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NTRP has very compelling trials/science in Alzheimer's, which has no drugs that can reverse the symptoms. NTRP has a good shot at changing that.
As far as I can see, you haven't offered any compelling insights on the debate of the science of NTRP.
I've seen this quote from another IHub poster (DewDiligence), and I think it captures the essence of market inefficiencies in specific stocks:
“The efficient-market hypothesis may be the foremost piece of B.S. ever promulgated in any area of human knowledge!”
Thank goodness the price of stocks are inefficient; creates situations where owning once-in-a-lifetime stocks is possible. NTRP may be one of them.
10 days sounds about right for the clearance to small amounts of memantine in the blood.
The half-life of Memantine is 60-80 hours. It usually takes 5 cycles of half life "degradation" to get to trace levels (3% of peak level).
Taking the max half-life of 60-80 hours, and multiplying by 5 half-life cycles, that's about 300-400 hours or 13-17 days to get to trace levels in the blood.
Looks like the company added extra time to degrade to well below 1% of peak blood levels.
I'm not an expert on receptors, but I would guess that a trace amount of memantine (<1% of peak levels) wouldn't even register as background competition with Bryostatin.
My concern, if I owned AVXL, would be that this class of drug (S1R) has failed well-controlled large-scale trials in AD.
NTRP's readout in a well-controlled confirmatory trial is in ~5 months. Don't have to sweat for 2 years like AVXL owners will, hoping that their drug doesn't follow the same fate as past drug trials in this class.
Maybe that will take effect some day...after AVXL finishes the 2-years remaining in its current placebo-controlled trial.
In the meantime, double-blind placebo-controlled trials is the only game in town.
I don't, maybe AVXL is about science, but it STILL needs to run a double-blind placebo-controlled trial. Until that release of results from an adequately controlled trial (in 2 years according to AVXL), there really is no comparison to the stellar results of NTRP to this point.
I think I speak for most everyone on this board--thanks for all your hard work and the hours of research into NTRP, Bryostatin and PKC, which benefits all of us.
Coach: I'm just now looking at this post of yours, involving nELAV/neural progenitor cells:
My synopsis of the first article (I'll review the 2nd article in a later post):
https://onlinelibrary.wiley.com/doi/full/10.1111/bcpt.12581
- The biochemical changes necessary for learning start with control of gene expression, and these biochemical events occur at the synaptic level (ties into Alkon's theory.
- Neuronal ELAV (nELAV) is a retinol-binding protein (RBP) that appears to regulate mRNA and contributes to synaptic strength.
- Up-regulation of nELAV in pryamidal cells occurs in the hippocampus when learning a spatial task (also saw enhanced expression of the synaptic remodeling gene GAP-43, a gene that nELAV targets).
- Significant impairment in learning in mice when nELAV is silenced.
- "In agreement with this concept, nELAV content in the hippocampus of patients with AD diminishes as a function of clinical dementia progression. Moreover, hippocampal nELAV levels inversely correlate with the total amount of Aß1-42 [Amyloid-Beta], which represents a characteristic hallmark of the pathology."
- Dysregulation of nELAV (and other retinol-binding proteins) is associated with other neuronal pathologies
- "...molecules able to stimulate or to mimic nELAV function may help to recover the AD-related deficits...."
- "PKC has been shown to be involved in the signalling pathway that stimulates nELAV function"
- "PKC activators, namely phorbol esters and bryostatin-1, induce up-regulation and redistribution of nELAV with a concomitant increase in their phosphorylation leading, down-stream, to a raise in GAP-43 mRNA and protein levels in a human neuroblastoma SH-SY5Y cell line."
- "Pharmacological or genetic inactivation of PKCa prevented both nELAV activation and the increase of GAP-43 gene expression."
- "The finding that bryostatin-1 administration in vivo is capable of producing up-regulation of nELAV in the rat hippocampus represents an experimental evidence that nELAV can be pharmacologically modulated by targeting PKC."
----------------
Looks like some real important evidence of the genetic/molecular proof of why Bryostatin-1 activating PKC-e unleashes a multi-modal genetic/molecular effect on the cells in the brain, including nELAV which is involved in learning in mamals. Thanks!
I only know a little about the AXSM story, but the stock is up ~600% in 2-3 months.
I'd be very happy with that kind of gain for NTRP if we announce positive results in late August. To be honest, I think we'd have a greater gain within 2-3 months of results, if they match the previous phase 2 results.
Yes, but we're still waiting for Anavex to prove anything in a double-blind placebo-controlled trial, so that's a long-shot "could eliminate the need for other drugs". A very long-shot.
NTRP will have confirmatory results in Alzheimer's in ~5 Months. Anavex reads out in 2 years. I'd be very nervous if I were an Anavex shareholder going into that readout.
Yet another benefit of bryostatin is increased BDNF, which leads better sleep? Excellent
I’ve heard better sleep leads to better test-taking. No wonder 15 of 16 patients on bryostatin (non-meantime) improved their SIB score in our last trial! Of course we also know that bryostatin also improves other aspects of alzheimer’s
And no competitors have shown improvements test scores ever before (double-blind placebo trial).
NTRP's market cap will change for the positive in the next 5 months.
You're right, both efficacy AND IP are big questions about 2-73.
Fortunately we don't have those questions about NTRP.
The point is that it is a very long process to determine if minor changes are (1) not toxic in animal studies and (2) more or less effective.
Then it's up to the lawyers to decide if the slightly modified drug falls under NTRP's patents or not; with lawsuits filed against competitors with drugs that have minor changes, it's likely YEARS before those drugs make it to markets.
But having a patent lawyer for our presideent certainly improves our chances that our IP portfolio will cover minor modifications to our drugs.
I'm very confident in our IP position, and more important, our president seems very confident in our IP position.
Wow, thanks for this post, coach.
This assessment of a sigma-1 receptor drug similar to AVXL's 2-73 should really put the nail in the coffin on that class of drugs. No wonder the market doesn't view their pipeline as holding promise.
As we progress towards late August results, the market will realize that NTRP may be the only game in town in the Alzheimer's arena.
Coach:
This post of yours is an important post on Ryan (president) and his expertise in IP protection. We can be certain that Ryan has been scouring NTRP's patents and advising the company on how best to protect our IP.
I'm confident he had a big hand in the patent/technology transfer of those patents last fall. Possession is 9/10's of the law!
Further, most executives would quietly resign from a company if they thought the company has no claim to their IP. If Ryan had any doubts on NTRP's patent protection for Bryostatin and all of the Bryologs, my belief is that he would have long ago resigned, with a vanilla statement about seeking other opportunities.
Conclusion? Our IP is solid and well-protected for many years, and the company is very active in extending our patents as far out as possible.
----
On another note, relevant to the discussion of making slight modifications to bryologs synthesis in order to get around patents:
My daughter is working in a lab doing basic research for potential use in CNS diseases.
She said that just making a very minor change to the amino acid chain caused a benign molecule to become toxic in animal tests.
Anyone making claims that "minor changes to bryostatin or bryologs will get around patent protection" doesn't have a clue what they are talking about.
Conclusion? Minor changes to a molecule, whether they are simple molecules or complex, lead to unanticipated toxicities and a useless drug in humans!
Yes, it was.
Hoping they will have more substantial PR's over the next few months. They are working towards initiating trials in other indications, including Fragile-X and MS:
https://neurotrope.com/#pipeline
Neurotrope, which is the last company running trials in moderate-to-severe Alzheimer's patients, may be worth a look, going into late-summer readout:
Neurotrope approaches Alzheimer's as a disease of synaptic loss (starting in the hippocampus). Their drug Bryostatin regrows synapses, clears Amyloid-Beta and Tau, and is neuro-protective.
https://247wallst.com/healthcare-business/2019/03/21/is-neurotrope-the-default-alzheimers-winner-after-biogens-implosion/
Here's a taste of what has been alluded to on this board, if we are successful in our late summer readout:
You're putting the cart before the horse.
First, AVXL needs to run a placebo-controlled trial to prove that the drug actually does something. The only trial to-date (~30 patients, non-controlled for goodness sake???) MAY have shown that the drug slows decline (not everyone is convinced that it even slows decline!). The current 2-73 Alzheimer's trial is scheduled to read out in 2 YEARS! That's a long wait.
Bryostatin on the other hand has shown that it REVERSES Alzheimer's disease. Confirmatory results in less than 6 months.
Which drug, regardless of delivery, do you think doctors/family members will choose for Alzheimer's patients? Bryostatin, of course--the drug that reverses Alzheimer's. Not 2-73 which may, possibly, could perhaps slow the decline of AD.
- 2-73 hasn't even been through a well-controlled trial, so everything to do with 2-73 is hypothetical until it can.
- Even the companies' exploratory 2-73 results (without placebo control) showed that the drug MAY only SLOW the progression of the disease in MILD Alzheimer's patients, who may have been MISDIAGNOSED.
- 2-73 is a me-too drug (S1R), which has not shown anything worth pursuing to large pharmas exploring this class of drug.
Neurotrope offers much more potential, showing REVERSAL in MODERATE-TO-SEVERE Alzheimer's patients.
Placebo in Alzheimer's trials is REAL, which is why your company is now running a placebo-controlled double-blind study in Australia...scheduled to read out in TWO years, according to your CEO.
Good chart.
The start of dosing in a new indication (Fragile-X or MS) should have a positive influence on the share price.
Although not as likely, a partnership would help as well.
Coach: such a clear and concise explanation of the essence of what is going on at the molecular level in Parkinson’s, and why bryostatin might help.
Between this post and your other today on MMPs/BBB/MS, two of your best posts, and that’s saying a lot.
Thanks
Bryostatin is doing just fine on safety, and scientists in biotech research see that and point it out.
No matter how you frame AVXL it's still going to require results from a double-blind, placebo-controlled trial. Pre-clinicals results won't do it. A few patients from uncontrolled trials won't do it. None of that matters to this board, until AVXL can show results from real trials in a few years (according to your CEO). NTRP is far beyond that.
The decision to run a shorter placebo-controlled trial has nothing to do with safety concerns.
I believe NTRP mgt is looking for the fastest route to approval--prove reversal of Alzheimer's with Bryostatin in a trial lasting almost 4 months (not weeks).
I ask again: If researchers and key opinion leaders are emphasizing Bryostatin's impressive safety profile, why should we doubt them?
The safety profile for Bryostatin is outstanding.
From a peer-reviewed journal (PNAS) article:
"The established clinical safety profile of bryostatin-1 in humans could expedite its development as a therapeutic agent in MS."
If researchers and key opinion leaders are emphasizing Bryostatin's impressive safety profile, why should we doubt them?
https://www.scribd.com/document/386853846/Bryostatin-1-alleviates-experimental-multiple-sclerosis
My mistake. Need my coffee lol
So 10-20X 2.8B in profit (typical earnings multiple) gives a market cap of 28B-56B, if we don’t partner (which I’m not expecting).
With the possibility of MS, fragile-X, etc
"...we are getting a little past getting excited over In vivo or vitro studies unless they are on a newer indication for the drug"
Exactly.
I looked up some pre-clinical work for a drug that was being pushed for Alzheimer's about 8-10 years ago. This was what was written:
"Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function... Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington's disease, or in the aging population..."
This was exciting preclinical work for 10 years ago.
But, despite its success in preclinicals and early trials, dimebon failed in a late-stage double-blind, placebo-controlled trial.
https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-6-7
Definitely true.
If there had been no placebo effect in the previous trial, the 20mg would have been statistically significant despite the interference of memantine.
+1
Great point
Yes, a pathway is being worked out for Bryostatin synthetic; may add several months to approval.
Anavex drugs are years away, if ever. Not worth discussing until they can present double-blind placebo controlled data.
Based on the recent financing, I share your concern. Hopefully some of his past experience will prove to be redeeming.
Excerpts from the hiring PR (December 18, 2017):
- Most notably, he served as Senior Vice President and Chief Intellectual Property Counsel at Forest Laboratories for more than 10 years, where he managed several intellectual property estates, including participating in the development and commercial launch of Namenda® (memantine HCL)...
- At Forest Labs, Dr. Ryan worked closely with the commercial and development teams as well as experts in the field, establishing a strong network in the AD space.
- [As] President and CEO of Orthobond Corp Dr. Ryan negotiated several partnership, financing and licensing agreements.
- General Counsel for Cold Spring Harbor Laboratory. In this role at Cold Spring, he provided guidance on business, legal and public policy issues, including licensing, patenting, partnerships, alliances, compliance and regulatory matters.
I agree with all you say...but I didn't say we'd STOP at $1B :)
My quote: "...should move well beyond $1B valuation"
But $1B is about 10X current market cap (fully diluted), so I figured it was a good starting point, lol
The "Emerging Growth" article has old info on the financials...doesn't include the recent financing:
"The company has a market capitalization under $40 million down over 60% from $100 million just 6 months ago. There are 7.9 million shares issued and outstanding and many long term stock holders which puts the effective float of the company at 1.0 million shares. The company has a strong balance sheet with $11.0 million in cash and cash equivalents as of Sept 30, 2018..."
From the "Emerging Growth" article linked earlier:
"On Sept 5th 2018 NTRP announced a collaboration with The Nemours/ Alfred I duPont Hospital for Children to conduct an open label pilot trial for Fragile X patients ages 8 – 18. This clinical trial is expected to commence testing soon."
The start of this trial will be welcome news.
Definitely a good interview.
It does seem like the coverage and PR from Investor Relations is picking up lately.
Posted by @Neurotrope1 (Neurotrope Inc IR) on twitter:
https://emerginggrowth.com/neurotrope-nasdaq-ntrp-offers-alzheimers-patients-hope-for-restoring-cognitive-function/?utm_campaign=meetedgar&utm_medium=social&utm_source=meetedgar.com