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We don't know if bryostatin will ever succeed and/or get approved, and the just failed trial makes it much longer odds than it was before the readout.
However, if the issue is "they don't know what the drug does in a predictable manner", that doesn't mean the science is a fail.
The science may be solid, but there is still much work to do in getting the drug to work in a predictable manner.
My view from reading all those 3rd party validation articles you posted is that bryostatin has a "multi-modal" MOA:
PKC-e activation -> BDNF, NGF, etc. activation.
Appears that the work continues, but really no hypothesis or explanation of why the subgroup that looked so promising in the 1st phase 2 didn't repeat in the 2nd phase 2.
Also, no discussion of why placebo performed so well.
What is the requirement to reset the NASDAQ compliance clock?
Is it the closing price greater than $1 for 10 straight days?
If so, hoping it gets back over $1 by close...
Not without news, lol
Regardless of what they decide to do (partner Bryostatin/Bryologs, small trial with Bryologs, new trial for Bryostatin, etc.), I'd hate to see the PKC-e work go dormant.
Seemed like there was something promising here, with the compassionate-use patients, a statistical trend in the 1st phase 2 (all patients) and statistical significance in the 1st phase 2 non-memantine subgroup.
Hard to tell if Ryan is as committed to continue the work as I'm sure Alkon is.
I wouldn't mind seeing them start a low-cost phase 1 trial with one of the bryologs (more potent/specific and smaller molecule), but we don't even know if pre-clinicals are complete enough to file an IND.
As far as Bryostatin, I agree with you that any further development should probably have a large pharma involved. That is, if they even find some sort of signal in the current data.
Over the past several weeks since top-line data, it seems like NTRP was in play with traders, noting the extremes over the past few months as well as many tweets focusing on NTRP by day-traders.
In the absence of news, I expect this to continue.
In the absence of measuring drug levels (not done), or saving the containers (not likely), the only way I can see to verify who got the drug might be to cross-reference AE's with the patients. The AE's could be used as a rough guide to determine who got Bryostatin.
It's a long-shot, though.
The performance of placebo in the confirmatory trial was surprising to me. Especially in light of our exploratory trial and other companies' trials (Forest Labs, etc).
The performance of on-drug was also surprising, in light of compassionate use patients, and that both 20ug (16 patients) and 40ug (7 patients) non-memantine on-drug performed so well in our exploratory trial.
That's SIB-L (Language), not SIB.
i thought the SIB scale was 0-100?
Can you provide a link to your 3.7 number?
I assume your error margin is an INDIVIDUAL error margin. The GROUP as a whole should be closer to what would be expected for any given trial in moderate-to-severe AD patients. That is, trending downward over time.
I noticed the same, coach. There's something strange about placebo in this confirmatory trial, when comparing to the first trial:
Confirmatory trial placebo group at 13 weeks was +2.1 SIB average
In the last trial, looking at placebo scores (weeks 5, 9, 13, 15):
All placebo (-1.2, -0.0, -.4, -2.7)
Placebo with memantine (-1.3, -.4, -.5, -3.8)
Placebo non-memantine (-1.2, .8, -1.1, -1.0)
SIB +2.1 is a relatively small improvement in the confirmatory trial, but I agree with you that it almost looks like going off memantine has a positive effect on SIB scores?
--------
Unfortunately, it isn't just a case of placebo outperforming, since the on-drug group only improved slightly.
CU = compassionate-use patients.
There were at least 3.
2 had newspaper articles written about them:
https://www.wvgazettemail.com/news/rockefeller-institute-drug-provides-hope-for-alzheimer-s-treatment/article_bf5bab5f-e40e-5f47-95ca-666f14b795e0.html
https://www.kansas.com/news/business/biz-columns-blogs/carrie-rengers/article229253744.html
I do see your point.
It's just those small n (CU patients and subgroup from last trial) that keeps me intrigued with Bryostatin in AD.
But at this point, with cash low, your path makes more sense, unless something glaringly obvious pops up.
If you were doing a data review, what things would you look for, other than Namenda obstruction?
- Moderate vs Severe stratification
- Other NMDA obstruction. Ketamines, Neudexta, etc. also affect NMDA receptor
- Match AEs to those on-drug
- Anomalies between clinical sites
- Anomalies between World Wide Clinical Trials testers
Anything else?
Thank you.
Thanks doc, for your insights. Very thorough, very upfront.
I know you say that you think AD is dead, but do you think there would be any merit to exploring a small trial for those with early onset AD? I think it involves a genetic defect that affects AP0e4.
The reason I mention this is because of the compassionate-use patient, Jenny Spencer, who reportedly did so well on Bryostatin.
Everything is a long shot now.
But having a cash cushion does give mgt the time to review this data. They will look for subgroups in this trial, and hopefully analyze whether memantine has a long-term negative effect on the NMDA receptors even after the 30-day washout period.
If anything is found in this trial over the next 3-4 months, the assets will probably be sold or partnered on the cheap, but in this longshot scenario some may still be made whole.
Having cash also gives them a chance to explore other diseases, but again, these will probably be sold or partnered on the cheap.
The only potential for short-term upward movement that I see is if there's a filing that another significant investor took a >5% interest in NTRP. Obviously, another long-shot. Because the cash is ~1.50/share, I would view this as a near-term ceiling on any new filing.
Here's an excerpt from the FDA label for memantine:
"Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60-80 hours."
Using 80 hours as the half-life, there should be less than .2% of the peak blood concentration of Namenda after the 30-day washout, which is trace amount.
What wasn't studied (and maybe should have been?), was whether the NMDA receptor was "burned out" by being on a daily dose of Namenda.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021487s010s012s014,021627s008lbl.pdf
"...was 30 days washout long enough..."
I agree. I'd really like to see the subgroups, including those that were memantine-naive or who hadn't been on memantine for awhile.
Also, I was expecting some placebo response, but not as much as we saw.
"I’m betting we’ll never know."
Whatever they find in the subgroups, they won't be able to do it alone, so it will have to be either with a partner that pays for a follow-up trial, or they sell the assets on the cheap to a big pharma willing to continue the work. Or perhaps a big pharma interested in it for MS?
I'm truly shocked.
And devastated for those suffering from AD.
I think a company can hold onto material information for as long as they wish as long as they don't disclose it to a limited audience, such as at a conference or in an off-hand comment. But, they would probably have to disclose it in the next 10-q or 8-k, as the Sarbanes-Oxley Act seems to imply that material disclosures are required at the time of annual and quarterly reports.
Here's Reg FD:
Reg FD states that when a publicly traded company or issuer of stock discloses any material nonpublic information regarding that issuer or its securities to a limited group of individuals, the issuer must make public disclosure of that information. Such disclosures must be made simultaneously if it is an intentional release of information. Non-intentional sharing of such information must be promptly followed with public disclosures.
https://www.investopedia.com/terms/r/regulationfd.asp
Is there another SEC rule/guideline on disclosure of material information?
“My guess is there will be some flexibility because there are so few actual patients to start with so I doubt it would take 1000 to be honest.“
Good point. Also, it’s taken, what, a year for them to enroll 15 patients? So even a 300 patient trial would take AVXL 20 years to fully enroll, lol
Another thing I like about Neurotrope mgt. Once the trial starts enrolling, predicting when the readout will be is relatively easy.
So if I read this right, coach, after neuren successfully completes their phase 3 trial in Rett’s, and gets approval, then all other competitors (AVXL, possibly Neurotrope) will have to prove in a phase 3 that their drug (2-73 or Bryostatin) is either better (not an easy task) or non-inferior (very large, expensive trial, likely 1000 patients at least) to the standard of care.
Sounds like a difficult path to approval for any company if Neuren is successful in their phase 3 trial.
I’m glad that Neurotrope is focusing on the fastest and most likely path to approval, rather than wasting valuable resources on indications (Rett) where there are competitors that are significantly (years) ahead.
The laser-focus of Neurotrope/Bryostatin is far superior to the scatter-gun approach of 2-73.
That’s not the way I read his replies in AVXL quarterly:
Does running a trial on 2 continents make it more likely to succeed??
You say the AVXL P2b/3 AD trial is already considered a P3. I’ve seen no PR of that by the company. Until there is a PR, how can anyone assume there has been a “seamless transition from P2b to P3”. That’s an assumption on your part without any facts to back it up.
Further, the 2 readouts in 2020 are the first in-human trials for these indications, so the likelihood of success is less than if they had data from previous in-human trials for PDD or Rett’s. Previous placebo-controlled trials would be even better, but AVXL don’t have placebo-controlled or even a non-controlled trial.
AVXL CEO is saying they are looking for a “signal”, which to me indicates if they don’t reach statistical significance on the primary endpoints in either PDD or Rett’s, then they will be running post hoc analysis to slice and dice the data for a positive spin, which takes time, and of course the data becomes suspect.
Given the above, what should an AVXL shareholder use as their cut-bait point on Anavex? When they get to end of January and no results? Or end of February and no results? Or end of March and no results?
The logic for your investment thesis doesn’t make sense to me.
“A post hoc hypothesis was then formulated”
This is a false narrative of NTRP’s analysis of the last phase 2 results.
The hypothesis that there may be drug interactions (both aricept and namenda) was pre-specified in the trial plan, and this trial plan was filed with the FDA before the trial started. The pre-specified analysis was run, which showed namenda had a profound negative effect on the efficacy of bryostatin
Since it was a pre-specified analysis, your use of the term “post hoc” is false and misleading.
Yes, cyosol, looks like our new ~9% investor, Mr. Haywood, has some outstanding connections!
President Obama? I’m even more impressed with Mr. Haywood’s resume than I was before. Lol
Snowie:
Good point, NTRP CEO Dr. Ryan IS a patent expert.
Successfully fought a big Pharma trying to use a paragraph 4 exception to infringe on Forest Labs lyrics patent.
Won the original case and won the appeal.
Made Forest Labs MILLIONS and MILLIONS by protecting patents.
And this past spring/summer brought another ex-Forest Labs patent lawyer/expert onboard to NTRP.
Other companies are shifting through poop, while we are doing company-building projects
Just based on reading this article, it’s clear Mr. Haywood puts a lot of due diligence and thought into his investments.
Importantly, he doesn’t look at a company just on the basis of near-term trial results and the sometimes head-scratching decisions of the FDA.
Which to me indicates he thinks we have a good shot at outright success, but even if we get a highly significant subset, there is still a path to success—long term thinking.
By contrast, my guess is he looked at the total compensation of the AVXL CEO ($20M over the last 4 years), as well as the drip, drip, drip of the constant ATM AVXL has going, and decided “hard pass” until they can deliver some successful results in a placebo-controlled trial.
“Anavex have 3 current placebo controlled trials, two of which are destined to readout Q1 2020. They too may fail or succeed. If the latter huge potential imo with a more universally applicable MOA.”
These 2 readouts are the first in-human trials for these indications, so the likelihood of success is less than if they had data from previous in-human trials for PDD or Rett’s.
Further AVXL CEO is saying they are looking for a “signal”, which to me indicates if they don’t reach statistical significance on the primary endpoints, then they will be running post hoc analysis to slice and dice the data for a positive spin, which takes time, and of course the data becomes suspect.
Given the above, what should an AVXL shareholder use as their cut-bait point on Anavex? When they get to end of January and no results? Or end of February and no results? Or end of March and no results?
This is not true!
“except of course with a bit of post hoc data mining”
The data analysis from our phase 2 trial was pre-specified subgroup analysis, written in the trial plan.
This is not true!
“except of course with a bit of post hoc data mining”
The data analysis from our phase 2 trial was pre-specified subgroup analysis, written in the trial plan.
FB&G:
Certainly is possible (SRPT sales to buy NTRP), but I think their recent share price drop was due to an FDA setback on their 2nd drug they’re trying to get approved.
But it does make sense to sell some stock that you’ve made good money on to buy something else that looks good.
NTRP science is more complicated than AXSM science, but with the data analysis from the previous phase 2 and the peer-reviewed articles, there certainly is a lot of information out there to assess bryostatin and the potential for success in this trial.
I’m guessing Hayward doesn’t think his chances of success are 98.2%, but I’m sure it’s greater than 50%. Could be much greater for all we know.
Anything over 50% makes it an asymmetrical bet, of course.
Heck, most biotech experts said there is NO WAY the FDA would approve SRPT’s etiplirsen. But they did, and this investor (Hayward) succeeded on that one.
No guarantees on this one, but it looks like he does his homework.
He must think the synthetic won’t work
He must think it’s a small market.
He must think it won’t work in moderate or mild.
He must think it only jump-starts the body like a battery so family can have a few more months to say goodbye.
He must think it will be too expensive
NOT
Nobody invests $4-$5 mil in a company with a drug they expect to fail.
I have a strong suspicion that our new large investor ”looked at the data” from the last trial, lol
That’s a big bet.
Seems very positive, although could be hedged with puts.
Interesting the filing was done on a Friday evening. Not done acquiring, and trying to stay under the radar?
Red:
What we know about this just-completed Phase 2b trial:
- Run at 28 trial locations, each location overseen by its own principal investigator for quality assurance.
- There were no changes to the inclusion criteria, except that patients who were on memantine had to go thru a washout period of 30 days. MMSE had to be in the same range, stratified to 4-9 and 10-15 same as last trial.
- There was no change to the Bryostatin formulation or delivery, via IV delivery over 45 minutes.
- There was no change to the supplier of the drug (NIH, I believe).
- There was no change to the placebo delivery.
- There was no change to the drug sequencing (7 treatments over 12 weeks)
- There was no change to the contract trial company (World Clinical Trials?)
- The DSMB has checked this trial at various stages and cleared the trial to continue at each step. That is, there were no SAE's that caused the DSMB to determine something is going wrong and the trial needs to stop.
- ~95/108 completed the trial, which I think is a better completed enrollment rate than the last Phase 2 trial (the last phase 2 trial had a 40ug dose that may have caused greater dropout). If there some dosing issue, I am sure that we would have seen far more dropouts.
All true, coach. NTRP is actually in a good position going into the readout.
And your description of AVXL's dilution to raise capital doesn't even include the significant dilution as part of their "total compensation" package to their CEO. I've never seen a CEO of a fledgling biotech get paid that kind of compensation.