Georgetown University asked me to share the most recent paper on Nilotinib with you all.
onlinelibrary.wiley.com/doi...
I explained that some who were involved in earlier trials did not get great results. I believe they are sorry and feel they have a better grasp on the protocol now.
The end result according to the study report:"phase 2 study met its primary objective and showed that long‐term nilotinib treatment is safe and tolerated in patients with PD. Exploratory clinical outcomes support the evaluation of nilotinib 300 mg in a larger multicenter phase 3 study to determine its safety and efficacy in PD. This study is underpowered and was performed in a single center. The small number of patients in each treatment group prevents any meaningful analysis for multiple comparisons."
I am tired of reading this conclusion in numerous studies. It simply say no safety issues were found but to determine the efficiency large scale trials are needed. And then the chapter closes. I guess that if we gather the statistics, it can be easily proved that only small umber of trials proceed to phase3 and then at phase 3 it disappears (PD trials, not the other diseases).
"The small number of patients in each treatment group prevents any meaningful analysis for multiple comparisons." - This is what they say when the results don't go the way they want.
The MJF funded study on the same drug showed it doesn't work at the doses which are safe for humans.
The science and the target for the drug all look good but this drug is not the drug to hit this target. Everyone should move on.
onlinelibrary.wiley.com/doi...
For the first 15 months of the trial they tested placebo versus active treatment.
Referring to figure 3, during this period, there was no consistent difference between placebo versus treatment. This says to me there was no efficacy to treatment. It is true that during the 2nd 15 months, where they compared 2 different dosages in an open label trial, they got better results with the higher dosage, but this is inferior evidence as compared to the placebo-controlled trial.
Skin rash is a known adverse effect of nilotinib:
ncbi.nlm.nih.gov/pmc/articl...
" cutaneous adverse drug reactions occur in approximately 34.3% of patients receiving nilotinib". The Georgetown investigators say: "Other common AEs were skin lesions (24%–30%) attributed to local infections or healing wounds." Not buying it.
As I read the conflict of interest statement, both Pagan and Moussa are financially invested in Nilotinib success. Do others read it that way?
Yes and good point.
I'm not sure if Dr. Moussa will want to respond, but I will give him a chance. I will check back in a while if anyone else would like to comment. Or you also can send the comments to Mark.Antonucci@georgetown.edu Just be sure to say that they need to be forwarded to Dr. Moussa and that he can possibly reply to pmmargo@gmail.com (me) or directly on Health Unlocked if he wants to join. The url of the page is: healthunlocked.com/parkinso...
I may be wrong, but I think the drug is more complex than what is published in the studies, to wit, its consumption of CYP3A4.
I took Nilotinib for nearly 3 years and lived in fear that I was going to kill myself most of that time. My feeble understanding of the drug includes believing that it competes for the 3A4 (which our bodies do not fully replenish every day) and therefore it cannot be taken except on a empty stomach and the user must discontinue grapefruit juice and any other food or pharmaceutical that is a strong competitor for that enzyme (which perhaps half of all pharmaceuticals are) otherwise the N builds up to a toxic level. I made the doctors at the VA crazy because I was running back there for an EKG every few weeks worrying about my QTc interval. It did relieve me of constipation, but I'm relieved to be off it.
All of which is to say, shouldn't they also publish a list of all the restrictions necessary to administer this drug?
Nilotinib is metabolized by CYP3A4. CYP3A4 inhibitors, which as you point out are commonplace, increase Nilotinib plasma half-life. If a person also had to take a CYP3A4 inhibitor, in theory this could be compensated for by reducing the dose of Nilotinib.
It may be that substances referred to as CYP3A4 inhibitors may be merely using some of it up. I am not clear on that point.
If inhibiting it or using it up leaves less of it to metabolize N, then doesn't leave us with the same problem?
Yes, the issue could be resolved by reducing the dose of N, but then doesn't that defeat the benefit of N?
Regarding the first question, yes, same either way.
Regarding the 2nd question it seems to me that if one were to reduce the amount of Nilotinib chewed up by CYP3A4 and thereby needed to take less to end up with the desired plasma level, it is all good.
"I took Nilotinib for nearly 3 years and lived in fear that I was going to kill myself most of that time."
Another example of a "toxicity" drug that is being evaluated as a "repurpose" drug for PD for which it has no business being evaluated. It is essentially a CML (cancer) drug used when Imatinib (brought to CT evaluation in 1998) doesn't work.
Additional CYP3A4 inhibitors ( such as ketoconazole) plus Nilotinib are an issue since they increase systemic absorption at least 200% if not more but also dramatically increase side effects, especially QT (along with the inhibition of hERG) intervals (as MBA noted) and liver failure. One reason for this type of addition is the low bio-availability of Nilotinib by itself, but it comes at a significant cost.
CYP3A4 inhibitor drugs ARE NOT "commonplace" prescriptions unless someone is on those specific drugs for a reason ( cancer therapy).
In and of itself, Nilotinib is a competitive CYP3A4/5 inhibitor.
Sharon
Does anyone know if the participants were screened 1st for heart issues?
YES...page 21.3- Exclusion Criteria
1. Patients with hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥461 ms
2. Concomitant drugs known to prolong the QTc interval and history of any cardiovascular
disease, including myocardial infraction or cardiac failure, angina, arrhythmia
3. History or presence of cardiac conditions including:
a. Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable
angina, or stroke)
b. Congestive heart failure
c. First, second- or third-degree atrioventricular block, sick sinus syndrome, or other
serious cardiac rhythm disturbances
d. Any history of Torsade de Pointes
Interestingly, they considered grapefruit a "strong" (really?) CYP3A4 inhibitor, and its use was excluded, along with all inducers.
sharon
Sharon
Thank you for this.
It seems to me that when they published the results of the study, this is important enough that it should've been included because otherwise one might assume it was a random sample of the general population, but when we add together heart considerations and contraindications, that might exclude 50% of PWP?
MBA
outstanding! Way to go.
If we look at cancer drugs (like Nilotinib) in general, they are simply too toxic (far too many adverse events to be acceptable) for repurposing to the PD population. I really don'y understand why they didn't do extensive animal trials. Unacceptable with this drug ... even with its questionable FDA approval in 2007. Everyone knew this CYP3A4 genre had a very narrow application.
RELEVANT STATISTICS
Stat wise, CML cancer incidence is about 1.8-2.0/100,000 with a 5 yr survival of 70%, while PD incidence ranges by age, but is far greater even among those < 50 and greater than MS or ALS.
PD incidence was estimated at 572/100,000 > 45 years of age (less in females) in 2010. LB PD dementia (not PD itself) was associated with an definite increase in mortality. CVD living in an "urban" area plus LB PD dementia was the most common mortality comorbidity.
LB PD dementia was found dominant in all age/sex/race cohorts WITHIN 6 YEARS OF DIAGNOSIS (70% incidence). (However, in reality, PD diagnosis is often delayed by PwP.)
Beyond 6 years from diagnosis, my statistical assumption is that PD patients are at MUCH GREATER RISK (ESPECIALLY THOSE WITH LB PD DEMENTIA) with Covid-19 than those without PD or with just "common" diseases.
I hope this info helps some who fail to understand why Covid-19 precautions are especially necessary for PwP.
Sharon
No sorry, I did not understand the narrow context from which you extrapolate the general recommendation. Rather alarmist don't you think? I would say if you are old and have CVD (cardiovascular disease) and PD you are more likely to die if you contract the virus, like everyone else on equal terms, almost.
But maybe I didn't understand correctly 🤔🤔🤔
Gio,
I'm not sure I understand your comment.
"Narrow" refers to the limited utility of Nilotinib or any drug in that class of inhibitors. It is strictly for cancer therapy, specifically CML cancer, which is a very minor cancer relatively speaking.
In terms of "extrapolating" PD risk and Covid-19 infection, I used the results from the Medicare (US) massive data 2010 study (135,000 records). Specifically, I suggested if you have Lewy Body Dementia, (common to PD beyond 6 years), you should take extra precautions to protect yourself given that study because you are already at high risk without Covid-19 complications.
Was it "alarmist" to suggest taking extra precautions? Especially if you have LB Dementia which many PwP have? I don't think so given the Medicare data mortality results for CVD+urban living+LB Dementia after 6 years. It is only a suggestion. So take it or leave it. Your choice.
As for CVD mortality, it increases by age with or without Covid-19... 65% of CVD deaths in the US are in the >75 group (males).
In the Dan study (2020), they found 10% of Covid-19+CVD had a mortality rate of about 50%, and as high as 70% with Covid-19 and high troponin.
Unfortunately this study sample was < 200.
Data available for PD and covid-19:
"The study showed that the death rate from COVID-19 of those without PD was 5.5%, and was 21.3% for those with. However, these results had to be adjusted statistically because the group with PD were also significantly older than the group without PD and it is well known that age alone causes a dramatic increase in death."
Specifically out of 80,00 records, they found 700 were PwP (.00875%) . However, risk with PD was elevated even without considering CVD or LB dementia for the PD group. Is 700 a decent sample? Not ideal, but decent.
Death from Covid-19 versus all cause deaths in the >65 US age group is about 10% of all deaths (as of 11/25 via US CDC). 50,000,000 > 65 in US.
US Covid-19 (>65) therefore has a mortality rate of .00136%. So far.
Sharon
S
My comment was in reference to the virus.
now it's much better for me.
After all, having the PD for more than six years weakens the body and mind.
thanks
Gio
Gio:
to sum up....
#1 Mortality due to COVID-19 among people with PD correlates with more advanced diseases such as CVD and cancers.
#2 Motor and non-motor symptoms increased during the COVID-19 lockdowns in people with PD who did not contract COVID-19.
#3 People with PD who contracted COVID-19 generally had new or worsening motor and/or non-motor symptoms in the setting of their illness.
Use your own judgement.
sharon
"I believe they are sorry and feel they have a better grasp on the protocol now."
When one of "them" says it. This whole thing smells of pure convenience and crass at that. I've already identified a half-dozen scientific fly-by-night shortcuts and omissions that suggest coincidence can't explain what seems to be a commercial intent and compromises that responsible scientists and PI would never accumulate without a COI at influence. Certain omissions and coincidences betray a mindset that, by their stepwise sequence, can't logically include ignorance or naivete. There was a motive disclosed here to the critical, perhaps cynical eye. Sorry.
I appreciate your comments. I can ask that if Dr. Moussa is unable to respond that someone else on the team do so.
Seemingly similar in meaning, efficacy and effect-iveness express distinctly different concepts. A medical intervention is efficacious if it works under strictly controlled (laboratory) conditions and it is considered effective if it works under real life conditions. Efficacy (or fastidious) trials test for efficacy and effectiveness (pragmatic) studies for effectiveness of a therapy. Discussion continues over which of the two approaches are more valuable.
onlinelibrary.wiley.com/doi...
They won't. Assuredly. Any scientists can see what they did and they know what they did. No way they want to admit to something in writing or print that would carry any liability attached for knowing ahead of time how they breached appropriate conduct taking advantage of desperate naive people by creative omission, downplaying, things that any scientist would immediately know, including themselves. The last thing they're going to do is commit to anything with a witness or print. There's a very good reason this stuff was never allowed to go to Stage III, and it wasn't humanitarian interest to bring a treatment to market to people who needed one as soon as possible.
Every scientist and physician knows the difference between efficacious and effective. Without efficacious first, there is no possibility of effective. in fact that's why they do efficaciousness first. Failure of efficaciousness was clear and dictates that effectiveness studies or claims (and bringing to market) will be pointless. It's like asking, after the game is over and the winner has won, whether the loser will win. Makes no logical sense. Like climbing a ladder when there are no more rungs and thinking maybe your foot will take you higher. Like throwing money into a wood chipper and, seeing the result, thinking maybe we should throw some more in. It's that insane to anybody in the business. It's like a mechanic selling you a new wheel without mentioning that there is no axle. Being a mechanic, there is absolutely no way he doesn't know what he's just done to you.
As Thomas Harris once wrote, "When the rabbit screams the fox comes a runnin'... but not to help."
MJFF apparently agrees with your (and my) skepticism:
statnews.com/2016/08/30/par...
"Fox disavowed the Georgetown project."
Wow, this reads like one of those Sixty Minutes scandal wars, and for huge huge stakes.
On the other hand, it looks like there was nothing any intelligent participant couldn't anticipate...in which participants we would have to include Novartis, the drug is their patent and already out in substantial dose after all for cancer...and Novartis could easily have smelled the potential (these people play and succeed at chess daily and long term for a living...a very good living...). Well, Novartis does not need anyone's money help to fund a multi-site, legitimate large scale double blinded and validat-able study if they want to... that money can buy all the sites and subordinate science activity on its own, and pay well enough to outbid anyone else...plus Novartis already owns the patent.
So to me the question of convincing Novartis to donate the medication just doesn't make sense to me as a real factor, unless you also think Novartis is stupid and would just give away rights to a gold mine they are sitting on already. And given the revenue potential and Medicare political funding potential, why would Novartis want to wait on and beg someone else to give or loan them outside money for research while the patent is a-wasting? Makes more sense in the case of this potential blockbuster that Novartis would think "why wouldn't we keep everything in-house?" And since the drug is Novartis's own patented creation, supplying the drug at marginal cost would be less than zero to Novartis, leaving just the research to do, and funding the research would be child's play to Novartis...the potential return would make it much more lucrative to get on with the work rather than allow for delays and sharing in the licensing down the road...well, Novartis would need nobody, nobody, else to do OR pay for the research if the potential return is justified, so it seems logical they would move on on their own and thus keep all the business risks minimized and the return potential maximized. So why didn't they quietly just do so? (Actually we don't know that they haven't...competition business does not do well if you don't practice The Art of War, which means you very clearly must never let anyone on the other sides actually know what you are really doing until it is all over.) So who is to know whether Novartis views collaboration, and sharing, or competition, and not sharing, to be the most promising approach to their fiduciary corporate enterprise? And does anyone really think that Novartis wouldn't see all this scenario mix coming?
Ergo, skepticism. Or maybe, Novartis wants to keep it all for itself, and in that case, why would they telegraph any of their thinking? They have the deep pockets and the expertise and they already paid to develop the drug for cancer. I wouldn't want to share on a trillion dollars of profit either, not if I was a fiduciary. In fact, how do we know they haven't gone ahead and started their own big trials, under house cover and confidential contract to some centers or sources of patients around the globe already?
Still, to have this much fighting, now that much energy makes it all seem rather promising, don't you think? More so than the tiny little case study open trial...well, maybe it is time to become more hopeful...maybe it is time to buy a few shares of Novartis, by the time the drug is proved out we'll have the money to pay for the treatment.
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