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"IGF drugs have known long term dangers."
You keep repeating this in the context of Bryostatin, even though it's not true.
Bryostatin is a macrocyclic lactone, which is NOT an IGF (a polypeptide hormone similar to insulin).
Two entirely different classes of medicines, with different side-effects.
IGF and it’s side-effects are irrelevant to bryostatin.
---------------
Further runncoach had an excellent rebuttal to a related statement of yours ("There are concerns about long term use of growth hormones - to say otherwise would be dishonest."):
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=143262124
That is growth hormone THERAPY. That's not taking a drug that bumps up deficiencies in BDNF, IGF, and NGF levels temporarily in elderly people. The LACK of ability of a drug to do this in the elderly population for alzheimer's (and in some other CNS cases) is a red flag in my book for successful MOAs.
If one had a normal level of growth hormones, of course I wouldn't recommend them to take growth hormone inducing drugs that could potentially do harm. It would be like taking testosterone supplements. You only take them if you need it. LOW levels of igf create all sorts of health problem and that's where the elderly are.
Even the conclusion in your article touts "an exemplary track record of safety and efficacy", while suggesting doctors inform patients of the benefits and potential risks. Once again growth hormone THERAPY isn't even close to being the same thing, yet doctors still promote it. Talk about apples and oranges.
Main point is FDA isn't concerned with bryostatin safety. That's proven in hundreds if not thousands of studies and [patients]. Company isn't worried about raising igf levels to normal and in fact they promote it as a modality. Shareholder's can make up their own minds whether "long term" use of a temporary enhancement of igf levels in a deficient elderly population not expected to live more than a couple years and losing their cognitive skills is worth it. I know I have. You are certainly entitled to your opinion.
What does grandma have to do with what I asked?
You said: "...and if 2/3 of the patients in the P2a start sleeping and feeling better they will get conditional approval without breaking the blind."
Conditional approval without breaking the blind???
Again, you have to break the blind to review the data to ensure there isn't a placebo effect. That's just common sense.
Breaking the blind before the final analysis is called an interim look, and it must be pre-specified in the trial protocol, and further it incurs a statistical hit to the final analysis.
If you can give a link to the description of this pre-specified interim look, then I guess we can discuss something. Otherwise, it's just wishful thinking.
"...and if 2/3 of the patients in the P2a start sleeping and feeling better they will get conditional approval without breaking the blind."
This doesn't make any sense.
You have to break the blind to review the data to ensure there isn't a placebo effect and to make sure there aren't any imbalances between placebo and on-drug arms of the trial?
Good to see a little PR work happening:
Neurotrope to Participate in the Sachs Associates 2nd Annual Neuroscience Innovation Forum
NEW YORK, Jan. 3, 2019 /PRNewswire/ -- Neurotrope Inc. (NASDAQ: NTRP), a clinical-stage biopharmaceutical company developing novel therapies for neurodegenerative diseases, including Alzheimer's disease (AD), today announced that Daniel Alkon, M.D., Neurotrope's President and Chief Scientific Officer, will be participating in a panel discussion entitled "Progress in Alzheimer's" at the Sachs Associates 2nd Annual Neuroscience Innovation Forum in San Francisco on Sunday, January 6th, 2019 at 10:25 a.m. Pacific Time.
About Neurotrope
Neurotrope is at the forefront of developing a new approach to combating AD and other neurodegenerative diseases. The Company's world-class science offers the potential to realize a paradigm shift to overcome one of today's most challenging clinical problems — finding a way to slow or even prevent the progression of AD.
In addition to the Company's Phase 2 trial of Bryostatin-1 in advanced AD, Neurotrope has also conducted preclinical studies of Bryostatin-1 as a potential treatment for rare diseases and brain injury, including Fragile X syndrome, multiple sclerosis, stroke, Niemann-Pick Type C disease, Rett syndrome, and traumatic brain injury. The FDA has granted Orphan Drug Designation to Neurotrope for Bryostatin-1 as a treatment for Fragile X. Bryostatin-1 has already undergone testing in more than 1,500 people in cancer studies, thus creating a large safety data base that will further inform clinical trial designs.
Please visit www.neurotrope.com for further information.
Forward-Looking Statements
Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements. These forward-looking statements include statements regarding the Phase 2 study and further studies, and continued development of use of Bryostatin-1 for Alzheimer's dementia and other cognitive diseases. Such forward-looking statements are subject to risks and uncertainties and other influences, many of which the Company has no control over. There can be no assurance that the clinical program for Bryostatin-1 will be successful in demonstrating safety and/or efficacy that we will not encounter problems or delays in clinical development, or that Bryostatin-1 will ever receive regulatory approval or be successfully commercialized. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties. Additional factors that may influence or cause actual results to differ materially from expected or desired results may include, without limitation, the Company's inability to obtain adequate financing, the significant length of time associated with drug development and related insufficient cash flows and resulting illiquidity, the Company's patent portfolio, the Company's inability to expand the Company's business, significant government regulation of pharmaceuticals and the healthcare industry, lack of product diversification, availability of the Company's raw materials, existing or increased competition, stock volatility and illiquidity, and the Company's failure to implement the Company's business plans or strategies. These and other factors are identified and described in more detail in the Company's filings with the SEC, including the Company's Annual Report on Form 10-K for the year ended December 31, 2017, and on Form 10-Q for the quarter ended September 30, 2018. The Company does not undertake to update these forward-looking statements.
Contact information:
Investors and Media
Sam Martin and Ryan Baker
Argot Partners
212-600-1902
I agree coach. Hopefully things will look better in January. Only 2 more weeks of tax-loss selling.
And maybe the tariff war, which looks bleak now, will be closer to resolved by sometime in January, stabilizing the markets.
Finally, it's quite possible we'll enroll our last patient in the confirmatory trial by end of January. I would hope NTRP will PR that milestone.
On the flip side, our non-memantine 20ug Bryostatin group did remarkably well.
The graph of the non-memantine placebo group was a head-scratcher, but the graph of the 20ug non-memantine Bryostatin group is very encouraging for the case of Bryostatin for the treatment of Alzheimer's.
FooBar:
You raise a very good point.
I'm just trying to reconcile our non-memantine placebo (overall greatly exceeded expectations + had 3 patients who did stunningly well) with the placebo seen by the 2003 memantine study (-6 average SIB)
Someone posted the "good day vs bad day" idea, which seems reasonable at first glance. That is, 3 of the patients had particularly bad days on the first SIB test, and remarkably lucid days on the last SIB test. HOWEVER "good day, bad day" might explain a few random patients, but still doesn't explain why the group as a WHOLE did so well (SIB change average of 0)
I still feel strongly that there is something to the greater intervention (IV)/depression angle. Each patient's SIB score is largely affected by the Alzheimer's, but IMO there is also a negative effect from depression on the SIB score. Subjective measures (like depression) have a greater chance of being affected by the placebo effect than objective measures.
I've been scratching my head on the 3 non-memantine placebo that scored so high on SIB (+12, +13, +15). So I decided to look deeper into the placebo effect, as nothing else explains these 3 moderate-to-severe AD patients.
Here is what I found:
- In looking at scientific articles on placebo effect, the more intervention there is in the medical procedure or delivery of drug, the more likely there will be a placebo effect! For example in a high intervention procedure like surgery, a sham surgery is likely to have a relatively high placebo effect. In the case of a drug, if the drug delivery is simple, like swallowing a pill, then the placebo pill is likely to have a relatively low placebo effect.
Why is this important? When comparing the Bryostatin trial to the 2003 memantine trial, the Bryostatin patients get an intravenous infusion which has much greater intervention (10-20 minute procedure with a needle) than simply swallowing a pill (memantine trial). Confirming this effect, our trial's placebo (SIB change of 0) performed much better than the memantine trial placebo (SIB change of -6). So, the Bryostatin trials are more likely to see a greater placebo effect than the memantine trial because of the greater intervention in delivering the drug.
- Further, in Alzheimer's, it is well-known that some AD patients will also have depression as co-morbidity. I think it's quite possible that a few of the non-memantine placebo patients in our trial were depressed and scored low on the initial SIB test. But after they received high intervention (IV infusion) medicine (even though it was placebo), this may have triggered a placebo effect reversal of their depression, helping them to improve their SIB scores, even though their Alzheimer's disease pathology was unaltered by the placebo IV.
---------------------
The good news: as discussed by runncoach and cyosol, a longer 24-week trial should see a greater separation between placebo and on-drug.
-----------------------
Sources:
https://www.sciencedirect.com/science/article/pii/S106345840900106X
"In general, the larger the intervention the higher the placebo effect. As in our systematic review1, greater placebo effects have been reported with injections than with oral medication in many conditions varying from pain relief in migraine28 to control of hypertension29"
https://www.ncbi.nlm.nih.gov/pubmed/26312426
"Therefore, it is common to find the presence of neuropsychiatric comorbidities such as depression, schizophrenia and bipolar disorder during the course or development of AD. These disorders can become severe enough to interfere with the patients daily functioning, and can worsen the course of the disease."
I have no inside info on this, but this strikes me as an "accounting" move:
- For instance another company that is currently negotiating a partnership is requiring that all patents be directly owned by Neurotrope
OR
- Our mgt is anticipating that FUTURE partnership negotiations will require Neurotrope to directly own the patents.
All conjecture.
[OT] Interim analysis.
For those interested, there was a recent discussion on this board of interim efficacy analysis with respect to a competitor, and how the alpha hit on an interim analysis makes final statistical significance more difficult to reach.
In a real world example, HALO just got an agreement from the FDA to DROP it's interim statistical analysis. That interim had an alpha hit of .01, which meant that the final analysis needed to reach a more difficult p < .04 (standard is p < .05). By dropping the interim analysis, they are now back to a standard p < .05, and statistical significance at final analysis is now EASIER to reach in this HALO trial.
The point is that all interim analyses for efficacy have to be pre-specificied, and further there is a hit to alpha, making final statistical analysis harder to reach.
See slide #5 for old trial design.
See slide #11 for new trial design (note: "Allows for 100% of alpha spend on OS")
https://s21.q4cdn.com/250105458/files/doc_downloads/2018/11/HalozymeInvestorCall1126Final.pdf
Cyosol:
Other diseases that Bryostatin may be able to treat (aside from those in the patent you cite):
Rett Syndrome
Lewy body dementia (mentioned by Dr. Alkon in September presentation)
Hearing loss (due to synaptic damage)
Chronic traumatic encephalopathy (CTE) (mentioned in another patent?)
Multiple Sclerosis (coach found it listed in a recent PR)
Hanuman:
Bryostatin is considered a small molecule, which is the class of drugs that has the most success in oral delivery. This doesn't mean that Bryostatin is guaranteed to be successfully given orally, but it has a better chance of success versus other classes of drugs.
The class of drugs known as biologics (like TNF-alpha inhibitors) can't be given successfully in oral form for 2 reasons:
- Biologics are difficult to absorb in the small intestine ("For biomolecules [biologics]...their large size and polar surface make it difficult for them to diffuse across the epithelial layer.")
- Biologics are easily degraded before being absorbed in the intestine: ("A second important issue for biologic APIs is their susceptibility to enzymatic and chemical degradation in the GI tract.")
"The main consequence of the poor absorbance and degradation of biologic APIs administered orally is low bioavailability."
http://www.pharmtech.com/oral-delivery-biologic-apis-challenge-continues
Good points. I just wish we were further along, rather than dealing with the 2 year delay we experienced with the last results. I'm impatient, and I'm sure a lot of people who know Alzheimer's patients would love to have a treatment ASAP.
Happy Thanksgiving to everyone.
Nice graphs!
Wow. I realize the numbers are small, but memantine sucks. Placebo minus memantine better than placebo plus memantine.
If only memantine had never been approved...we would have been off to the races after the last trial...
Alternatively, bryostatin may treat the 70% (roughly) of correctly diagnosed patients, as well as the 24% with other types of dementia (lewy-body dementia, vascular dementia, etc).
I added.
Biotechs nasty the last few weeks...
No proof of any other drugs showing superiority to Bryostatin. That requires a blinded placebo-controlled trial, which we have.
What NTRP is trying to do with Bryostatin is revolutionary. We've shown in a placebo-controlled trial, that moderate-to-severe patients IMPROVED in their SIB score. That has never been done before, and it's nothing that any of the competition can claim. Further, by eliminating the memantine patients, the treatment effect is increased almost 3-fold.
When Bryostatin is used long-term, as was done with our compassionate-use patients (moderate-to-severe), the improvements were miraculous. We have seen patients' MMSE scores improve by several points and restoration of activities of daily living. With long-term use of Bryostatin, such as we saw with these CU patients, I believe we will see the same life-changing properties of Bryostatin shine through.
Finally, Bryostatin was administered safely in the phase 2b trial for 15 weeks, and has been administered safely in other trials for over a year at higher doses.
What NTRP is trying to do with Bryostatin is revolutionary. We've shown in a placebo-controlled trial, that moderate-to-severe patients IMPROVED in their SIB score. That has never been done before, and it's nothing that any of the competition can claim. Further, by eliminating the memantine patients, the treatment effect is increased almost 3-fold.
When Bryostatin is used long-term, as was done with our compassionate-use patients (moderate-to-severe), the improvements were miraculous. We have seen patients' MMSE scores improve by several points and restoration of activities of daily living. With long-term use of Bryostatin, such as we saw with these CU patients, I believe we will see the same life-changing properties of Bryostatin shine through.
Finally, Bryostatin was administered safely in the phase 2b trial for 15 weeks, and has been administered safely in other trials for over a year at higher doses.
Sorry...I meant to say why AVXL has no Alzheimer's double-blind, placebo-controlled trial approved in the US. I assume the Rett's trial is unblinded and not placebo-controlled...those are the parameters we're talking about with the Alzheimer's trial.
In any case...if the Aussie AD trial is as you described, good luck with it. You'll need it.
If what you say is true, and this is how they propose to run a Phase 2b Alzheimer's trial, then I can understand why they haven't been able to get approval to run a trial in the US.
Pre-specifying interim statistical analysis is such a no-brainer that the FDA would shake their head and say try again.
Doesn't matter if it's centralized or single-payer or whatever.
Every unblinded interim analysis has to be pre-specified, with a hit to final alpha, or it is a meaningless analysis.
Otherwise, why not run the statistical analysis every time someone completes the trial?
For example: 3 patients complete the trial. Oh, look: 2 of the 3 patients improved. Stop the trial! This drug works! We don't need to see the other 400 patients.
That would be an absurd way to run a trial, and an even worse way to approve a drug.
This is why each interim analysis has to be pre-specified, and why there is an alpha hit for each interim analysis.
The easy questions are: how many interim statistical analyses will there be? What events trigger each interim anaysis? What is the alpha spend on each interim analysis?
"...and there should be an interim analysis of the Alzheimer trial in Q3 or Q4 2019"
Is this a check on safety by the data safety monitoring board (DSMB)? If so, we won't see any information on efficacy at this interim.
Or are you saying this is an interim STATISTICAL analysis? If so, this would mean that this is a pre-specified unblinded statistical analysis on the EFFICACY of the drug and management can view that information and may release it to the public. BUT, there will also be a corresponding hit to alpha in the final statistical analysis, which means it will be harder to reach statistical significance in the FINAL (trial end) statistical analysis.
If management views this as a possible registrational trial, then doing an interim STATISTICAL analysis for a drug that hasn't had a placebo-controlled trial would be like playing Russian Roulette with a 2-chamber gun.
Therefore, my best guess is it will be an interim SAFETY analysis next year, with no report on the progress of patients other than that the drug is well-tolerated and not many patients are dropping out. In the scheme of things, I think that result is to be expected.
"The rate of progression for Alzheimer's disease varies widely. On average, people with Alzheimer's disease live eight to 10 years after diagnosis, but some survive 20 years or more."
https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-stages/art-20048448
Interesting. So, we've never seen Multiple Sclerosis in a patent until the recent patent you posted, and now that the patent has been published (or accepted?), NTRP is including Multiple Sclerosis in the "about Neurotrope" section of our PRs.
Tough to tell without more info if this could lead to a collaboration like the Fragile-X trial.
Or could this even lead to a partnership?
Multiple sclerosis is distinct from the cognitive diseases that we potentially treat, in that it takes many years for mental deficits or dementia to develop in MS patients. For this reason, MS would be a good candidate for us to partner, as there is no overlap with the symptoms of the cognitive diseases (AD, Fragile-X, etc) we can potentially treat for many years.
The Multiple Sclerosis area of drug development is lucrative, and competitive. It wouldn't surprise me to see a partnership for a promising drug like Bryostatin, but because it is preclinical, I would expect a smaller upfront (most likely less than $20M) and low royalty (mid single-digit).
Thanks for posting, coach.
I noticed a few neurological diseases listed in this patent that I hadn't seen before. The complete list from the patent:
3. ... the neurodegenerative disorder is chosen from Alzheimer's disease, chronic traumatic encephalopathy (CTE), Parkinson's disease, multiple sclerosis, traumatic brain injury, Fragile X, Niemann-Pick C, frontotemporal dementia, vascular dementia, depression, bipolar disorder, schizophrenia, Post-Traumatic Stress Disorder, stroke, mental retardation, or brain injury.
An expanding list. Dr. Alkon also mentioned Lewy-Body dementia in the September presentation. Rett's has also been mentioned before.
Looks like we're very close in timelines.
Yes, I agree it's frustrating.
With new enrollment sites coming online rapidly, I would expect the enrollment rate to increase significantly. The goal 100 patients enrollment should be completed by January or early February of next year. With 15 weeks follow-up, final SIB scores will be gathered by mid-May.
The company should require ~10 weeks for data scrubbing and analysis, so that would suggest results probably by end of July?
10-Q out:
http://secfilings.nasdaq.com/filingFrameset.asp?FilingID=13030496&RcvdDate=10/30/2018&CoName=NEUROTROPE%2C%20INC.&FormType=10-Q&View=orig
"As of October 29, 2018, the Company is ahead of plan for its current clinical Study, having enrolled 37 patients into the dosing phase. Contracts have been finalized with 28 clinical sites that will participate in the Study."
Ragnaroc:
I have often wondered what would happen if the company adds another component to these trials:
What if, in addition to administering Bryostatin (or placebo) to the patients, there was also a component of frequent 1-on-1 work with the patients in "retraining" their brains in memory activities and in activities of daily living.
At the end of the trial, would the Bryostatin patients improve even more than the 6+ points in SIB score? I think they would. In contrast, I suspect that the placebo patients would still decline in their SIB score.
From your background, I'm sure you know that using/exercising the brain can be an important part of delaying patient decline.
Of course, as you point out, this costs money. However, if this retraining becomes an integral part of a drug that reverses AD/dementia, it may be possible that these patients that require round-the-clock care can be converted to an assisted-living scenario, which would save our healthcare system significantly in the long-run.
I will be interested to see if the severity of the disease plays any part in drug efficacy in any time frame, either short term or long term.
Babaji:
Patients in this trial won't be on Bryostatin long enough to improve from severe to moderate AD or from moderate to mild AD.
Keep in mind, though: if this trial shows a 6 point improvement in SIB score, it will be the first drug ever to show improvement in a trial in moderate-to-severe AD patients.
---------------
For better insight into the long-term improvement in patients, here are the results in patients who received Bryostatin under compassionate-use program (From a slide at a 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.
My guess is NTRP's trials use the full SIB.
At the clinical trials site page for NTRP's trial, there is no mention of using the Severe Impairment Battery - Short Form (SIB-S):
https://clinicaltrials.gov/ct2/show/results/NCT02431468?term=bryostatin&rank=2&view=results
In that the SIB-S is used to assess patients with very severe dementia, and NTRP's trials are in moderate-to-severe AD, it would make sense for NTRP to use the full SIB.
Here's one abstract that I found on BDNF's protection of brain vasculature:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811757/
"These findings provide novel mechanistic insight into vascular protective effect of BDNF in cerebral circulation."
I could be wrong, but I have a vague memory of someone posting an article that showed one of the pathways (BDNF?) that is activated by PKC-e had a positive effect on the health of brain vasculature.
I agree coach. Data really strong.
The 15 of 16 number could turn out to be really important, as follows:
As discussed before on this board, according to the literature, true Alzheimer's Disease, as distinctly characterized by Amyloid-Beta and Tau Tangles, is correctly diagnosed in somewhere between 60-80% of patients.
Why not 100%? Because the diagnostic tools (PET scan, etc) are only now beginning to catch up with the difficulty of diagnosing a patient with AD while still alive. Previously, the only way to definitively diagnose AD was with a post-mortem dissection of the brain.
So, what is the cause of dementia in the other 20-40% of patients that have the symptoms of Alzheimer's but don't have A-Beta and Tau? Vascular dementia is high on the list, as well as Traumatic Brain Injury (either a single incident of severe brain trauma, or repeated minor concussions as in contact sports).
If we take 70% as the number of correctly diagnosed AD patients, that means that of the 16 non-memantine patients who received Bryostatin, we would expect ~11 of them to actually improve in their SIB score.
But the post-hoc analysis shows 15 of 16 improved in SIB score.
It's quite possible that the post-hoc numbers are too small to draw any conclusions (small n), that is, we were lucky to get 15 correctly diagnosed AD patients in that group of 16.
Or, it's also possible that Bryostatin, because of it's multi-modal nature, not only improves the symptoms of Alzheimer's Diseases, but also improves the symptoms of other forms of dementia.
The new information that 15 of 16 patients improved in SIB score MAY be showing that Bryostatin will work in other forms of dementia, as well as Alzheimer's Disease.
heldnova:
https://www.nejm.org/doi/full/10.1056/NEJMoa013128
To add to what coach is saying, if you look at figure 2a in the article above, Memantine DOES slightly improve SIB for roughly 12 weeks, and then the decline in SIB continues on the same trajectory as placebo. So Memantine only delays the decline, and the brief improvement is seen only when starting Memantine.
The patients in our trial who were on Memantine have probably been on Memantine for many months or years. Therefore, the initial boost in SIB when starting Memantine in the first 12 weeks has long since passed for these patients, and wouldn't be reflected in the poster/graph NTRP presented yesterday.
Grich:
Great to see!
I can't take all the credit--it was a midnight project suggested by Coach.
Actually, the market is usually wrong at pricing risk-reward.
This is one of the best risk-reward propositions there is.
> I believe even if approved, use of this drug will be limited. <
If Bryostatin reverses AD in moderate-to-severe, I think you're way off. Will also be used off-label in those with diagnosed mild-to-moderate.
Add in the possibilities in other diseases (Fragile-X, Niemann-Pick, TBI, MS, etc), and Bryostatin has the potential to be a blockbuster drug.
> I didn't make the original statement so I won't defend it...
Understood
> By the way, wouldn't treating the cause of that "synaptic degradation" at an earlier stage be preferable?
In the long run, yes. But reversing moderate-to-severe AD may be the fastest way to a partnership and/or approval.
RE: "MOA is stimulating growth". To be more specific, Bryostatin encourages synaptic growth. Preclinical and post-mortem research suggests that synaptic degradation may be the cause of Alzheimer's Disease, as well as other neurological diseases.
Trying to compare Bryostatin to a statin is a false narrative. Or to be more specific, a lie.