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Great stuff. Very helpful in understanding the synthesis. Thanks
Good points--thanks.
Above my paygrade, too, lol
Scanning the journal article, it's hard for me to get a feel how much Wender, et al improved the synthesis of Bryostatin.
A rough guess is that they combined 4 steps into 1 step.
Last I checked I think they were at 29 steps.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714505/)
So has Wender now improved the process to 25 steps?
The number of steps gives a rough idea of the economics: the fewer the steps, the less it costs to make.
25 steps is still a very complicated synthesis, but every improvement on the process improves the economics and helps the bottom line.
(As an aside: my understanding of the contract between Wender's group and SNPX does not change, even with improvements in synthesis economics. That is, this improvement will only improve Wender's bottom line; However, this should help to make synthetic Bryostatin more readily available for pre-clinical and clinical trials).
Also, we have a new CEO. It is the discretion of the CEO (and COB) as to what to PR. Perhaps this CEO has a more conservative view on what needs to be put in a PR?
Having said that, I agree with most on this board, that it would be better to be consistent with past practices.
Just looked up the 2nd trial, and our dropout rate was 1/2 of this donepezil trial, ~11%. Hopefully we get similar numbers in the current trial.
Thanks for the link. One comment:
"Indeed in this 6-month trial, the overall withdrawal rate was 22%. Although different imputation methods for handling missing data revealed similar results, this high drop-out rate should be considered during interpretation of the data."
This is something to watch for in our trial. If I recall correctly, we had relatively low drop-out in previous 2 shorter trials. Will be interesting to see if this low drop-out rate continues to hold true for the current 6-month trial. Especially if we get statistically significant results.
Ah, gotcha. I see there are 2 ADAS scales now. Thanks.
From the TauRx press release:
"The overall baseline MMSE score was 21 for the study population spanning MCI through to moderate disease. There was minimal decline over the first 12 months in participants receiving the 16 mg/day dose on both coprimary cognitive and functional endpoints (1.3 ADAS-cog11 units and -1.0 ADCS-ADL23 units). The expected decline over 12 months in an untreated population would be approximately 5 units on both scales."
Am I reading this correctly, that they expect a 5 unit (point) decline in MMSE in the course of a year, starting from a level of 21?
Seems a tad high expected decline?
Also, I wonder what this would translate to in SIB decline?
Good for BIIB/ESALY.
Their trial was in early AD, which might be the best population for the Amyloid hypothesis to work.
This article highlights decline issues with discontinuing memantine (and other meds):
https://pubmed.ncbi.nlm.nih.gov/35608903/
The only way this imbalance theory works in the context of our trial is if less severe AD patients (placebo) rebound after stopping memantine, while more severe AD patients (on-Bryostatin) don't rebound or worsen.
A few possibilities to explain differing rebound:
- more severe patients (on-Bryostatin) don't adapt cognitively as readily as the less severe patients (placebo)
- more severe patients have been on memantine a lot longer than less severe patients and their NMDA receptors rebound more slowly.
Clearly, all of this is just a theory, and there's barely enough info in the literature to even make an educated guess. But my viewpoint is the improvement in placebo patients is a significant statistical outlier, and needs an explanation. The memantine withdrawal syndrome is a known phenomenon. My theory of different rebounds is a guess, but supported by the data we saw in our last trial.
You're right--the bioequivalence study should provide some good info in Q4.
Just a theory, but my thought is there is an initial negative effect from the washout, followed by a potential bounce back:
- 30 day washout in last trial, causing worsening of patient status until first SIB test.
- Patients start to rebound from washout period during the trial, and 5-week, 9-week, 13-week and 15 week SIB tests reflect that rebound.
The only way this theory works is if the Bryostatin arm patients don't experience worsening from washout and then rebound. The trial imbalance might explain this.
Attempting to explain the unexpected placebo effect and less positive effect in the on-Bryostatin arm.
Way too kind, coach--you're the gold standard here. And a lot of good comments from many other posters.
Battle: if things ease up on the home front, I'll consider it.
SNPX: Would really like to see at least one more trial started before December. Brain trauma was always the one I favored, with concussions being a big issue in sports and military. But I think that's still on the back burner.
Point taken, but all other AD trials show how difficult it is for placebo arm to (1) improve and (2) continue to improve.
From our last trial, placebo arm:
Week 5 +.7
Week 9 +1.4
Week 15 +2.1
I'm no expert, but from my perspective, looks like more than just a statistical aberration.
Source:
https://www.clinicaltrials.gov/ct2/show/results/NCT03560245?term=bryostatin&draw=2&rank=5
(midway down the page)
Agreed--IV delivery (vs pill or even IM injection) could definitely be a factor in potential placebo effect. Hopefully bryostatin arm sees a clear and pronounced positive effect.
Looking forward to results...less than a quarter now.
"Any potential effects from withdrawing Memantine use before the trial would also apply to the Bryo group..."
Not necessarily. Trial imbalance in last trial could explain.
One hypothetical scenario (mistakenly stated "MMSE" instead of "SIB"):
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=169853097
The reason I stay focused on Memantine having an influence on placebo in the 2nd Phase 2 trial?
I don't recall placebo having significant improvement in the 1st Phase 2 trial. The only variable between 1st & 2nd phase 2 trial was 30-day washout period from Memantine use.
Extending that washout period to 90 days seems like the right thing to do.
Exactly.
As a hypothetical:
What if placebo patients in trial feel worse (withdrawal) for a few weeks after stopping memantine...and they score lower on initial MMSE test than if they continued taking memantine.
About the same time they are receiving first placebo dose, the memantine withdrawal is coming to an end...and the next time they are tested, they feel better and score better on their 2nd MMSE test.
---
For this hypothesis to work, memantine withdrawal would have to have less of an effect on the Bryostatin group. Trial imbalance may explain this.
Less than 5% of drug in system should be negligible, so ~15 days should get drug down to ineffective levels.
But, I'm with you Coach. Post-memantine withdrawal is a little-understood phenomenon, and may have an effect on placebo when memantine was recently discontinued.
"I really hope they PR when they gain the bioequivalence. I think that could be as significant from an investor perspective as announcing FragileX or MS trials."
I agree, coach.
Synthetic Bioequivalence ->
Unlimited supply ->
Oral tablet development (no more infusions) ->
Optimized dosing (daily at lower dose?)
- Vascular dementia is 15-20% of all dementia cases
- 5.8M total cases of dementia in US
- ~1M patients in US with vascular dementia
If Bryostatin proves successful in vascular dementia, that's a huge patient pool and potential revenue
Great find.
Vascular dementia is the 2nd most common form of dementia, about 15-20% of dementia cases. Alzheimer's is 1st, about 60-80% of dementia cases.
Coach: If most of the warrants aren't exercised by the expiry date, I wouldn't be surprised to see an extension filed (6-month?), in order get the desired cash inflow. Would make more sense than trying to do a cash raise at lower prices.
February release? Looks good.
There was an earlier article from Johns Hopkins group over a year ago. Is this the same group? How is the Feb ‘22 article different from previous article? Different mechanisms?
Thanks
RE: synthetic analog. Seems like it would depend on what they determine is the optimal preclinical dosing for MS. If a daily dose is required, IV delivery won't work, and getting the synthetic into pill form would make the most sense.
I've heard some development biotechs are being advised to hold news until after the new year...even good trial news has been rewarded with lower share price the past several weeks. Sure hope we hear something by JP Morgan conference (Jan. 10-13).
In this preclinical trial, Bryostatin clearly demonstrates remyelination capability.
Hope we can get a human trial in MS going soon, to see if unencapsulated Bryostatin has a similar effect.
Before the BIIB aduhelm bubble, there was at least one company that sported a $2B market cap after a successful P2, and leading up to P3 results that weren’t successful.
I could see > $2B MC with successful P2, but maybe not right away.
Some AVXL enthusiasts were predicting Aussie healthcare would notice amazing results from the AVXL Aussie AD trial and approve AVXL drug last year. Did that ever happen??
FDA sees things differently than you do.
At the very least, IMO, the FDA will require AVXL to do preclinicals and/or a longterm safety study (with imaging) to prove their drug doesn't increase amyloid plaques in patients.
Wow! AVXL's Blutarsky may INCREASE amyloid plaque?? [assuming there is readthrough from Harvard doc's preclinical tests on Sigma-1 drugs to AVXL's drug]
FDA just approved Aducanumab to decrease amyloid plaque. Seems like AVXL/Blutarsky is going in the wrong direction.
Oh that's right, Jenni. Thanks. And she had the early-onset APOE gene defect.
Interesting. Coach, were any of the compassionate use patients female? Can’t recall off the top of my head.
That's as good a guess as any.
Looking forward to hearing the details.
From the PR:
"Nemours' team of clinical experts will guide the direct interactions with the children, oversee administration of drug protocols, conduct a broad range of psychometric evaluations, and implement a novel Bryostatin efficacy biomarker."
I'm assuming they mean "test for" when they say "implement".
What is the biomarker? A marker in the blood? Or in the CSF? Or an imaging biomarker?
lol...yeah, that's some of what I'm thinking too.
True, the variability from day-to-day. I would hope we have that variability accounted for by having a large enough placebo-controlled trial.
As cyosol said in an earlier post, we had that Harvard biostatistics guy help design the trial. Should give us a better chance to succeed than previous trials.
"...sounds like data manipulation to me."
Patients are excluded from trials for many reasons.
Just look at clinicaltrials.gov...every trial has inclusion and exclusion criteria.
And, I wasn't saying exclude EVERYONE that improves, I would just exclude those who are super responders to placebo (greater than a certain threshold).
If a patient is shown to respond remarkably to placebo, seems like as good
a reason as any to exclude that patient in a neuro trial.
If AD is a real disease with no cure, why would they even respond to placebo over the short-term?
Obviously there is more at play. Some patients respond to just being treated (taking a pill or getting a shot or getting an IV infusion), whether there is sugar in the vehicle or actual drug.