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You are correct, Coach:
March 17, 2006 - There were 11 deaths in vascular dementia patients taking the Alzheimer's drug Aricept in a clinical study -- and no deaths in patients taking inactive placebo pills.
Clear reversal of Alzheimer's, such as we saw in the compassionate use patients, would leave AF speechless. And that will be a sight to behold...
Thanks for pointing that out, SF.
It seems unusual that the press release is at 6:30am. Most companies PR at 7am or later, followed by 8:30 conference call.
Seems like NTRP is giving a little extra time in between PR and conference call...perhaps to attract more media exposure, such as what Benzinga is doing?
I'll be watching the business channels to see if the the story gets picked up.
Also noticed that the website hasn't been updated with the Friday PR...investor relations too busy with other things?
"Alzheimer's will probably require some sort of combo treatment imho."
Looking forward to hearing if there's any synergistic effect between Bryostatin and Namenda and/or Aricept.
Might not be on Monday that we hear, but hopefully there's some synergy.
IMO, the fact that the news is on Monday morning is positive, and I agree it increases the chances of great news, good news or barely missed primary endpoint (but probably made some of the secondary endpoints). Thanks Flash for getting IR to do their job, and give us a heads-up this morning.
The thing I'm most anxious about for Monday's release is how many patients dropped out. As Flash has pointed out, this can skew results unexpectedly. In our case, it may cause p-values to LOOK disappointing, when they're not. However, if there is significant SIB improvement in those on-drug patients that complete the trial, we can still get successful p-values.
Watch carefully the secondary endpoints. Other drugs don't seem to have any effect on the activities of daily living (ADLs) in moderate-to-severe AD patients. Our compassionate-use patients did astoundingly well in the ADLs (anecdotal), so if there's something significant in the secondary endpoints, big pharma/biotech will be VERY, VERY interested, even if the SIB scores barely miss.
Finally, look close at the 17-week test scores vs. the 12-week test scores. Dr. Alkon stated at the Sach's conference (late March) that they have reason to believe that Bryostatin has a residual effect. This is our first glimpse at their theory of residual effect.
Good luck to all longs!
Seeking alpha article released yesterday, but just now available to non-subscribers:
https://seekingalpha.com/article/4065660-neurotrope-bioscience-interesting-binary-event
Long bias. I haven't read, but looks very thorough.
Great! I wish you equal or better good fortune with NTRP! :)
Maple: did you make good coin on CPXX?
True...and all management options were recently priced at 19.60s.
$30 Billion spent over the last 20 years on Alzheimer's research, drug development and clinical trials...with no drug that can actually halt or reverse the disease.
Tells me that 95%+ of neurology researchers don't understand the causes of AD.
I'm convinced that Dr. Alkon, with 45 years of research, understands the underlying causes. And, after re-listening the February 13 BIOCeo Neurotrope presentation, I believe he is certain that he has identified a drug that can halt or reverse this insidious disease.
Let's hope that almost all of the patients, drug and placebo, were able to complete the 17 week course of drug infusion and psychiatric tests.
If the results show no difference between Bryostatin and placebo, I think we wake up Monday morning to a sub-$1 stock. Realistically, if Bryostatin fails NTRP has nothing else to offer.
It's very important to remember that although NTRP currently has a small public float of just a few million shares, the company has shareholder approval to issue 150 million more. If we then do a back of envelope calculation and grant NTRP a $15 billion market cap with a float of 155 million shares, we get a price per share of $100. Again, that's if the company issues all the approved shares - not a given.
I certainly understand skepticism, as no company has ever found a cure for Alzheimers. However, human history is filled with stories of impossible things that had never been done, and then someone did them. Perhaps this week will reveal yet another. I hope so... not just for my wallet - but because my father has dementia and I would dearly love to get something into his brain to stop his decline. That would mean more to me than any profits that might be coming our way. Good luck to all and God Bless Dr. Alkon.
Good point.
Chupacabra:
Coach, he made an interesting comment at one of the recent conferences, he basically stated that some of the mouse models were shot with so much amyloid that when it was removed the mouse responded more so to the volume than affect. I never heard that before, he went on to saying some of the mouse models weren't realistic in these previous trials.
RE: registration of shares from the private placement 18-nov-2016.
http://www.prnewswire.com/news-releases/neurotrope-announces-private-placement-of-20-million-300365721.html
"The securities to be sold in the private placement will not have been registered under the Securities Act of 1933, as amended, or state securities laws as of the time of issuance and may not be offered or sold in the United States absent registration with the Securities and Exchange Commission (SEC) or an applicable exemption from such registration requirements. Neurotrope has agreed to file one or more registration statements with the SEC registering the resale of the shares of common stock underlying the warrants purchased in the private placement."
That is, NTRP was required to register the private placement shares and warrants for resale, or face penalties (probably more shares issued) for failure to register in a timely manner. Standard operating procedure to list all owners/shares/warrants.
In other words, after the shares were registered, the owners of the shares/warrants MAY sell their shares at any time, but they don't have to. They may look at the Phase 2b data and decide to hold for a much higher price.
Easy...it's for flexibility.
Let's say phase 2b results are stellar, the share price goes to $300 over the next year, and the company decides to do a forward split, say 5 new for 1 old; each new share would now trade for $60.
On a fully diluted basis, there are approx. 13M shares/warrants right now, so they have to issue 52M new shares/warrants to do the forward split, bringing the total to 65M shares/warrants outstanding (out of 150M authorized). Without the authorized shares, they would have to get shareholder approval first.
However, as with all forward splits, the company market cap is exactly the same before and after the stock split, so even though new shares are issued, no stock holder has lost any value:
1000 shares X $300 = 5000 shares X $60
----------------------
"Reverse stock splits don't affect the number of authorized shares, but a forward stock split issues new stock from the company's authorized shares."
Rhett's syndrome (with Bryostatin):
Pre-clinical work for Rhett's started last May, with funding from Rettsyndrome.org.
My guess is we are within a few months of announcing a Phase 2 trial to commence using Bryostatin. No need to run a Phase 1 trial for safety, as that's already done. Perhaps a quick proof-of-concept trial leading into a double-blind placebo-controlled Phase 2b trial. Or, who knows, maybe NTRP would be bold and jump right into a double-blind placebo-controlled Phase 2b trial.
It affects 1 in 10,000-20,000 females in the US, so it would qualify for orphan drug designation.
If the phase 2b trial is designed correctly, might even get Accelerated Approval?
Rhett's syndrome, as an example of another disease using Bryostatin (getting preclinical work funded by someone else):
http://www.prnewswire.com/news-releases/neurotrope-enters-into-research-collaboration-with-the-international-rett-syndrome-foundation--rettsyndromeorg-300271272.html
"The study will be funded and managed by Rettsyndrome.org."
That's got to be worth several hundred thousand dollars.
If results are positive, this also opens the door to other diseases that have been studied pre-clinically with Bryostatin:
Rhett's syndrome
Traumatic Brain Injury
Stroke
Nieman-Pick disease
With a successful phase 2b, I expect the news flow over the next year will be tremendous, not only in Alzheimer's, but in these other diseases as well.
With a successful phase 2b, money won't be an issue, with probably $100M raised at >$50/share within 2 weeks.
With a successful phase 2b, funds and institutions will be piling into NTRP at a rapid pace under $100/share. No fund or institution will want to be caught without NTRP in their portfolio.
With a successful phase 2, and trials starting up in multiple diseases, I can easily see NTRP market cap getting in the range of $1-3 Billion within 3 months.
So far, Bryostatin has a much better side-effect profile than Gleevec,
which was given accelerated approval, based on Phase 2 trials.
Gleevec side-effects:
Low blood counts. ...
Nausea and vomiting.
Edema (swelling of the face, feet, hands)
Muscle cramps and bone pain.
Diarrhea.
Hemorrhage (see bleeding problems)
Skin rash (see skin reactions)
Fever.
Accelerated Approval
https://www.fda.gov/drugs/resourcesforyou/consumers/ucm289601.htm
Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available. Instead, less traditional measures called surrogate endpoints are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions, or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs.
Gleevec (imatinib mesylate), an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia (CML), received accelerated approval. The drug was also approved under the FDA's orphan drug program, which gives financial incentives to sponsors for manufacturing drugs that treat rare diseases. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three large Phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood.
Most drugs to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to confirm that its effects on virus levels are maintained and that it ultimately benefits the patient. Under accelerated approval rules, if studies don't confirm the initial results, the FDA can withdraw the approval.
Because premarket review can't catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a postmarketing surveillance program.
Post-marketing safety studies are done all the time for long-term safety. (besides which, we HAVE long-term safety: administered to 1500 cancer patients, some for long-term).
If we see clear reversal of symptoms (SIB scores, MMSE scores, ADLs) and reasonable safety over 3 months in the Phase 2b results, there is a distinct possibility that the FDA may suggest to NTRP that they submit an NDA, with the possibility of conditional approval of Bryostatin for moderate-to-severe Alzheimer's.
The approval would be conditional that NTRP will start a Phase IV post-marketing safety trial of Bryostatin within a reasonable amount of time, and marketing of Bryostatin could be revoked if there are any major long-term safety concerns.
Phase 2b reversal of Alzheimer's would have to be convincing, and the FDA would have to be reasonably comfortable with the safety data from the Phase 2b, Phase 2a, compassionate-use patients, and prior cancer trials (1500 patients, some for long-term use).
----------------------------
The FDA has recently shown flexibility in conditionally approving drugs for diseases where no drug is available to directly treat the cause of the disease: e.g., Eteplirsen for Duchenne Muscular Distrophy (Sarepta Therapeutics).
Further, Scott Gottlieb, who will be the new FDA director, is much more open to getting effective drugs to market ASAP, compared to his predecessors.
I don't think we'll get a direct answer on the data. More like:
"Based on our research and compassionate use, we anticipate some patients will experience reversal"
"We have heard anecdotally that some patients want to continue on the drug"
Since this is Dr. Alkon, I think this interview will strictly be an explanation of the science to the research community, investment community, and medical community.
Bryostatin, if successful, is a MAJOR paradigm shift in the treatment of Alzheimer's, and needs some introduction, so that the impact of the results (if successful) can be fully appreciated. Reversal of Alzheimer's has never been heard of before.
And, of course, I'm hoping that the next TV appearance will be on 60 minutes!
Definitely sarcasm.
I think he takes exception to the Accesswire article with the headline: "Neurotrope nears Breakthrough in new Alzheimer's treatment". (headline reads like success in Phase 2b is a done deal, which he objects to).
As I've said before about AdamF, I don't think he's dug deep enough to understand the bull case.
Several points about PKC epsilon and Bryostatin, based on the literature and Dr. Alkon's conference presentations:
- Normal PKC epsilon levels are necessary for synaptogenesis, natural clearance of Beta-Amyloid and tau tangles, and for neoronal protection.
- Most cases of Alzheimer's are characterized by abnormally low PKC epsilon, which leads to a loss of synapses, buildup of Beta-Amyloid and tau tangles, and increased death of neurons.
- The goal of using Bryostatin is to artificially restore normal levels of PKC epsilon.
- Those who have normal levels of PKC epsilon, don't experience "unregulated synaptogenesis" or seizures or "behavioral/psyche" issues or "long-term health problems like steroids".
- So, if normal levels of PKC epsilon doesn't cause health issues, we should turn our attention to the drug Bryostatin (used to elevate PKC epsilon to normal levels) to see if it has any nasty side-effects. Bryostatin has been given to >1500 patients, long-term, at high doses. So far, the mild side-effects at the doses in the phase 2b trial of Bryostatin has required the use of tylenol. Maybe we need to investigate tylenol to see if it has any nasty side-effects, because so far, Bryostatin is safe.
-------------------
Hypothetical concerns about "unregulated synaptogenesis causing seizures or behavioral/psyche issues" or concerns about side-effects similar to anabolic steroid use are non-sequitors.
- Seizures hasn't been reported as a side-effect of Bryostatin in 1500 cancer patients who were given Bryostatin, including in those who have taken Bryostatin for > 2 years, and those who have taken higher doses of Bryostatin than those in the Phase 2b Alzheimer's trial.
- Seizures hasn't been reported as a side-effect in the 100 patients who received Bryostatin for 12 weeks in the Phase 2b for Alzheimer's.
- The only incidence of seizure that I'm aware of while taking Bryostatin is Jenni Spencer, one of the 3 compassionate-use patients.
--------------
So, let's take a closer look at Jenni Spencer's family history:
- Jenni Spencer had the PSEN1 genetic mutation for early-onset Alzheimer's.
- Jenni Spencer's mother also had the PSEN1 genetic mutation, was known to have been having seizures by age 35, and evidence of cognitive impairment was present several years before that.
- Looking at an NIH article on early-onset Alzheimer's, those with the PSEN1 mutation often have associated seizures.
https://www.ncbi.nlm.nih.gov/books/NBK1236/
AD3 (PSEN1 mutations). Age of onset is usually in the 40s or early 50s. Onset in the 30s and early 60s has been reported. Onset after age 65 years is thought to be rare. Relatively rapid progression over six to seven years is common and the disease is often associated with seizures, myoclonus, and language deficits [Fox et al 1997, Gustafson et al 1998, Menéndez 2004]. Several families have had associated spastic paraplegia with "cotton wool" amyloid plaques [Crook et al 1998, Brooks et al 2003, Ataka et al 2004, Hattori et al 2004, Raman et al 2007].
I've been informed by a neurologist that unregulated synaptogenesis has a downside, increased incidence of seizures and behavioral/psyche issues for people that have Alzheimers.
If we have positive results in Phase 2b, then we're in an enviable position. We will have a drug that works in one disease, and the mechanism of action and preclinical results suggest that it will work in multiple diseases. Neurotrope is looking at a lot of blue sky, blu:
- Moderate-to-severe Alzheimer's
- Mild-to-moderate Alzheimer's
- Fragile-X syndrome
- Rhett's syndrome
- Traumatic brain injury
- Stroke
I haven't bothered to look at the addressable market in each of the above diseases, but I imagine the total is several billion $.
You're $10 prediction is ridiculously low, if we have positive results.
Oh, and I forgot to mention no competition for years, and an FDA that wants to get drugs quickly to market that successfully treat Alzheimer's.
Good point, RE: "fresh frozen blinded Alzheimer's brains". (Wow, does that sound disgusting )
I'm glad as well for this phase 2b trial design. If results similar to the compassionate-use patients, will be very difficult to question, except for the longevity of the trial.
Should also quickly get FDA approval for the open-label extension study for the 150 p2b patients.
"My biggest concern is nobody is looking at or touching this."
Biotwitter "thought leaders" (Adam F/Alfredo F, etc) are only giving it a cursory look or aren't even reviewing it, so most of their "sheep" aren't digging much deeper. And I don't know of anyone else with a following on twitter (other than @KSSMDPhd) who gives it >50% chance of succeeding.
Unfortunately, Bryostatin Phase 2a (single dose, safe, PK/PD positive) doesn't give much readthrough to Phase 2b (7 doses across 12-weeks, double-blind placebo controlled) SIB results.
So we have to rely on the extensive preclinical mouse/mammal models published by Dr. Alkon, upbeat scientific presentations at conferences by Wilke/Alkon, and 3 compassionate-use patients.
It's either the buy of the 21st century or just another startup biotech. I believe we'll see positive results, but there's a lot of extrapolation in my belief. There's no certainty to results being positive, but the deeper one digs, the more intriguing this binary event looks.
But...but... what about "unregulated synaptogenesis".
I stopped at "retarded rats", lol!
Let us know if anything intelligible comes from the board.
My bad! :)
Some are using the 4-letter word "scam" on twitter.
I think we can unequivocally state that, with all the failed trials in Alzheimer's, anyone who thinks Beta-Amyloid as a PRIMARY target are the ones scamming.
This is based on the scientific research related to the Elan drug (2008). Completely clearing amyloid plaques doesn't change the process of Alzheimer's; further, many elderly have amyloid plaques, but no signs of AD.
And, Tau as a primary target has fared just as poorly in clinical trials.
Hopeful that April will bring good news for NTRP and Bryostatin, and for the patients who suffer this horrific disease.
SF_Wolf:
I just found it yesterday, but it is a great overview of the state of affairs.
Top scientists in industry and government are STILL going after Beta-Amyloid and Tau as primary targets. And "The Street", funds, institutions and retail investors are following like sheep.
SGMO just released a news release yesterday that they have new animal model data (human in vitro), using their zinc finger gene technology, that eliminates 90% of tau...and the stock is up almost 20% from 2 days ago.
Even after all the years of trial failures in treating Beta-Amyloid and Tau, publish a news release that states reduces or eliminates these symptoms, and it's greeted with an increased share price.
"The Street", fund managers, investors, scientists, biotech companies are mesmerized. About to change dramatically in a few weeks, I hope.
From this article:
"In 2008, another team of scientists studied the autopsied brains of Alzheimer’s patients who had been in a study of an experimental Elan drug, an antibody that removed amyloid plaques. They found that a number of the brains had completely cleared amyloid; the antibody worked. But those patients had shown no cognitive improvement.
At minimum, that suggested that by the time amyloid plaques appeared, a brain was too far gone to be rescued with an anti-amyloid drug. But it also raised the possibility that the plaques are markers of cell death, not causes of it, since many people have plaques but not loss of synapses or Alzheimer’s. If so, then destroying amyloid plaques — as many drugs in company pipelines still aim to do and as virtually all the failed drugs did — would not treat the disease. The same might be true of tau tangles, the deadly filaments that form inside neurons and the target of the compound that had disappointing results this week."
https://www.statnews.com/2016/07/28/alzheimers-drug-failure/
When you don't understand the disease, you're bound to make 30+ years of mistakes in going after the wrong targets! For 30+ years, the industry has been targeting the symptoms of AD (tau tangles, Beta-amyloid, etc), not the cause of the disease (loss of synapses, low PKC-e).
Article from July 2016 (Dr. Alkon quoted):
https://www.statnews.com/2016/07/28/alzheimers-drug-failure/
NTRP trades about 70,000 shares every day.
Good news, Reddy.
https://finance.yahoo.com/news/neurotrope-inc-announces-approval-listing-123000632.html
Will also ring the NASDAQ Opening Bell on March 31.
I agree. AKAO was a good one; I sold too early.
Saying that NTRP is a "lottery ticket" is proof that his DD is cursory and he hasn't looked closely or listened to a presentation by Dr. Alkon.
If a major Pharma or research lab reported compassionate-use patient results similar to NTRP, it would be front-page news.