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"NTRP is a licensee..."
...with the right to re-license. If results are positive, a partner or outright buyer will determine how much they can make from the drug and then decide how much to pay to license or buy from NTRP.
"How much dilution will NTRP see before that happens.."
We'll have a much better idea in less than 6 weeks. Zero dilution is a distinct possibility.
Could be the golden type of egg.
Drug benefit vs side-effect:
A drug that reverses Alzheimer's (potentially Bryostatin) would be given a LOT of leeway in terms of side-effects.
Further >1800 patients on drug mostly in cancer trials, some for long-term, and most at much higher doses, is a large safety database to start from. So far, Bryostatin is very safe.
Revolutionary vs evolutionary:
CAR-T, a revolutionary treatment, can be a very harsh treatment for liquid cancers. But it's gone through FDA trials, proven to have better survival outcomes, and FDA approved.
I think the FDA is saying, yeah, every drug has side-effects, some worse than others, but we're willing to approve drugs that improve survival, some with severe side-effects, and let patients/doctors decide if the side-effects are worth it for survival.
Other regulatory bodies have different views on the subject. We work with the FDA, so we follow their rules.
My apologies.
But it's the only way to reply to non sequitur posts that are steeped in "ifs" and "maybes" and "Bryostatin may be a band-aid" and posts pointing to "failed trials that may work if they are only run the right way" and "gut microbiome" that has no applicability to Bryostatin trials and...
Here's a gross oversimplification, not backed up by any science: "Pretty simple - regrowth may not be maintained if the method of destruction is not dealt with."
I know...everything with Alzheimer's is "pretty simple", right?
Greater than $20B spent by MAJOR global pharmaceuticals trying to discover how to stop the progression of the disease, never mind reverse it. Must be "pretty simple".
As runncoach says: endogenous brain enzymes. Everybody has them. May be some genetic outliers, but this won't hamper a potential revolutionary treatment.
Good evidence that PKC-e is the master switch of these endogenous brain enzymes. We have treatment(s), including Bryostatin, that elevate PKC-e.
If results in less than 6 weeks are positive, NTRP will get a lucrative partnership (or buyout?).
Lucrative partnership should be worth at least a 10X market cap.
Lucrative partnership in AD should lead to more revolutionary trials in MS, Fragile-X, etc.
Yes, but so far no other drug has shown in placebo-controlled trials to help with the "method of destruction" in Alzheimer's.
"Pretty simple" is in theory only for all other drugs for now, until there is a placebo-controlled trial in Alzheimer's that proves it.
Further, we'll know within 5-6 weeks if NTRP's "band-aid" is a revolutionary treatment that has the potential to reverse the most significant underlying characteristic of Alzheimer's, namely synapse degradation.
Yeah right, regrowing synapses is only a band-aid. lol
Nothing in this article suggests Bryostatin will be a band-aid.
Thanks, doc. Very informative; appreciate your insights.
"Powdered, nasal?"
That's a real good question for the experts, lol.
Every type of delivery (IV, IM, SubQ, Oral, Respiratory, Transdermal, etc) has positives and negatives in terms of PK/PD of the active drug, convenience, side-effects, etc.
For now, I'm happy we don't have the added complexity in our trials of trying to determine if gut bacteria is having an effect on the uptake of our drug.
Adding on to this discussion, Red:
"Since it is not a pill, doesn't it avoid the gut?"
The real question is what is necessary for Bryostatin-1 to activate PKC-e in the brain, which is necessary to reverse the damage caused by Alzheimer's.
Bryostatin-1 via IV is NOT a prodrug formulation. This means it doesn't have to be metabolized in the liver (the primary site for drug metabolism) or the gut in order to work in the brain.
It fact, the intact macrolactone ring of Bryostatin is needed for good PKC binding activity.
So, IV (or IP, intraperitoneal) is currently the ideal delivery form for Bryostatin-1, since maximum bioavailability (100%) ensures more precise plasma levels, and ultimately ideal levels of Bryostatin in the brain after crossing the BBB.
For most drugs, oral formulations are done for convenience or for PK/PD characteristics such as long-acting. But this adds a layer of complexity in terms of metabolism, absorption and plasma levels of the active ingredient.
In summary, in its current delivery formulation (IV), gut bacteria is NOT necessary for Bryostatin to work. And liver metabolism isn't needed either.
As an aside, this doesn't mean that oral versions of Bryostatin won't work. It just means that by passing through the gut, it is more complex to get the intact macrolactone ring of Bryostatin into blood plasma and ultimately to the brain.
Whoopddew:
I agree 100%.
As backup on your statement ("It’s given iv it works iv imo big deal if oral never becomes available"):
Eisai and Biogen ran a trial in mild-to-moderate Alzheimer's in BAN2401, which is a MAB. Guess what? BAN2401 can only be dosed via IV: ("10 mg/kg biweekly (once every 2 weeks) administered as i.v. infusion.").
https://clinicaltrials.gov/ct2/show/NCT03887455?intr=BAN2401&rank=1
Further, Eisai is taking BAN2401 (IV infusion) in combination with another drug into clinical trials in patients who are clinically and cognitively normal (sub-threshold or elevated brain amyloid):
https://www.outsourcing-pharma.com/Article/2019/05/14/Two-new-Alzheimer-s-drugs-to-enter-clinical-trials
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So I guess it's okay for "large pharma" to run IV trials in mild-to-moderate and sub-threshold normal patients.
But hey, when a small company like Neurotrope tries to use IV in moderate-to-severe Alzheimer's, all sorts of red flags go off??
Give me a break.
"Sure, any drug can be metabolized in the liver after entering the bloodstream via IV (but doesn't NEED to be metabolized by the liver in order to work)."
Link please, to show me where I'm wrong in my statement above.
But, as I've stated a few times, this discussion of metabolism via "gut bacteria" (I hope it's obvious the original article means gut bacteria in the intestinal tract) is meaningless in the context of Bryostatin at this time, which is delivered via IV.
By your definition of "gut" (intestinal tract) in your original post on this subject, yes, you are interpreting the diagram incorrectly.
No, my statement is correct ("NTRP doesn't "need" the gut bacteria to metabolize properly. Many approved drugs are given IV. Apparently they didn't need the gut bacteria either.")
Sure, any drug can be metabolized in the liver after entering the bloodstream via IV (but doesn't need to be metabolized in order to work).
But I was using YOUR definition of "the GUT" (intestinal tract), so your reply is meaningless in the context of your original post on this subject:
Here is the title in your original post:
Scientists disentangle how human gut bacterial strains metabolize drugs
Unless you're suggesting that bacterial strains in the liver metabolize drugs??
That would be a very unhealthy, abnormal patient, and that type of patient probably wouldn't even be allowed in a clinical trial or study of intestinal tract bacteria, due to elevated liver enzymes.
So, I don't think the author of YOUR article was referring to bacterial strains in the LIVER. Do you?
"Since it is not a pill, doesn't it avoid the gut?"
Exactly, Red. Bryostatin is delivered by IV, avoids the gut, doesn't need gut bacteria to properly metabolize, crosses the BBB via the bloodstream, activates PKC-e as proven by compassionate-use patients and pre-specified non-memantine subgroup from last p2 that was highly statistically significant.
Further, one can infer from pre-clinicals that with the activation of PKC-e, the neural pathways of BDNF, NGF, etc. are engaged, and these pathways are the genesis of synaptic regrowth, neuronal protection, clearance of amyloid-beta and tau, etc.
"...does that mean that without gut bacteria to assist, drugs are not metabolized properly and some will not benefit from a druga as much as others?"
NTRP doesn't "need" the gut bacteria to metabolize properly. Many approved drugs are given IV. Apparently they didn't need the gut bacteria either.
"Does it mean possible overdose for patients with healthy gut microbiota if gut metabolism is low in the general trial population?"
Meaningless at this time for us.
You: "Yes, it's a small trial and may not catch the genetic outliers."
If it turns out NTRP has a drug that is going to revolutionize the treatment of Alzheimer's through the reversal of the disease, then catching the "genetic outliers" doesn't matter at this point. We'll need one P3 (6-month treatment) followed by a P4 post-marketing trial to CONFIRM no long-term detrimental side-effects. That's the FDA guidelines.
Alternatively, we could wait another 8-10 years of finding every last one of those pesky genetic outliers who may have a longer course of tummy ache or myalgias than the average patient, so we have to make sure they get exactly the right dose of Bryostatin based on their genetic makeup.
Because, with what we know of the side-effects of Bryostatin, based on over 1500 patient long-term safety database, you're asking every Alzheimer's patient to wait for precise dosing in order to make sure they get Pepto Bismol and/or Tylenol at the right time and in the right dose, or perhaps to slightly alter their Bryostatin dosing.
Ask all those Alzheimer's patients (or even more importantly, their care-givers) if they would prefer to wait 8-10 years to conclusively show proper dosing and sequencing of Pepto Bismol/Tylenol after receiving Bryostatin?
Seriously, side-effects of drugs will always be there. FDA decisions (and ultimately patient decisions to use a drug) weigh the benefit against the potential side-effects.
And if Bryostatin is a drug that can reverse Alzheimer's with low side-effects, I don't know a single Alzheimer's patient/care-giver that would say, "No, I don't want a tummy ache; I can live without my brain".
You: "That is precisely my point - they are following the classic trial regimen. The one that has given us a whole field of toxic CNS drugs."
The classic trial regimen has proven exceptionally good in the process of moving from more toxic, less effective drugs to less toxic, more effective drugs.
Take cancer. Used to be chemotherapy and radiation were the only treatments, but both have horrible side-effects. But at that time, those treatments were the only game in town and THOSE TREATMENTS SAVED LIVES in spite of the awful side-effects.
Fast-forward to today, and we now have revolutionary immunotherapy treatments, with fewer side-effects and better outcomes. And cyberknife radiosurgery, again with fewer side-effects and better outcomes.
The FDA "classic trial regimen" is working fine.
Hopefully it will lead to a revolutionary treatment for Alzheimer's, namely Bryostatin.
Doesn't have any effect on NTRP's data readout in less than 6 weeks.
Since we use IV, this research doesn't seem to have much applicability to what NTRP is doing at this time.
Interesting. Does that mean there is a significant advantage to IV or IM administration of drugs?
Don't have to worry what's in the gut and how drugs get metabolized by gut bacteria?
If positive results, I expect share price to increase dramatically and many of the warrants to be executed.
If positive results, I believe there will be a lucrative partnership within 3 months.
Baby steps. Can't expect patients to suddenly regain full capabilities after losing synapses and so much function over a dozen years or more. It's not going to be like some Hollywood movie ("Awakenings"), where every patient suddenly wakes up from a severe disease and is fully restored. Sure, there may be a few outliers that respond dramatically, but it won't be the norm.
If a 15 week course of Bryostatin can accomplish 8 SIB points improvement (or 6 or whatever), imagine what several courses will do, especially when including some occupational therapy to restore some function with those restored synapses.
Further, imagine giving courses of Bryostatin earlier in the disease, such that patients never decline from mild to moderate or from moderate to severe?
All excellent points, SFW.
Certainly no guarantees, but the preponderance of evidence is in favor of those who think there will be a positive outcome when the top-line data is released.
Here's the paper, linked by Cyosol I believe:
https://www.scribd.com/document/421260635/10-1016-j-tips-2019-07-008
You've been stating that it will fail, so what is your reason?
Good to see all shareholders have equal confidence in the results that will be released in the next 6 weeks.
FDA realizes SIB is the only game in town for this patient population, and since we’re trying to get approval with the FDA, might as well work with them.
SIB was also used for Donepezil and memantine in their trials, and data accepted as part of NDA.
Fixed it. Thanks.
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You say: "Thanks for confirming that NTRP is indeed a one trick pony hedging the entire company on trial results with a 99% failure rate due any day now."
No, based on the subgroup analysis from the previous trial, NTRP has a really good shot at success. Do you have a scientific or analytical reason why there is a 99% chance for NTRP to fail?
AVXL's trials? Shot-gun approach. What happens if both near-term trials (PDD and Rett) fail? CEO keeps getting paid obscene total compensation while waiting for the AD readout in 2021? Meanwhile, shareholders suffer until AD readout.
2nd one is not true. Wasn't post hoc analysis.
Untrue statement in #2 probably reflects on the accuracy of #1, #3 and #4.
You say: "Thanks for confirming that NTRP is indeed a one trick pony hedging the entire company on trial results with a 99% failure rate due any day now."
No, based on the subgroup analysis from the previous trial, NTRP has a really good shot at success. Do you have a scientific or analytical reason why there is a 99% chance for NTRP to fail?
AVXL's trial? Shot-gun approach. What happens if both near-term trials (PDD and Rett) fail? CEO keeps getting paid obscene total compensation while waiting for the AD readout in 2021? Meanwhile, shareholders suffer until AD readout.
"The CEO is getting options, not lots of cash."
Dilution by any other name is still dilution of shareholder equity. $20M (total compensation, cash and options) over 4 years to AVXL CEO is a LOT of dilution, especially when it's on top of treasury shares that are sold to keep the lights on and run trials.
NTRP warrants will only get exercised if NTRP is successful. And then it's cash in the bank for NTRP to use for the next indication (MS, Fragile-X)
"As I said - this stock doesn't look good for retail entry at market pricing. Too many insiders."
AVXL has one big insider, the CEO, who keeps getting handed piles of cash and options. OBSCENE
"AVXL has already started PLACEBO controlled trials for Retts and PDD, unlike NTRP the one trick pony."
AVXL's plan is to pay it's CEO $20M in total compensation over the past 4 years, while it dilutes the heck out of shareholders. Nice shareholder-friendly plan!
"What is NTRP's backup plan when ALZ trial results due any day now fail for a 2nd time?"
IMO NTRP has a really good shot at success:
- That success may be outright statistical significance, comparing on-drug group to placebo group.
- Or succeess in a highly significant subgroup analysis. But, if this is the case, NTRP won't wait 9 months (like last time) to report this. I believe it will be reported immediately when results are released by end of Q3. And, as learned at the AGM, the goal will then be to get Alzheimer's indication to the goal-line, probably with a significant partnership with a major biotech, especially since the Alzheimer's research groups at large companies are desperate for new ideas. NTRP's CEO doesn't have a shot-gun approach like the AVXL CEO. His goal is to get Bryostatin in AD to the goal-line, and then work on the next disease.
Why is this a good plan for NTRP? Using AVXL as a counterpoint, what if both Rett and PDD trials are failures? Then what? Wait 1.5 years for the AD trial to hopefully read out positively? Sounds like things could be miserable at AVXL for 1.5 years if both Rett and PDD fail, which is a distinct possibility since this is the first in-human trials for 2-73 in these diseases.
"Do another 1:32 stock split?"
Not going to happen. Plently of cash in the bank to get AD indication into the end-zone.
Precision dilution more accurately describes what is going on at AVXL.
$20M in total compensation given to the CEO over the past 4 years is OBSCENE.
A failed drug still has a MOA.
For instance, a drug validated with an MOA in pre-clinicals may be too toxic to be delivered in human trials at high enough doses to adequately activate the targeted receptor or can't reach the target (e.g. cross the BBB) or if delivered systemically the molecule may be degraded before it reaches it's target.
"Anavex works and the others didn't work."
TBD if it can deliver successful results in a double-blind placebo-controlled trial.
Apparently, the drug classification I was referring to (MOA) was different from your classification (chemistry).
Classifying drugs by MOA is valid.
Drugs can belong to multiple classifications.
"A drug class is a set of medications and other compounds that have similar chemical structures, the same mechanism of action, a related mode of action, and/or are used to treat the same disease. In several dominant drug classification systems, these four types of classifications form a hierarchy."
Technically, 2-73 belongs to both classes, S1 and M1, based on MOA.
As referenced by runncoach, S1 drugs have failed in trials and M1 drugs have failed in trials.
A failure in a drug in one class + a failure in a drug in another class has a good chance of failure when combined.
Nothing to do with the drug, but it has everything to do with how the company treats it's shareholders:
According to SEC filings, almost $20M in total compensation to ONE individual, the CEO of AVXL, using cash and options issued from the company (over the past 4 years).
No transaction with other individuals noted in the filings.
Obscene precision dilution by AVXL.
Anavex?
Correct me if I'm wrong, but isn't AVXL the company that had a total compensation package for their CEO of almost $20M over the past 4 years?
That's an OBSCENE compensation package for a CEO in a development-stage biotech. All development-stage bios need to raise precious cash, and that must hurt their shareholders to see such dilution (cash and shares) handed to their CEO.
Sounds like precision dilution to me.
Ah, well then, simple answer:
If there's no interim statistical analysis planned, then there will be no interim statistical analysis done. For the primary endpoint or for secondary endpoints (sleep).
Trials don't work that way.
DSMB's don't take it upon themselves to do more than they are asked to. If the interim look is for safety, then that is what they will look at. They will NOT spend 4 weeks gathering, scrubbing and statistically analyzing data, unless that is in the trial protocol. Since that hasn't been disclosed, it's a good assumption analysis of any primary or secondary endpoint won't happen.
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As far as timelines:
Why not ask your highly compensated CEO for a better timeline for Alzheimer's data release?
Last time I checked, his total compensation for 2016-2018 was $16.3M or > $5M/year
Surely for that kind of money AVXL shareholders deserve better?
Hysterical assumption:
"The data is there in the EHR, if 2/3 are sleeping better, 1/3 sleeping much better the only conclusion that could possibly be derived from that data is that the drug is working. You don't have to unblind."
I'll spell it out:
- 24M EHR's in Australia (total population)
- ~150,000 have AD (for argument sake)
- The 450 patients in the trial are a blip in terms of AD patients, so just looking at the 150,000 AD records, there won't be any "sleep signal"
- Therefore, healthcare worker (HW) has to WILLFULLY/ILLEGALLY peak into those specific 450 patients. How does HW do that? Search for 2-73? That only gets the 300 patients on-drug (not the placebo patients).
- Now comes the hard part. HW has to collect/scrub/analyze incomplete data on whatever percentage of patients have completed the trial, and make a decision if they think there is statistically significant data here. That's not as easy as it sounds.
- As we know, HW can't determine if this incomplete data is statistically significant unless we have the placebo data to compare to.
- Hopefully this is a smart HW who understands why on-drug data has to be statistically compared to placebo data because of that pesky placebo effect that can happen in up to 35% of patients.
- If the HW isn't smart, and they think they found a signal in 2-73 (based on what criteria??) and they ignore placebo and tells the company and the public, "Hey, Anavex has significant sleep data in it's 2-73 patients". Uh-oh, HW just set themselves up for a criminal and civil lawsuits. Revealing confidential company information (trial information) breaks SEC laws, and HW is also open to civil lawsuit from shareholders for breaking the blind and corrupting the trial.
- And the on-drug-only data revealed by HW isn't even valid, because statistical package hasn't been used to run against placebo.
- And now comes the REALLY complex part of this whacky scheme. If the HW IS smart, he/she will statistically compare on-drug to placebo, both the high dose and the medium dose. How to find the people who are not on drug? Maybe the healthcare worker decides to steal that info from company (crime) or maybe that info is in the EHR?
- HW then needs to find the statistical plan for this trial (might still be confidential, so should he/she steal (crime) that or ask the company for it, making the company complicit in the crime?).
- Finally, HW needs to get access to a statistical software package to run a proper statistical analysis (according to the company's statistical plan).
- Illegally accessed company-confidential EHR data (on-drug and placebo) as a rogue agent? Check
- Illegally accessed AVXL statistical plan? Possibly check
- Illegally break the blind and tell company/Australia Healthcare that a secondary endpoint (which probably isn't even good enough for approval) was met at a checkpoint that isn't even the primary endpoint? Check
Go directly to Jail. Do not pass go. Do not collect $200.
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The short answer is no rogue healthcare worker is going to illegally access/scrub/statistically analyze AVXL's company-confidential data.
It sounds good on paper, until you look at the details.
It'll be a long time before we get the AVXL AD data...almost 2 years, according to the CEO.
No, you're definitely wrong.
Here's the full quote for context:
Clayton Berger
"...So for the Alzheimer’s study, do you think the primary completion date still stands at December of 2020? And then do you believe that you will need to conduct a second Phase 3 trial for FDA approval on the Alzheimer’s study?"
Christopher Missling
"So the expected date is provided in ClinicalTrials.gov and I think that’s what you’re referring to. That’s all the estimate which, we don’t provide or confirm. It is point in time. But obviously, we want to finish a study as soon as possible. As I mentioned today in all our studies, they all are with the aim of before or done undertaking to finish it as soon as possible. But the question is, so we will provide an update on the timing when we have more granularity on the overall continuous enrollment, which is very good so far. So I would basically not provide a comment on the timing of the end of that study yet. Regarding the question of if a second study is needed. That’s also a question I would defer to once we are able to share the data with the FDA, with the agency and that determination is done by the agency. So it’s not something which we can anticipate at this point."
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Missling sure missed a good opportunity here to say that there would be an interim report on the phase 2 portion of the trial BEFORE March 31, 2021. Why didn't he? IMO, because he doesn't want to be pinned down to an interim release of the phase 2 data, in case it isn't good.
He could have clarified all of this for the investment community, but instead chose to be completely opaque about the data release.
When to expect a data release based on his comments? Use the only date etched in stone (FDA clinical trials website)...March 31, 2021...plus 10 weeks to scrub/evaluate data...June 7, 2021...1 year and 11 months from today.
Further, it would be foolish to halt a very expensive and important (to the company) phase 2/3 AD trial in the middle because a trial in another disease is successful. And there's no planned interim look for any of the primary or secondary endpoints, and some obscure secondary sleep endpoint isn't going to be evaluated early by a rogue healthcare worker in Australia.
June 7, 2021 for data release, until updated otherwise.