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Another failed Alzheimer's trial:
http://finance.yahoo.com/news/acceras-alzheimers-trial-fails-yet-133000260.html;_ylc=X1MDMTE5Nzc4NDE4NQRfZXgDMQRfeXJpZANjNGphaDlwY2JhdnMwBGcDZFhWcFpEeHVjejVsTkdOak5UUXpNeTAyWWpreUxUTXdNREV0T0RReU15MHpaakUzTUdKak5EWXpNelE4Wm1sbGJHUStiWEpyBGxhbmcDZW4tVVMEb3JpZ19sYW5nA2VuBG9yaWdfcmVnaW9uA1VTBHBvcwMwBHJlZ2lvbgNVUwRzeW1ib2wDTVJL?.tsrc=applewf
Nestle SA-backed Accera, late-stage study, in mild-to-moderate AD, failed to achieve statistically significant result.
1204 drug is based on the theory that decreasing ability to metabolize glucose leads to deposition of amyloid.
After successful mid-stage trial, Accera changed 1204's formulation, but that led to lower bioavailability of the drug. They have fixed the formulation and will start another late-stage study.
"Industry analysts say any treatment that successfully interferes with the cause of the disease would be virtually guaranteed multi-billion dollars in sales."
SF:
Great post.
I also believe it was a HUGE tell that the Chief Science Officer (Dr. Alkon) discussed in detail the science of Bryostatin and the 3 compassionate use patients.
If the CEO had presented info about these patients, it wouldn't have the strength of the CSO talking about these 3 patients in glowing terms of recovery.
Dr. Alkon is a 30-year research veteran of the NIH and I don't believe he would present information on patients that isn't backed by objective testing and observation.
Re-read my post. I said positive, not ambiguous
Science magazine: "Second cause of hidden hearing loss identified" (2/17/17). Synapse loss.
https://scienmag.com/second-cause-of-hidden-hearing-loss-identified/
SF:
I agree 100%. If the company in April reports something along the lines of "We met our primary endpoint in both drug arms of our trial of Bryostatin. The drug was well-tolerated, with myalgias treated with analgeisics. We are the first company in the history of drug trials to show improvement in the lives of moderate-to-severe Alzheimer's patients. We look forward to trials of Bryostatin in mild-to-moderate Alzheimer's patients, Fragile X, Rhett's syndrome, etc., etc.", IMO NTRP stock won't trade less than $50/share, but more likely much more. How does retail lose in that scenario?
Xena: "There is no way retail can win unless they do some very astute trading"
There is no way retail can lose if results are positive in April.
If the mice aren't buying up the stock, who is?
Dr. Alkon on the 3 Bryostatin compassionate use patients:
"No other reports have ever shown comparable benefits in such severely demented patients — albeit in the absence of age-matched controls."
Runncoach:
This is a very good point! I've been assuming the placebo group would be stable, but it's certainly a possibility that placebo scores could drop during this time period, as well.
Kid:
It's not about "how many", but more of "how much": objective measurements.
Meeting the primary endpoint is the goal, although meeting secondary endpoints is important and can help in designing the next trial. All of the goals are pre-specified.
They submit each patient to baseline tests (SIB, ADL, NPI, MMSE) at time of entering the trial, give the drug (20 or 40 micrograms or placebo) for 12 weeks, give the above objective tests to patients again, run statistics on the numbers, and out comes a p-value and HR and other numbers for each of the doses, that says whether your trial succeeded or failed to meet endpoints, and which dose is more effective.
The threshold for a successful trial is a p-value of .05. The lower the p value, the more confidence in the results.
Nobody here cares about the 2-73 (AVXL) trial, an open-label trial which is subject to patient and investigator biases.
So far, the only side-effects I'm aware of for high-dose Bryostatin are myalgias, treated with Tylenol.
One study found the average lifespan is 4.5 years after being diagnosed with Alzheimer's disease or another form of dementia.
Even if my life isn't extended by a potential therapy, if I have Alzheimer's, I'll take my chances on the side-effects of a drug that makes my life more bearable for my remaining days:
- Patient 1: intermittent coma, nonverbal. With Bryostatin, able to enjoy tv and mind more active.
- Patient 2: non-verbal, unable to swallow, inability to move. With Bryostatin, return of some language, swallowing, increased attentiveness with people
- Patient 3: With Bryostatin, MMSE score of 2-3 increased to 10-12, adcs-adl-severity score of 18 improved to 33, returned to swimming, billiards.
Bornagain:
I believe her name is Jenni Spencer.
http://www.wvgazettemail.com/article/20150718/GZ01/150719268
In the slide from the presentation, patient 2 is "JS", so I think she is already accounted for in the slide.
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This is biggercapital's tweet:
Michael Bigger ?@biggercapital Feb 17
Michael Bigger Retweeted Kenneth Dreesen
I got confirmation that the drug was given to only four patients and the results shown are not"super responders" biased. $NTRP
SF:
Great post. Questionable for anyone to try to minimalize the compassionate use patients and say that we're only relying on mice studies.
By the way, from biggercapital on twitter, it's my understanding that there were 4 treated with compassionate-use, so 3 out 4 showed impressive results.
To follow up on your quote: "No other reports have ever shown comparable benefits in such severely demented patients", below is the text of the slide from the corporate presentation.
-----------------------------------------------------------------
Compassionate Use Patients: Overview
Bryostatin Compassionate Use Program:
Severe Alzheimer’s Disease
No other reports have ever shown comparable benefits in such severely demented patients — albeit in the absence of age-matched controls.
Patient 1 – 95 y/o male (JT) – disoriented, intermittent coma, non-verbal
Course: Became alert, attentive; remembered date, place, time; mind active, engaged, watching TV, requested to return to work.
Patient 2 – 38 y/o female (JS) – familial Early-Onset AD due to PSEN1 mutation, Non-verbal, drooling, unable to swallow (fed with gastrostomy), attention grossly impaired, spasticity, inability to move
Course: Return of some language and vocalization, swallowing, increased attentiveness to environment & persons, increased range of motion
Patient 3 – 76 y/o white ? (FC)
Course: MMSE: 2-3, improved to 10-12; recognizes, vocalizes words. ADCS-ADL-severity score: 18 improved to 33; hallucinations: reduced; Return of complex motor skills — e.g. swimming, billiards.
blu:
There are so many moving parts here, I think it's difficult to answer your question:
- Trial results: mild improvement? or significant improvement in > 50% of patients? Durable improvements?
- Long-term safety: if there are long-term safety issues, this will directly affect which AD population Bryostatin is prescribed for. Only for severe AD (low bar)? or also include mild-to-moderate (significantly increases patients treated and revenue)?
- Treatment duration: a lifetime of regular treatment, one-time treatment cycle, or 2-3 cycles of treatment per year? (I'm thinking the latter)
- COGS: how much it costs to synthesize in large quantities is an unknown.
- Are there other diseases (Fragile X, etc) that Bryostatin is effective in that bring in further revenue?
- Reimbursement: how will the insurance landscape change over the next few years, considering the drug pricing rhetoric among politicians?
- If results are positive and we aren't bought out, it's likely we will need a partner, which means our revs are no more than 30% (that's generous).
-------------------------------
My near-term expectations: In April if Bryostatin shows real improvement (signs of disease reversal) and no significant safety signals, conservatively gain 4-10x.
Long-term: If Bryostatin is SOC and widely prescribed by physicians in only moderate-to-severe disease cycling on and off for the rest of the patients' lives, improving cognition in > 50% of patients, without a Pharma partner, our market cap should conservatively be several billion.
Pharma companies have spent literally billions of dollars chasing a theory that has proven to be wrong ("amyloid causes Alzheimer's"). And Dr. Alkon has explained in scientific detail why Amyloid plaques are only one part of the problem. Further he has explained how PKC Epsilon (Bryostatin) plays a role in many aspects of a healthy memory--PKC Epsilon is multi-modal.
His analysis is backed up with years of research, meticulously analyzing healthy and diseased cadaver brains, performing myriad animal tests with Bryostatin, and culminating in what we know today: Bryostatin was administered to severe Alzheimer's compassionate-use patients that were remarkably improved by Bryostatin.
No other trial drug has ever had a comparable remarkable effect on severe AD patients.
While Bryostatin may not be the ultimate solution, there's a lot of evidence that suggests it has a decent shot at working, on its own merits without any other drugs. There is risk, of course, but everyone has to asses their own personal situations as to whether the risk here is worth taking.
The Lancet journal article (Clive Holmes Phase 1 Alzheimer's trial) referenced in the Benzinga article (from EdenRahim on Twitter):
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61075-2/abstract
Interpretation (summary):
"Although immunisation with Aß42 resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration."
Not just Dr. Alkon, but other independent, peer-reviewed studies show the false narrative of the amyloid plaque theory:
A study by professor Clive Homes published in the Lancet supports the criticism of the amyloid hypothesis. Homes found, during autopsies of dementia patients who'd undergone treatment for the removal of amyloid plaque, that while some had virtually complete plaque removal, seven of the eight still died with severe end-stage dementia. "In the whole cohort," Homes wrote, "there was no evidence of improved survival or of an improvement in the time to severe dementia" versus the placebo group.
Yes, he is...good article!
RE: NTRP Patent estate:
Neurotrope holds around 70 patents on its bryostatin and even more importantly, the rights to use PKC epsilon for treatment of AD. Alkon put it this way, "Suppose somebody else, let's say Lilly, came up with a new PKC epsilon activator, and let's say that it had good efficacy. The drug they came up with would be theirs, but to use it to treat Alzheimer's they'd have to work with us." And of the prospect of teaming up with pharma partners? "We'd be happy to work with them."
A study by professor Clive Homes published in the Lancet supports the criticism of the amyloid hypothesis. Homes found, during autopsies of dementia patients who'd undergone treatment for the removal of amyloid plaque, that while some had virtually complete plaque removal, seven of the eight still died with severe end-stage dementia. "In the whole cohort," Homes wrote, "there was no evidence of improved survival or of an improvement in the time to severe dementia" versus the placebo group.
Alkon would disagree [RE: Amyloid trials]. "These trials are not working, and moving it up earlier and earlier is not going to change it," Alkon said. "Look at Biogen's trial. What people don't realize is that Biogen moved their trial so far up that there wasn't one Alzheimer's patient in the trial. They only looked at people who were mild cognitively impaired or confused. Only half of which go on to get Alzheimer's."
Alkon said, "There is a long line of trials, all going after amyloid in different ways, that never have worked. What we're trying to say is, look at the elephant in the room. The elephant in the room is look at the loss of wiring in the brain."
New Benzinga article includes NTRP (touches on things that most people here already know):
https://www.benzinga.com/general/biotech/17/02/9061803/after-merck-stops-study-what-remains-of-the-alzheimers-drug-pipeline
Nothing that concerns me with what has been reported to-date, and considering the horrific nature of moderate-to-severe Alzheimer's--even leading to death--a significant amount of latitude will be given to any treatment that can improve this disease.
Nevertheless, safety is always something to keep an eye on in clinical trials, and should be carefully reviewed at each reporting of results. Long-term use will still need to be assessed.
Maple:
In recent presentations, the CEO said, and I'm paraphrasing, that the infusion of Bryostatin resulted in myalgias (muscle pain) in some patients. According to her, this was managed with Tylenol.
This might be classified as a grade 1 or grade 2 adverse event, depending on the severity of pain, but good to hear that it's relieved with something as simple as a low-level analgesic (Tylenol).
Kid:
Might be silly for who to buy at these levels?
If you don't own any shares, $12.50/share might be the best buy of your lifetime if results are good (realizing that there is risk at any price, whether it's at these prices or lower).
If you're already loaded and holding from $8, then you aren't buying, but you might be selling a few to lower risk.
If you're trading the shares, now might be a good time for an entry, hoping to catch a run-up into results in April.
Everyone is in a different position and has a different perspective on this stock, so there is no way to say whether the current price is good or not.
Unless you know what the insiders are going to do (buy, hold, sell), nobody has any idea whether this is the bottom before results or not.
Further, who knows what news might come out in the next 6 weeks?
Also, will funds start buying once it moves to the NASDAQ?
So many questions...
Dr. Alkon at BIO Ceo (minute 10:00-28:00) gives a clear, concise scientific explanation of why Bryostatin worked in the 3 compassionate-use Alzheimer's patients, and why it should work in the Phase 2b Alzheimer's trial, as well as in Fragile X disease, stroke, traumatic brain injury, mood disorders, and Niemann-Pick disease.
A must-listen:
https://www.veracast.com/webcasts/bio/ceoinvestor2017/18111483071.cfm
XenaLives:
Have you listened to the BIOCeo presentation?
Dr. Alkon (beginning minute 10) reveals much more of the Neurotrope story than what the share structure reveals, in my opinion.
Regards
RE: The slide describing 3 compassionate-use patients (presented by NTRP/Dr. Alkon):
Amazing results, albeit with a small n. April will give a more complete picture.
I'd like to see Neurotrope keep the Phase 2b patients on-drug past the 12-week cutoff, and continue to follow them for a year. If the April Phase 2b readout has efficacy and safety anywhere close to these 3 patients, and that efficacy and safety continues for a year, that could lead to an accelerated approval.
Most important takeaway from that slide:
"No other reports have ever shown comparable benefits in such severely demented patients - albeit in the absence of age-matched controls."
runcoach:
Good points; agree with all you say.
Heck, if we "only" see 3 of 15 (20%) severe AD patients in the Phase 2b show the kind of improvement those compassionate patients saw (with safety), then Bryostatin is a blockbuster in the making! (edit: and, of course, the results would have to be sustainable)
Kid:
I agree with both of your posts.
I don't think I've ever said they would get approval out of this trial.
But you never know...Sarepta got approval for it's drug in a small-n trial (10 patients) in a deadly disease (Duchenne Muscular Dystrophy). :)
Seriously, though, I don't think it will be possible. Too many unanswered questions: treatment duration, dosing, manufacturing, etc.
Still, the upcoming phase 2b results, if we see efficacy and safety, could launch share price significantly.
In that this is cutting-edge science, it's difficult to compare timeframes between current treatment paradigms and bryostatin.
Who knows, perhaps only 12 weeks is needed for synaptic regeneration? Maybe we will later learn that burst exposure is what is needed. Alternating 12 weeks on and then 12 weeks off, in order to reset PKC activation?
Yes, there is a lot to learn and a lot of work still to do, but I'm hopeful there will be some meaningful results in a few months.
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I took the liberty of extracting more text from the same article you cut-and-paste from:
https://www.revolvy.com/main/index.php?s=Bryostatin%201&item_type=topic
Neurological
Bryostatin 1 has appeared very promising in enhancing memory in animal models. It was able to increase the duration of memory retention of the marine slug Hermissenda crassicornis by over 500%.[7] Additionally it also increased the rate of learning in rats.[8] This makes it a possible drug candidate for the treatment of Alzheimer's disease. As of 2014, bryostatin 1 is in clinical trial phase II for the treatment against Alzheimer's disease.[4] [9]
The ability of bryostatin 1 to alleviate brain damage in ischaemically brain-injured rats also seems promising and may open another therapeutic field for bryostatins.[10] [11]
A phase II clinical trial (running from 2015 to 2017) is comparing two IV doses over 12 weeks against placebo for Moderately Severe to Severe Alzheimer's Disease.[12]
If bryostatin improves AD in Phase 2b trial and safety is there, this is a 5-10+ bagger.
Lots of work still to be done, but there enough info out there to infer that there is a decent chance bryostatin can improve AD and safety won't be an issue.
Hate to be short this stock, especially if they release results early (March?)
The purpose of the Phase 2A was to test safety, tolerability, PK/PD and efficacy of a single dose. Animal studies showed that a single dose isn't expected to have efficacy.
Safety has been somewhat proven for high-dose and short-term, but what about long-term chronic use, for a year or more? I'm assuming patients will need to take Bryostatin for the rest of their life.
I agree: if Bryostatin reverses moderate-to-severe AD and is safe to take, it could be one of the biggest selling drugs of all time, and after a year of sales, would have a market cap much greater than $10B.
If Phase 2b results are effective and squeeky-clean safe, it wouldn't be a bad move for a smart, cash-rich Pharma to make a buyout bid for $3B (realizing that there is still a lot of work to do to get to approval, with a Phase 3 and PDUFA).
All current AD drugs only slow the progression of the disease. If Bryostatin can IMPROVE the disease state (regain cognition, motor function, etc), this would be a breakthrough in the treatment of AD.
IMO, before Phase 2b release, NTRPD could get to $20-$30+ ($200-$300M MC).
If Phase 2b results improves disease state and no safety signals, could trade at $60-$100+ ($600M-$1B).
If Phase 3 trial improves disease state and safe and durable, could trade $500-$1000+ ($5B-10B)
----------------------------------------------
But, before anyone mortgages the house, and bets it all on NTRPD, this is a high-risk investment:
- Will the current dose levels (20ug or 40ug) show the same remarkable improvements seen in compassionate patients?
- Will the current trial (12-week, 9 treatments) continue to show no major AE's?
- Will AD improvements and safety continue if drug is used for a longer period of time (probably a 1-year Phase 3 study)?
- Will AD improvements be durable for the entire time patients receive treatments, or will disease state slowly return?
------------------
Certainly worth investing some of your high-risk capital, realizing that the trials can still fail.
This woman, treated under compassionate use, had ApoE4 gene mutation (not the PSEN1 variant):
http://www.wvgazettemail.com/article/20150718/gz01/150719268
---------------------------------------------
When they PR'd their Phase 2b trial initiation, they stated: "tolerability and efficacy of Bryostatin 1 in the treatment of moderately severe to severe Alzheimer’s Disease". No exclusion mentioned based on a genetic mutation.
Finally, the front page of their website says, "Entry criteria based on the MMSE score". MMSE is a Mini-Mental State Examination.
Kid:
Agree on microcaps. High hopes, but don't always work out, which is where DD comes in.
Also of note, the 9 patients in the Phase 2A had mild AD; Phase 2B patients have moderate-to-severe AD, so if Bryostatin works, it's more likely to work in this group of patients.
No guarantees Neurotrope will work out, but I feel much better about continuing to hold, and we can repeat some of the compassionate use outcomes.
Hope to be able to sell a little at higher prices to lower risk...
Good luck
Kid2:
I listened to the Noble presentation, and I had the same reaction as you: it seemed like she just breezed over the Phase 2a results, answering someone's question at the end. Something like "we got what we were expecting", "we saw responses after a few hours", "we're going to release the results in a future presentation/journal". I thought she was just brushing off the questions, and it was concerning to me.
So, I did a little digging into past PRs, and I now feel much better about holding my investment here.
The purpose of the Phase 2A was to test safety, tolerability, PK/PD and efficacy of a single dose. Animal studies showed that a single dose isn't expected to have efficacy.
----------------------------------------------------
Here are the 2 press releases on the Phase 2a results:
1. 2/24/15 PR (top-line results):
"...positive top-line results from its...single dose Phase 2a clinical trial evaluating bryostatin-1 for Alzheimer’s...no safety signals...well tolerated. The secondary objectives...were the preliminary evaluation of the efficacy of a single dose of bryostatin in the treatment of patients with AD, its pharmacokinetics and pharmacodynamics...
2) 3/17/15 PR (final results):
CEO Ramat said: "...confirm the preliminary findings of the Phase 2a study...showing good safety and tolerability. Now we can add that we achieved expected outcomes on the exploratory endpoint of PKCe activation...this is a small trial population [but] we are still greatly encouraged...”
----> An additional secondary objective of the study was the evaluation of efficacy following a single dose of bryostatin. As expected with a single dose of bryostatin, there was no measurable improvement in cognition in this mildly impaired patient population. It is important to note that in previous animal studies improvement of learning and memory was first observed following multiple doses of bryostatin. <----
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Multiple doses are required. In the Phase 2b, I believe there are 2 initial doses, followed by 9 doses over 12 weeks. There are 2 groups, each with a different dose level (20ug and 40ug).