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The calculation is flawed and so is the market. I'm not saying it's right, but it makes sense.
The company, the NIH, the bulls on this board and several others all agree there's a signal here worth pursuing, but the fact of the matter is that this drug has never been tested in humans for 6 months, and a lot of investors seem to ignore the huge question mark it puts on this whole thing.
I'm cautiously optimistic. The subgroup data looks promising but I think many of the bulls are too optimistic about the chance of success and too pessimistic about the value of good results.
Either way, we'll know for sure in only 2 months.
It makes more sense if you consider that most people either don't know about this company or don't expect it to succeed after failing to prove efficacy above placebo twice in a row.
If an approved AD drug is worth $20 billion and 99% of trials fail, then it would make sense that the first shot on goal is worth 1%, the second shot on goal is worth 0.5%, and the third shot on goal is worth 0.25%, which is $50 million.
A lot of people seem to believe that good results are worth $1 billion, which is strange to me because that would imply a 95% chance of failure.
Valuation reflects previous topline data and the market expecting history to repeat itself.
Of course it's undervalued if results are good, but there's no guarantee they will be.
What makes you think they would agree to a buyout instead of a partnership? It makes no sense for them to give up control over their IP when they can just license it.
As an example, Biontech developed the most widely used covid vaccine in the world but was never acquired by Pfizer. Now they're worth over $30 billion.
Don't forget the warrants. Most of them have a strike price below $10.
Market is forward-looking and will most likely account for future dilution.
I'm not a scientist or a doctor, but my personal theory is that AD can be caused by several factors, so if you eliminate all of them you prevent the disease entirely, yes.
I doubt it's only genetic though because there's plenty of AD patients that don't have those genes and still get the disease.
They measured a group of people with amyloid beta in their brains, with specific genetic variants that increase the risk of getting AD, and found that the patients that declined over time had less soluble amyloid beta in their brain than the patients that remained normal.
So the basic gist of it is that they're debunking the theory that amyloid is toxic and destroying the brain, because if it is toxic you would expect declining patients to have more of it in their brain than the patients that retain normal cognition, and yet the opposite is true.
So is the cause of AD just a lack of soluble amyloid beta in the brain? Of course not, but the authors say you could predict how a patient with amyloid in their brain and these specific genetic variants is going to progress based on the amount of soluble abeta in their brain.
Correlation =/= Causation
Clickbait article that completely misses the point.
Here's what the actual paper says:
"In conclusion, higher soluble Aß42 levels are associated with reduced risk of CDR progression, normal cognition, normal hippocampal volume, and normal precuneus metabolism to a greater extent than lower brain amyloid, lower p-tau, and lower t-tau levels in amyloid PiB-PET-positive individuals with autosomal dominant AD-causing genetic mutations. Brain toxicity in AD may be predominantly mediated by a reduction of the soluble protein pool, its functional fraction, rather than its accrual into amyloids."
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad220808
I couldn't find any mention of beta secretase (BACE) which cleaves APP in the wrong place and actually creates the amyloid beta. They did however mention that BACE1 inhibitors worsen symptoms, which has been proven in several failed trials over the years.
In the ibox there's a 2007 paper where Dr. Alkon et al. explain how the process works:
https://pdfhost.io/v/v0ARwmN0V_doi101016jtips200612002.pdf
There's plenty of technical traders out there that don't care about results and only want to make a quick buck. We also have a lot of index funds invested in the stock that need to sell shares whenever investors pull money out of their funds because of the overall market downturn. There's also market makers that make their money through arbitrage that don't care about fundamentals.
Sure, there's always a possibility that someone is manipulating the stock, but there's also a possibility that there's simply just a lot of people out there that don't care about the results. There's also the fact that people talking about manipulation usually do so because they can't imagine why the market would move in the opposite direction of their bet, rather than have definite proof of a coordinated effort to bring the price down. I would expect the short volume to be much higher if that was the case, and yet it isn't.
I'm sure most of the bulls on this board have already bought the amount of shares they want to hold through results, so if investors like that are done buying then why would the price be going up while the market is going down?
Just saying. This happened before results in 2019 too.
I don't mind the warrants (except for the ones they regularly give to consultants instead of cash). The alternative would be to offer shares at a 50% discount with no possibility to collect more money from exercised warrants if the price rises.
And I'm pretty sure the next cash raise isn't happening until they know how much they'll need for the next trial.
Short volume is actually pretty low. What's more likely is someone has been eager to offload their shares but hasn't been able to because of the low volume and lack of support at these prices.
Now that volume has picked up they were finally able to sell without tanking the price.
The price dropped before results for the previous trial too, so it wouldn't be unusual for it to do so again.
They have always believed they have something, but that doesn't change the fact that the trial is still ongoing, which means they haven't received any data yet.
No one will know what the data looks like until early November, and the public won't know until early December.
Like I mentioned earlier, the price movement before results is irrelevant because the public won't know what the data looks like before then.
"Synaptogenix Welcomes Lecanemab Phase 3 Trial Results"
https://www.prnewswire.com/news-releases/synaptogenix-welcomes-lecanemab-phase-3-trial-results-301635747.html
If you're in it for the long run and have an amount of shares you're happy with then the price before results is irrelevant.
Everyone wants to buy the all-time low and sell the all-time high, but that's not how real life works.
Don't forget Bioarctic which owns the patent.
Here's what it currently looks like:
Biogen: +$11.6 billion
Eisai: +$1.6 billion
Bioarctic: +$400 million
Total market cap change is +$13.6 billion.
Slows down cognitive decline by 27% after 18 months and 21.3% of those who received the drug experienced brain swelling or brain bleeding, while only 9.3% of those on a placebo had those problems.
Should be interesting to see how much Biogen, Eisai and BioArctic stock will have increased by close.
Not only does a small sample size make it harder to say but it also increases the risk of errors.
"As the trial size increases the absolute size of imbalance in baseline characteristics will reduce owing to reduction in sampling error. Hence the absolute magnitude of any chance bias in outcome will tend to decrease with sample size."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1116277/
That article mentions memantine discontinuation worsening cognitive decline, and yet every group in our trial improved except the severe patients on Bryo.
From the 2022 paper:
"As noted above, the #203 study showed a chance imbalance in the baseline SIB between treatment arms. Initial exploratory analyses showed that baseline SIB is statistically associated with both SIB score at 13 weeks post-randomization (Pearson’s ?=0.81, p<0.001) and the change in SIB scores at 13 weeks from baseline (Pearson’s ?=–0.25, p=0.014), suggesting that an imbalance in baseline SIB may confound the analyses."
For reference (Mean baseline +/- mean change (standard deviation)):
Moderate bryo: 83.0 + 3.94 (7.80)
Moderate placebo: 86.8 + 2.15 (4.78)
Severe bryo: 56.2 - 3.65 (7.42)
Severe placebo: 62.3 + 1.87 (15.26)
Take a look at those standard deviations and you'll immediately see why the real issue here is the small sample size, which is why they pooled the data to get a more accurate reading where placebo improvement drops to +1.17 (0.82).
It took them about 4-5 weeks after completion the last two times, so I think it's reasonable to expect the same for this time too. They did also explicitly say early December when asked about it.
Maybe it'll be delayed for some reason, but my gut feeling says it's gonna be the 12th.
That's true. If it ever was a problem before it will certainly not be one for the current trial.
Something I've been thinking about lately is the announcement itself. In 2017 they announced a Monday morning CC on a Friday afternoon to talk about "positive" results. In 2019 they announced negative results on a Monday morning without a CC or warning beforehand.
Now this is just me speculating, but maybe the past can be used to predict results before they are out.
We could then expect results to be announced on December 5th or 12th, and if it's positive we could expect them to announce a CC on the 2nd or the 9th.
No announcement on those Fridays could then be seen as a bad sign, while the opposite could be seen as a good sign.
We'll just have to agree to disagree then, because I think you guys are blowing this Memantine washout thing way out of proportion based on a 2% improvement in placebo patients.
From the 2022 paper:
"In the Moderate Stratum Cohort, the imbalance was much smaller, reporting a treatment group difference of 3.8 points in the means and 4 points in medians of baseline SIB scores (mean and median baseline SIB=86.8 and 89.0 in the placebo arm, and a mean and a median baseline SIB=83.0 and 85.0 in the bryostatin arm)."
Placebo patients going from a mean of 87 to 89 after 3 months is not that big of a deal imo.
Any potential effects from withdrawing Memantine use before the trial would also apply to the Bryo group, and yet we see that Bryo patients in both trials have almost the same score at 13 weeks.
Look at the tables and slopes in the latest bryo paper and you'll see it's the #203 placebo results that are statsig, not the #202 one.
I think the real issue is the small sample size which lead to negatively skewed placebo results in the #202 trial and positively skewed placebo results in the #203 trial.
Combine the two groups and you get a 1 point improvement, which is exactly what I would expect from placebo.
A good thing about this latest trial is that they can create a pooled analysis with data from all three trials, bringing the sample size on each side to almost 100.
Whatever the 6 month data may say, we'll at least get a proper look at how both groups perform after 3 months.
Maybe the Memantine trial had a lot more placebo patients not on any drug slowing the decline. It's the earliest one of the trials.
My guess is current standard of care puts placebo patients at about -1 to -4 after 6 months.
Added the Donepezil paper to the ibox for those that want to skip the paywall.
https://pdfhost.io/v/xU~FcgHoq_winblad2006
Slowing the decline may be enough for market approval, but it's not what the company is aiming for.
Outperforming Aricept with a positive slope is what would really blow everyone's socks off.
Sounds about right. Anything over 6 points above baseline would be a game changer.
Now that I think about it, didn't they already check patients on Aricept after the #202 trial and decide to keep them in because there was no significant difference between them and previously drug-free patients? I don't remember what the reason was.
In that case a lower score than Aricept might still mean patients can get additional benefits from taking both of them at the same time, since patients on Aricept will presumably already be on the decline before using Bryo.
It also depends on if the curve flattens or declines after 15 weeks for bryo patients I think. If the 13 week slope for combined bryo data stays the same (about +0.3/week) then that would imply an improvement of about 8.4 after 28 weeks, but that's a big if.
Failing to beat Donepezil scores would be even worse then, since it would imply patients are better off taking Aricept alone.
I seem to have missed the fact that Donepezil (Aricept) showed a 5 point SIB improvement in severe patients after 3 months and a 4 point improvement after 6 months:
https://www.sciencedirect.com/science/article/abs/pii/S0140673606683505
So I decided to quickly make a simple chart that shows the progression of drug and placebo groups in the Donepezil, Memantine and Bryostatin trials:
https://i.imgur.com/1e9AaAD.png
Keep in mind that the Donepezil patients had severe rather than moderate AD, that Bryo data is based on the combined non-memantine moderate data from both the #202 and #203 studies, that the 3 month mark means 13 weeks for Bryo and 12 weeks for the others, that the 6 month mark means 28 weeks for Memantine and 25 weeks for Donepezil, and finally that the numbers are rounded.
Staying above baseline alone may not be enough if people are hoping for it to outperform Donepezil, in which case it needs to show a 5 point improvement or more. Bryo patients in the #202 study did show a 6 point improvement after 15 weeks but no one knows if they can maintain or go beyond that after 6 months. All groups in the Donepezil and Memantine trials declined between the 3 month and the 6 month mark.
I guess what I'm trying to say with this is that we may have to aim for more than a 6 point improvement over baseline and placebo to establish Bryo as the best drug on the market. Less than 5 and we might get another article about it being worse than Aricept.
I don't think the employees are that unique and hard to replace (other than Dr. Alkon who's responsible for most patents). It's the patent portfolio and drug platform that would become the most valuable assets if results look good.
Any pharma company can find a way to manufacture and sell bryo now thanks to Dr. Wender. What they don't have is the IP rights to do so.
An acquisition would have to be approved by shareholders, while a partnership can be signed without that approval.
Either way it doesn't make much sense to speculate about something that depends on so many unknown factors.
I would say let's wait for the results first. Like you mentioned, it's only about 6 or so weeks left before they receive the data.
Damn, maybe I wasn't wrong after all.
No. Bad study designs should be blamed on the company that created them, not on the CRO that runs the trial according to those designs which they're contractually obligated to follow.
They wouldn't have hired WCT for a third time if the trials weren't conducted correctly.
More than a 6 point difference would mean it's better than Memantine, and if they stay above baseline it will be the first AD drug in history to accomplish that.
An improvement over baseline after 6 months would be revolutionary.
Any improvement over placebo with a two-sided p-value below 0.05.
First trial had a 2.6 point improvement over placebo but it got slammed for having a one-sided p-value of 0.07.
Second trial went so bad they didn't even need p-values.
Most of the optimism comes from analyzing subgroups post-hoc, but that's not going to impress markets.
For those that weren't there, here's what they wrote about the first trial:
https://www.science.org/content/blog-post/neurotrope-shameful-pr-stunt
https://www.thestreet.com/investing/stocks/a-neurotrope-stock-promotion-scheme-is-underway-but-who-s-paying-for-it-14117285
Note that there's no such articles about the second trial.
I wouldn't worry about that. There's a good reason for why the price dropped after the last two trials.
All they need is a statsig improvement over placebo, which the last two topline data announcements failed to provide.
I have to say, this stock has been remarkably stable for the past month considering the overall market turbulence. You'd think the low volume would make this easy to sway towards either direction but it has consistently remained around $8.
Maybe I was wrong about the market dragging this down with it.
They have already shown a 4 point increase (+4) in moderate non-memantine bryo patients after 13 weeks, so if the drug works as intended I would expect an even higher increase after 6 months.
The placebo group in the Memantine trial showed a 10 point decrease (-10) after 28 weeks, so maybe that will be the case here too. Who knows though. I was wrong about the last two trials and I could be wrong again.
Let's see if third time's the charm.
The OL study started in July and they already know the drug works after 3 months. The problem is that placebo also works after 3 months, in some cases even better than the drug.
By the time they receive any longer term data from the OL study they will already be busy going through the more important 6 month double-blind placebo data.
Open label means everyone knows what they're getting throughout the trial.
In this case there is no placebo and there is no blinding, so everyone will know they're getting bryo on top of what dose they're getting. Company is probably getting realtime updates too, but they may also choose to check the patients at a later date.