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Agree here with Antii and Coach and Cyosol.
If we can reproduce the outstanding p<.02 results, showing that Alzheimer's patients improved (never been done before by any drug), then NTRP is in control of a drug that should be approved and should be one of the best-selling drugs of all time.
If we can get similar p-values from this confirmatory trial, NTRP stock should move well beyond $1B valuation within a few weeks/months of results.
Here's why: Not only will biotech funds ("specialists") need to own NTRP stock, but I believe "generalist" funds (those funds that can buy any stock, not just a sector) and hedge funds will want own stock in NTRP. This type of demand should see NTRP market cap easily get over $1B IMO. I see signs that the company is gearing up to get the word out if we are successful.
Yes, there's still risk, but I like the NTRP risk-reward proposition from here.
I don't think "Baseline through 30 days post end of treatment" includes the 30-day washout period, if patient is on-Memantine.
"Inclusion criteria: Subjects who are memantine naïve or have been off memantine for at least 30 days prior to initial treatment with study drug."
August it is.
If these last patients don’t require the 30-day washout, then early August. If they do need the washout, then early September. I’m leaning late August/early September.
I've seen transduction and transfection used when a gene therapy is delivered with a virus.
FooBarAndGrill:
I understand the concern, but the use of a virus ("vector") to deliver most gene gene therapies is a standard delivery mode--usually an adenovirus, which has mild side-effects. But, perhaps your concern should be taken seriously, considering the brain is an environment with different immune characteristics than the rest of the body?
Of greater concern to me: how much will this therapy cost? Gene therapies can cost $150,000-$300,000 or more. So, while exciting if this works, it will see limited use unless they can lower the prohibitive cost.
Thanks coach. Your response has far more insight than I could have provided.
The only thing that I will add is that the study involved ~10 subjects in each group—control (C), parkinson’s (PD), parkinson’s with dementia (PDD) and Alzheimer’s (AD). Each disease group showed less hippocampal volume than control, but Alzheimer’s had the least (C > PD > PDD > AD).
This shows that while Parkinson’s does have an effect on the hippocampus, it is not as severe as seen in AD.
A few other differences between parkinson’s and AD:
- about 50-80% of parkinson’s Patients also have dementia.
- it takes about 10 years from initial Parkinson’s diagnosis to develop dementia, which is a much slower decline than seen in AD
- as coach mentioned, a distinct feature of PD is microscopic deposits of alpha-synuclein; this is another name for Lewy bodies, also seen in Lewy body dementia.
- Parkinson’s patients also have plaques and tangles which are seen in Alzheimer’s
- based on the above, Parkinson’s appears to my untrained eye to be a hybrid of Parkinson’s and Lewy body dementia.
Thanks for your insightful analysis of the patent. I didn't pick up on the "clumps", but with your explanation it makes much better sense now why they would combine Bryostatin with the CARM1 inhibitor.
Sounds like this CARM1 inhibitor has already been used in human trials (for cancer), which is a big plus. Now it's just a matter of delivery through the BBB.
Several years off I'm sure, but would increase IP for YEARS if the additional treatment is helpful at all.
Thanks for posting this patent.
Seems to focus on synaptic regeneration of hippocampal neurons specifically. From research, disruption of the hippocampus is implicated as the location of onset of Alzheimer's.
Using an arginine methyl transferase inhibitor seems to enhance the effects of Bryostatin, apparently by affecting other pathways (PSD-95, etc) involved in synaptogenisis.
Two important things of note:
- I could be wrong, but I don't ever recall one of our patents SPECIFICALLY focusing on hippocampal neurons (I believe other patents discuss neurons in general).
- It's great to see ongoing research and patents. This will ensure that NTRP owns proprietary technology/drugs related to synaptogenesis for many years.
Thanks FooBarAndGrill for the notes
Good take Antti. I only listened to half the call.
Their take on Aducanumab sounded non-committal.
The last 5 mins was very important:
Cost vs efficacy vs chronic treatment or 1-time treatment.
Significant efficacy will get rewarded with being able to charge a higher amount for treatment.
High cost drugs (mentioned an RNA treatment that may cost $300,000!) may not get 3rd party payer acceptance or it will be very restricted, but will still get prescribed and used if it's effective.
My opinion: If Bryostatin is successful, and we are the only treatment that improves outcomes, and we can deliver for less than $20,000/year, I think we will be sitting in a golden cost-benefit paradigm. Especially if we can improve people from being "full-time care" to "assisted living".
Good find! If enrollment completed, results could be ready by mid-August? (Assuming 16 weeks to final SIB tests + 8 weeks to scrub data, lock database, run statistics and report).
Not unless it's in the agreement to sell the shares. I didn't see any clawback clause.
I definitely agree with you on the absurd valuation. $50M market cap right now...should be more like $250M.
Management needed to raise cash before the end of last year, so that they would have enough cash to get through the new fiscal year (2019). Otherwise, when the accountants certified the year-end filings, they would have to flag the company as a "going concern", based on having insufficient cash to meet the upcoming year's expenses. Having this designation in the financials is a red flag to institutions and funds.
Having said that, I think a wiser strategy would have been to raise what was NEEDED to get through 2019 (about $10-12M or 2.5M shares @$4.50 + warrants). Any additional funds for other trials could have been raised with an ATM, which would have a dual benefit: (1) no warrants and (2) take advantage of anticipated higher prices leading into the AD results this summer.
MULTI-billion if they can get some other trials going, and succeed in all of them, lol.
It's important to see a separation, such as you point out (on-drug better by 4 or 5 or more points).
But the real key will be seeing a statistically significant p-value (<.05). The most recent post-hoc analysis showed a p-value of ~.01.
A successful p-value in a double-blind placebo-controlled trial is what investors and institutions are looking for.
I just did a search on the more common side effects that can occur with memantine:
drowsiness
dizziness
headache
confusion
constipation
No wonder the off-memantine placebo group did so much better than the on-memantine placebo!
The bar might even be less than 2 years. Namenda had a successful trial delaying decline for 6 months.
And if we can IMPROVE mental capacity the sky's the limit!
Not sure if this has been posted here before, concerning rare diseases:
- Starting last September, NTRP has added a comment about rare diseases in the "About Neurotrope" section of news releases ("Neurotrope has also conducted preclinical studies of Bryostatin-1 as a potential treatment for rare diseases...including Fragile X syndrome").
- A disease qualifies as a rare disease or rare pediatric disease in the US if it affects fewer than 200,000 persons. Fragile X affects approximately 80,000 in the US, beginning in childhood.
- If the FDA grants "Rare Pediatric Disease designation" (usually in phase 3) to a drug, and the drug is approved, then the sponsor company is eligible to receive a priority review voucher.
- Priority review vouchers can be sold or transferred to another company. The going price for a priority review voucher in recent years has been in the range of $150M-$300M.
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Of note, the recent news release concerning CD-22 + lymphoma and B-cell cancer is in Pediatric and young adult patients. It seemed a bit odd to me that this was only being pursued in pediatric patients.
In light of this most recent news release, and the pursuit of Fragile X (a rare pediatric disease), perhaps a component of Neurotrope's ongoing development strategy is to target rare pediatric diseases, in order to qualify for lucrative Priority Review Vouchers (as well as Orphan Drug Designation)?
I think the main difference between AXON and us is that we are not yet perceived as having a successful trial. The post-hoc analysis all looks outstanding and clearly indicates that Namenda interferes with Bryostatin, but we still need a successful phase 2 trial before we can hope for a market cap similar to AXON at its peak (>$2B leading into phase 3 readout).
Still, I think a reasonable market cap going into the phase 2 confirmatory results would be > $300M, and here we sit at ~60M.
As you say, our situation is better, since we can potentially IMPROVE AD scores, which I don't think AXON could. Also, if we can get a pipeline going, as coach suggests, we could potentially be in a great position. Imagine having a successful confirmatory phase 2 AD trial, and potentially a Fragile-X readout at the end of the year.
Yes, I agree:
No. 5 — “Saving Brain Connections by Targeting Synaptic Proteins May Treat Alzheimer’s, Study Finds“
"Researchers at the Karolinska Institutet in Sweden reported how proteins in nerve cell synapses — the junctions between two nerve cells that allow them to communicate — are abnormal in the brains of patients with Alzheimer’s disease, correlating with the rate of cognitive decline. The findings support the therapeutic targeting of synaptic proteins as a potential strategy for early disease intervention."
This is the core thesis of Bryostatin. Synapses are lost in AD, and Bryostatin, through PKC-e pathway, restores synapses.
The Karolinska Institutet appears to still be doing preclinical work.
Good luck with it...you'll need it.
Of course insomnia is seen in Alzheimer's patients in nursing homes, and of course caregivers will administer drugs to help treat some of the symptoms of Alzheimer's, including insomnia.
But we were talking about curing Alzheimer's with improved sleep.
I've never heard of a documented case of curing/reversing Alzheimer's with a sleep aid.
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I repeat:
Sleep aids (sleeping pills, anti-anxiety drugs and anti-depressants) help patients get to and maintain restorative sleep.
Many Alzheimer's patients are using sleep aids.
Therefore, if your sleep theory were true, it would have been seen many years ago in nursing homes, and advanced as a possible cure for Alzheimer's a long time ago.
Sleeping pills and anti-depressants aid in getting to restorative sleep.
Many Alzheimer's patients are using sleep aids and/or anti-depressants.
Therefore, if your sleep theory were true, it would have been seen many years ago in nursing homes, and advanced as a possible cure for Alzheimer's a long time ago.
Ms. Spencer had a genetic defect that caused early-onset Alzheimer's. No amount of extra or better sleep would help her outcome.
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Whether we design a trial that has induced coma or just adding sleeping pills, at least it would be a placebo-controlled, double-blind trial. We could then trust it was a reliable trial with no false signals.
Further:
“Sleeping pills...and some anti-anxiety medications cause drowsiness. Either way, these medications can offer tremendous relief to people who have trouble falling asleep or maintaining restorative sleep."
Yeah, just take a sleeping pill and you can cure Alzheimer's. Lol!
Do you think Jenni Spencer, one of NTRP's compassionate-use patients, would have benefited from more sleep? Absolutely not. She was nearly comotose. Bryostatin was the difference in her improvements.
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Here's a great idea: why don't we take a few of these moderate-to-severe Alzheimer's patients who have ~5 years to live, and put them in an induced coma for a year. Far more sleep than the average Alzheimer's patient.
Then we'll follow those patients for the remaining 4 years and see if this repairs their BBB and their synapses such that they survive beyond the 4 remaining years.
Finally, this should be a placebo-controlled, double-blind study. Wouldn't want to get potentially false signals, like trials run by other Alzheimer's companies, who claim success based on uncontrolled, unblinded studies.
And because we influence so many pathways, we will be able to treat many diseases, unlike most of the other treatments that work on only one cause of one disease. The importance of this will become clearer as the competition catches up. Especially if synthetic Brystatin is relatively inexpensive to manufacture and we prove we can reverse all of the brain damage listed above.
Great stuff, coach. Unfortunately, my reading list just got much longer, lol.
One common thread I'm seeing in all of this research, including the BBB articles you comment on, is that a normal functioning human body has an incredible array of mechanisms/pathways to heal itself. Just focusing on the brain, there are mechanisms/pathways:
- to repair the blood-brain barrier (PDGF)
- to fight infections such as HSV
- to clear tau and amyloid-beta and toxins
- to repair synapse damage
- to protect neurons
- to repair damaged vasculature
The breakthrough discovery from Dr. Alkon's research is that pkc-e is the master switch for most of these pathways!
If pkc-e levels are normal, these pathways will work successfully to heal the body in most cases.
If pkc-e levels are low, these pathways are less successful at healing the body, and over time, the components of the brain are overwhelmed. If the BBB is damaged, pathogens and toxins make their way into the brain, potentially overwhelming it's ability to fight pathogens and toxins.
Immunological responses to these pathogens/toxins results in an increase in tau/a-beta. If the brain is overwhelmed and can't successfully clear tau/a-beta, they eventually cleave to the synapses (a-beta) or are found in neurons. The synaptic network is damaged, memory fails, and over time the brain works less and less effectively.
I think the multi-modal aspect of PKC-e is what will distinguish us from all other approaches/drugs, since PKC-e is involved in most pathways that are involved in brain health.
Research suggests there may be many causes of Alzheimer's disease, such as genetic or dietary or environmental or brain trauma or BBB damage or infection or toxins, all of which eventually leads to synapse damage and loss. Through it's effect on multiple pathways, PKC-e fixes damaged BBB. PKC-e clears out tau/a-beta. PKC-e repairs damaged synapses. PKC-e protects neurons. PKC-e repairs vascular damage. PKC-e compensates for genetic defects such as apoe4.
And because we influence so many pathways, we will be able to treat many diseases, unlike most of the other treatments that work on only one cause of one disease. The importance of this will become clearer as the competition catches up. Especially if synthetic Brystatin is relatively inexpensive to manufacture and we prove we can reverse all of the brain damage listed above.
In reading all of these articles, it’s easy to get lost in the maze of symptoms and treatments, and forget all the amazing properties of PKC-e, triggered by Bryostatin.
Thanks for highlighting yet another pathway (PDGF) that Bryostatin will help by targeting PKC-e!
Based on how important this BBB hypothesis may work out to be, I have the feeling that the NIH is going to wish they had spent far more than $300K/year on researching BBB repair.
The articles I've seen you post and other articles posted elsewhere appear to be relatively new articles on the BBB and platelet-derived growth factor (PDGF), within the last 3-5 years. I foresee biopharma ramping up their research into the BBB.
Heck, a leaky BBB may explain a few of the other current working hypotheses, such as the one where herpes simplex virus (HSV) correlates with AD. My understanding is that HSV is a very aggressive virus, which would elicit a VERY strong response from our immune systems. And, if I recall correctly, these immune responses may be the cause of tau and amyloid-beta buildups.
Thanks for pointing out that PDGF is one of the pathways that is triggered by activating PKC-e with Bryostatin. Looks like we got this one covered.
PKC-e is looking like the master switch of all master switches for CNS diseases.
I would sum up my response to his article with: "Occam's Razor".
That is, the simplest explanation (placebo effect) is more likely to be true.
Yes, there was a significant placebo effect, but placebo is to be expected in any trial, and the 20-30%(?) placebo percentages are right in the expected range.
Further, as I've detailed on this board before, the nature of the drug delivery (IV) will increase and/or heighten the placebo response.
I would agree with him that it's quirky that the 3 best responders were on placebo, but we don't have enough info on each patient to understand that anomoly better. For instance: by chance, did these 3 patients have loving relatives that were telling them daily that they were going to get better because they were most likely on a drug that works? The placebo effect, in ANY trial, is very real.
Finally, it's too small of a sample to assess the placebo effect, so we really need to get the current trial results to better understand this.
You're probably right that we won't get data from any other trial before the AD readout this summer.
I suppose a partnership in another indication (MS?) is possible, but certainly can't predict if/when that will happen. I guess the only solid, concrete milestone is, as you point out, that the board is secretly voting on a buyout this week, lol.
Looking forward to the clean data readout in AD, and whatever else the company puts out on startup of other trials.
Seems like a good analogy.
It would be ideal if we can get preliminary results from a trial in a different indication (MS? Fragile X?) before Alzheimer's results. Having a backup indication would certainly boost confidence.
Interesting NY Times review of the book "THE BREAKTHROUGH Immunotherapy and the Race to Cure Cancer."
https://www.nytimes.com/2019/01/07/books/review/breakthrough-charles-graeber.html?action=click&module=Discovery&pgtype=Homepage
This quote from the article looks like a parallel to what might happen here with Alkon, the synapse theory, PKC-e and Bryostatin:
"That moment [late 19th century] could have signaled the beginning of the field of immunotherapy and, perhaps, the beginning of a new way to fight cancer — but no one else in the medical field bought it. Instead, as Graeber points out, Coley was relegated to quackdom, and the conventional, respectable treatments for cancer remained those of surgery, chemotherapy and radiation — “cut, burn and poison” in the words of the author and the medical establishment he writes about. It is simplistic but probably accurate to say that most cancer research went in the wrong direction early and stayed there: The conventional wisdom held that it was best to attack the disease instead of looking for ways to help the body heal itself."
As a follow-up post RE: the safety of Bryostatin, I was reading this article (posted by runncoach, I think):
https://www.scribd.com/document/386853846/Bryostatin-1-alleviates-experimental-multiple-sclerosis
The authors of this peer-reviewed PNAS article unequivocally state:
"The established clinical safety profile of bryostatin-1 in humans could expedite its development as a therapeutic agent in MS"
Agree with your comments, coach.
From any angle, it doesn't make sense.
Not much more to add to this subject.
There's next to zero chance that a government agency would usurp the trial oversight from the DSMB and PIs and trial sponsor.
Trial integrity is paramount, and any government agency knows that.
Wow, I can imagine the size of the lawsuit against the Australian gov't, if a mistake is made.
Again, there's no chance that any rogue individuals or a group in the Australian government takes it upon themselves to review ANY trial data outside of the pre-specified trial protocol.
And then the "hard evidence" would have to be unblinded to review the data as an interim look with a hit on the final statistical analysis.
In the example you gave, Grandma is anecdotal, which can't be used for approval. That's why a placebo-controlled trial is needed, to prove whether a drug works or not. Further, unblinding is necessary to understand if the placebo effect is playing a part. This is just common sense.
"We haven't seen the trial protocols on the Australian web site yet."
Until we see the protocol, IMO any unplanned views of the data are just wishful thinking.
No, it's not a similar MOA. Not at all.
"Long term tinkering with biological processes is scary."
Yes, I guess we should stop all drug development.
The projected Bryostatin use is that it will be used in BURSTS because of the downgrade of PKC-e with extended use. So, some # of weeks on, some number of weeks off, repeat as long as needed. This is NOT because of any safety issue.