants were much more advanced with their PD ( I think there was one person at Stage 3, the rest were 4 & 5.
The Phase II participants (were 2.5 to 3.0) in the GU trial. I gauge myself to be 2.0, one of the healthiest of the bunch. That said, there was "improvement" in all participants of Phase I (with one noteable exception). He had a heart attack. The report of the improvements for Phase I trial was so over the top . . . that I have refrained from even mentioning the results for fear of sturring up controversy once again.
I get your point , Frank, about the context being meaningful.
About your point on the odds, I understand what you are saying and possibly meaningful also, unless you happen to be in the group of 17 who died! It is a tough situation in my mind because I am a proponent of the use of supplements and if any supplement is proven to have killed less than 10 people, we will not likely ever see that supplement for sale again. Point of view and perspective can change how two people view the same thing. On the one hand there is the potential benefit weighted against the potential risk and on the other hand there is the very strong desire to obtain the benefits. For me it would be a tough call based on the risk to benefit. For you it seems as though the risk is worth the potential benefit. Another important point is that I do not have PD and can not truly understand what is going on in your head. I can only imagine, which is clearly not the same as being you.
A realistic appraisal of PD research is like walking through a field full of quicksand. Pick where you want to put your next foot step very carefully because most of it is a fantasy full of funding dreams which you never here about five years hence.
10 years from the last PD approval by the FDA should tell you a little something, if you care to take the rose colored glasses off. Is it the FDA's total fault?
Since you were in the placebo group, but did not know it until the end, during the study period, did you feel anything that you would describe as a placebo effect?
At the end of the Washout period a neurologist I'd never seen before came in to my room an said, " I'm going to unblind you and tell you which group you were in. But first I'd like to ask you a few questions:
1. Do you think you were on the trial drug or in the placebo group?
2. How did you feel during the trial period (first 12 months), during the washout period? and now when you are on the nilotinib drug?
3. What did you like about the trial? and not like ?
4. What recommendations would you make about future clinical trials [assumed for this drug].
Here are my answers given before knowing whether I was on the drug or not . . .
1. Honestly I don't know. At one point I told the nurse that I thought I wasn't getting the drug (and she said to me "everybody thinks that."
2. During the trial period I noticed very little advancement of symptoms. However, since the beginning of the washout period I've noticed a significant advancement of symptoms (I described them) Since I have no idea whether I'm on the real drug or not, I've decided that they are due to either, a) the real drug has stopped or b) I happen to be at the end of the "honeymoon period" (May is exactly 5 years since I was diagnosed).
I went on to discuss what I liked about the trial - the staff was very professional, and the advice I got in terms of explaining symptoms and recommendations of meds was "orders of magnitude better than I got from my regular neurologists. What I didn't like was the fact that there was no coverage [in the Consent Agreement] for "bad outcomes" and that there was no incentives for patients (stakeholders too!) of the 4 stakeholder groups. No plan for provision of drugs (if test successful) for those of us who have "risked life and limb".
In terms of recommendations for the future: You guys have wasted two precious years getting Phase II going, which was a repair on Phase I. Phase I trials (for PD) should always include a placebo group and be blinded. The reason is "what you think (positively) can effect dopamine production, for one thing. As I see it, you could/should have skipped Phase I altogether.
I'm afraid my neurologist got a tad more than he bargained for. We had a very pleasant conversation. He told me I was in the placebo group.... and I didn't even get angry. Didn't mention my 15 soon more trips from Phoenix or Maine and 66 travel days to DC.
What are your thoughts (about the placebo effect in my case?) I am definitely a glass half full guy.
It is really great to have a look inside of what goes on in these studies. For me this is a first and so I am trying to grab as much information as possible so from that point of view, you are the inside man with the information.
As far as the placebo effect and you, I have little doubt that you experienced it and I am a firm believer in just how powerful that can be. As a very simple example, I would suggest going on Amazon and looking at reviews of colloidal silver (CS) products. You will consistently find people claiming they were cured of this that and the other thing using only a tablespoon or less of colloidal silver. That is scientifically not possible because it is already known exactly what the minimum amount of CS in the blood stream is in order to start seeing actual neutralizing of pathogens and one tablespoon is nowhere near enough to come close to that level. I am not saying this because I am anti-CS, on the contrary, I am a firm believer in it and all it can do, but there is just no way those tiny doses are going to work and that to me shows how powerful the placebo effect can be. I think it may partially be because it is colloidal silver and some people mistakenly believe it is more powerful than it is because the product labels recommend these ridiculously low amounts prompting users to "believe" that a tablespoon is all that is needed. Like these CS users, I think you were well aware going into the study that Nilotinib was very likely to offer benefit for PWPs and I think that in a sense, that fact primes your mind to expect a certain outcome and then you mentioned that you thought you were not in the real drug group, but possibly everyone wants to believe they are in the active group, at least subconsciously and that may be all that was required under the circumstances to activate a placebo response in you. All just speculation on my part, but that is what I would think in your case.
Given that the placebo response is so strong and can be so effective, perhaps it would be more useful for scientists and researchers to spend their efforts on trying to determine how to trigger the placebo effect/response and create a true cure all! Well, one can dare to dream can't they!
In any case, it is good to see a study from the participants point of view as opposed to a cold study that rarely if ever discusses patients feelings and thinking.
I meant to say "half empty". I am a born pessimist and its a rare day that the sky isn't about to fall. However I have a hunch that we've got something here.
I so appreciate you posting about your experience...good or bad, information like this helps us all to make healthcare decisions in the future. Thank you for participating in the trials. You are a hero in my book.
Thanks for identifying the source I used in gathering info for my original post. This will be helpful to PwP's to give to their MD's. The Georgetown team mentioned something about being in late breaking section.
Great post Fmundo.
Not the full quid on clinical trials: what would a phase 3 trial look like?
Going to be very interesting to see if it continues to work for you medium to long term. Hope so!
Ecxuse me but although it has been presented in Nice, France for the annual International Congress of Parkinson's Disease and Movement Disorders, I don't find authoritative comments on this phase II trial, nor recent articles.
I collected about 40 items/articles pn Nilotinib Phase i trial including patent application of Moussa for use of drug for neurodegenerative diseases. Far to much time has elapsed since 2013 when testing of this promising drug started.
The trial is still runnimg. What is remarkable is how fast results are being reported, due in part to the fact that both Fox and GU are running trials at the same time, a race to the finish
Okay let's wait for it to be prescribed, but there is so much need for a solution that every slightest delay is incomprehensible to PD sufferers. An authoritative positive evaluation would help, but I see caution.
Certainly your right to wait a few years. I chose to take the drug now and try to stop the inevitable advancement of PD. Unlike some people who have taken the drug and claim reversal of symptoms, i am skeptical that this is possible. I am ever watchful. ...
Phase III trial for Nilotinib....? Well, MJFF and GU wasted two years , more interested in bickering with each other than getting on with Phase II after the successful Phase I.
A logical move in furthering research would be for Phase II Trial participants to be offered extension of time on the drug of additional years. This would mean offering drugs and monitoring tests.
One would think that those people and organizations that contributed time and money for the Phase II trials would have interest in doing this. Apparently this is not the case. Participants in the trial are all interested in continuing on the drug but are being dropped (after at 12 month extension) to fend for themselves (i.e. acquire the drug and organize testing).
Sharon is correct in describing CT's for Parkinson's as "walking thru a field of quicksand . . . ".
I think PD patients interested in taking nilotinib should plan to take it for the rest of their lives and make arrangements for acquiring the drug from alternative sources and/ or outside the U.S. In their spare time they should work to end the enormous disparity in drug pricing between the U.S. and all the other countries in the world. End the "America Last" situation: Price per 150mg capsule (needed daily) in US Dollars: Canada $37, India $9.80, U.S. $178.
And where is/are all the R&D and Clinical Trials are being done? . . .
Thanks for posting your experience at the nilotinib drug trial. But how can you very if the drugs from outside the US are not fake,especially from India,which you suggested above.Price is good though.
A very important question. Apparently there are labs that can do this. Send them a sample of the real thing and a shipment from your source. Payment for shipment would be held in escrow until lab confirms the drug as equivalent. My choice is to use contacts in medical field who can vouch for Pharmacy. India has an advanced medical system. I am interested in purchasing the legitimate product from Novartis.
I am skeptical about the price from India, which I am looking into further. With further investigation of Canadian pricing, its looking more like a cost around $27 a day which puts the cost a bit under 10K a year. When the research article is published in JAMA next month, I suspect interest will in nilotinib will go up considerably.
Thanks ,another question,does the trial include all phenotypes of PD?If so, was the drug effective in all the phenotypes? For instance,I am non tremor dominant,will it work for me?
As far as I know the selection criteria was H&Y 2.5 to 3.0 (down from more advanced in Phase I trial). No phenotype restrictions. Primarily the focus was double blind with placebo. The neuro tests were UPDRS and PDQ-39. Bio tests seemed to focus on speed and amount of drug making it thru to spinal fluid (in 1 to 4 hrs) for varying dosages, Primary researcher Dr. Moussa is focused on PD and Lewy Body Dementia - essentially has patent for use of nilotinib in "neurodegenerative diseases." Small test population and that goal shows interest at this point is not down to different types or genetic sources at this point
They are planning a Phase III trial, but as with all things, $$ is an issue. Because the Novartis patent is expiring soon (2023 I think), I suspect funds must come from foundations and donors, not the pharmaceutical company. Multi-site trial with many participants . . .
No, You meed to continue taking drugs that restore dopamine level. It appears that some people reduce the drugs by as much as 50%. Trial tesults indicate that over time drugs may not need to be increased as is needed for people who are not taking nilotinib.
MJJF provided top line description of their study at michaeljfox.org/publication... - "no observed clinical benefit or biological benefit seen" - hugely disappointing.
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