Nilotinib seen to be safe and tolerable, but study strictly excluded those with heart issues or other health challenges
No observed clinical benefit nor biological effect seen
c-Abl remains target of interest and research in Parkinson’s disease
NILO-PD steering committee has accelerated announcement of study results to keep Parkinson’s community informed.
Bummer.
How does one square these results with the Georgetown data? Maddening....
The Georgetown trial was a phase 1 without a control group. I reviewed what I could find at the time that result was announced. Perhaps I missed a properly organized report, but what I saw regarding that trial was sketchy.
Also, Michael J Fox foundation received some criticism for parting ways with the sponsor of that trial. It was my take on the situation that they that they had some problems with the sponsor's methodology. So regard those phase I results as tentative.
It doesn't. It proves there were flaws in the Georgetown study.
I spoke to Dr Yaghi (at Georgetown) about this and he said the initial protocol adopted by Fox was preliminary and they needed to modify it. He said the new protocol showed good positive results after a year.
RATS!
Kia, much thanks.
As we all know, the results of any trial do not apply to every participant. There was no benefit to the cohort as a whole, but was there some percent of the cohort that did benefit?
Maybe we'll find that out when they report in Miami.
You’re correct, there are times when drugs work for subgroups of the larger cohort. Those analyses have not yet been done, but they will be soon. However, I believe the key point of the results was not the lack of any indication of efficacy. It was the biological and pharmacological data. Nilotinib had very poor BBB penetration. Essentially, it doesn’t get into the brain, or, 99.5% doesn’t get into the brain. So, we really don’t know at this point if a c-aBl inhibitor is a viable treatment for PD. What we do know is that Nilotinib isn’t the right one. The good news is that there are several other c-aBl inhibitors going into trials that appear to have much better BBB penetration.
With regard to the GU trial, the biological results were actually pretty similar, less than 1% penetration. They just like to report differently. Like trying to come up with an explanation for why their lower dose cohort had better results than the higher dose (particularly when we know the biological results).
Gary
I just got off the phone with Jim (is this the one) and he is certain that when he was on the higher dose, he got more effect.
So it's possible that it does relieve me of constipation, i.e., it does penetrate neurons in the gut?
Interesting theory. It certainly does penetrate the neurons in the gut, where we know there are also a-syn clusters. Maybe......
Gary,
Do you know if it's true that PWP deteriorate more quickly when they discontinue Nilotinib?
Marc
I don't know if that is true. This trial didn't show any differences between the cohorts after the drug was stopped. It is common in many trials to see deterioration after the drug is stopped. It's the opposite of the placebo effect.
thank you.
Very unfortunate. My neurologist told me my results could be a placebo effect. Can anyone explain how I was able to lower my daily intake of L-dopa from 2,000 mg to 600-800 mg? Or explain my 15 hours between doses of Sinemet?
Park Bear, i heard from an insider, MJFF wanted more than Georgetown was willing to give. That ended the collaboration. As you may recall it was a very messy divorce.
Jim,
We have to watch for Georgetown's response to this news.
The other issue which I hope gets addressed is that both of us felt it took a few months for this stuff to kick in, in your case for 5 months.
Definitely within 5 months, more like 3 months. I waited another month before disclosure, because I wanted to be sure my results weren't transient.
As a member of the steering committee from the beginning, I can tell you that wasn’t the reason for the split. There were several issues, but they were mainly about protocol and design. GU likes to do research their own way and MJFF likes funding research designed differently. I personally don’t like trials of this importance to be single center with the lead investigators directly involved. We also offered to combine samples to make for a larger, more powerful, design, but were turned down. Finally, we will be making all of our data and biological samples available to others in the research community for analysis. I don’t think GU is offering to do that at this time, although they were asked to do so. We will keep working on that as I think it would be great to have independent eyes looking at the two trial results.
We need to hear from Georgetown. Remember there was far more than hurt feelings when MJFF and Georgetown went their separate ways. And don't forget Novartis (Tasigna patent holder for CML) and GU (Tasigna patent holder for PD).
Whilst it may be interesting to see further data, and I believe PD research needs to focus on a sub group methodology to recognise the disease has different manifestations, never underestimate the reality of placebo effects and coincidence. Placebo effects are not patients imagining benefits. They are also real physiological effects caused by the brain responding to the anticipation of a real treatment.
I have this disease (syndrome?). Only in it's early stages. I recognize the urgent need to tackle it and not be late to the party for a potential real benefit. But it is a confusing area, particularly regarding disease modification rather than symptomatic relief, and easy to jump on too many fruitless bandwagons.
If I read this right the trial that is mentioned here lasted only 6 months, did anyone else get that impression seems kinda short. How long does it take to realize benefits?
My understanding of the Nilo-PD trial was that the study was in 2 parts: first a 6 month assessment to check safety & tolerability and collect enough clinical/biomarker evidence to justify moving forward to the second part which would have been a longer 12 month study (clinicaltrials.gov/ct2/show.... From the press release it appears that while safe at the low dose used, nilotinib showed "no observed clinical benefit nor biological effect" in that first part so the steering committee decided not to press ahead. I also note that the original Georgetown pilot study was just 6 months long (clinicaltrials.gov/ct2/show....
Your understanding is correct. NILO was designed as a two-part study. Unfortunately, the results just did not support, in any way, a continuation to the second part of the trial. It sucks and I was quite disappointed. However, I’m not giving up hope on c-ABL inhibitors. There are at least three others right now, and possibly more, that will be studied, and they all appear to have greater bioavailability in the brain. Even if the trial was successful, Nilotinib was never likely to be a long term solution. Better inhibitors, designed specifically for neurological use, are already being tested. So, this trial showed it was safe for use, which was the primary purpose of the study. The lack of any indication of efficacy was more likely due to it’s bioavailability rather than an indication that c-ABL inhibitors aren’t a viable treatment.
Georgetown Phase 2 trial was for a year on, 3 months off (washout period). Double blind. Trial is just concluding. I don’t think results have been officially released.
Georgetown has reported the results of their Nilotinib clinical trial. They may interpret the data differently, however, the results really are quite similar to the Northwestern trial. I believe they are hopping to get support for a phase 3. I honestly think, though, that given the limited amount of research dollars available, the funds would be better used to research the other three c-abl inhibitors that are going into trial. They all have better neurological profiles than nilotinib.
Kinda wish I'd seen this thread some time ago. I was #71 in the GU Nilotinib trial, got the placebo for first 12 mos then Tasigna 150 for second. I am interested in corresponding with others who were participants in the trial. Please contact me. frank.mundo@gmail.com or private message me.
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