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IMO the 30 day washout should be enough, but there’s a reason they went to 90-day; whether it’s just to be sure there is no memantine effect, or there is some scientific basis for extending the washout to 90 days.
As you point out, the more important feature of the new trial design is extending the trial to 2 cycles. Should “wash out” at least some of the placebo responders.
I heard an interesting trial design awhile back that could help in neuro trials, which are notorious for high placebo:
For the first dose (or first few doses if drug is given daily), give every patient placebo, while telling each patient they may be getting the drug from the first dose. Anyone who responds to the placebo, above a certain threshold (for SIB you might use > 1.5 or so) is removed from the controlled trial and paced in an open-label separate trial.
This would weed out at least some of the strong placebo responders.
[This post from 2019 analyzes the half-life of Memantine/Namenda:]
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=151028423
The peer-reviewed article in the journal “Expert Opinion on Therapeutic Targets”?
Wow…that’s a prestigious journal, lol.
"After an initial titration period, Aduhelm is to be administered at a maintenance dose of 10 mg/kg, given as an intravenous infusion over about one hour every four weeks."
Some analysts see the new BIIB AD drug Aduhelm as a $5-10B/year drug (blockbuster status). In spite of IV delivery. Positive read-thru for Bryostatin in it's current delivery (IV), if successful in trials.
Even better for Bryostatin/SNPX if it can be converted to pill form (or SubQ) and shows more definitive beneficial results than Aduhelm.
Outstanding summary.
Just to add: concurrent with the 2 trials over the past few years, the Wender group (contract manufacturer) has developed a process to economically produce a synthetic equivalent to natural Bryostatin.
This should lead to several major improvements in the development of Bryostatin:
- Abundant supply of synthetic will enable development of a pill and/or subcutaneous (SubQ) delivery
- Pill/SubQ will have better patient tolerance
- Less invasive delivery will result in less placebo effect (false positive) in trials
- More frequent/smaller doses (pill or SubQ) should mean greater consistency and predictability in patient outcomes
Looks like Silverman (Director) joined the insider buying party today, as well.
Silverman: 10,000 shares at $8.30
Alkon: 10,000 shares at $8.26
"How/when will we know who bought it?"
I think there's a clue in today's NR:
Tuchman (CEO): "We are appreciative of the continued support from our existing shareholder base who led this financing..."
Ha! True...
The only reason I see for further delay is if the preclinical work (in MS for instance) showed a daily dosing or 3X/week dosing is required for enhanced and/or consistent efficacy. And therefore need to wait for further PK/PD preclinical testing with subcutaneous or pill form.
Tuchman (CEO): “...and we look forward to continuing to update investors on our NIH sponsored Phase 2 AD trial, as well as discussions with strategic partners on other central nervous system indications."
THIS is the near-term catalyst that could/should move us higher, while we wait until Q3/Q4 2022 for AD results.
Don’t mind doing the financing now to fully fund our trial, while AD stocks are hot.
Not thrilled with the full warrants.
Synaptogenix Announces Phase 2b NIH Sponsored Alzheimer's Disease Trial Update
- Data Safety Monitoring Board confirms Bryostatin-1 Safety
PR Newswire
NEW YORK , June 9, 2021 /PRNewswire/ -- Synaptogenix, Inc. (Nasdaq: SNPX), an emerging biopharmaceutical company focused on developing therapies for neurodegenerative diseases, today announced an update on its ongoing National Institutes of Health ("NIH") sponsored Phase 2b clinical trial of Bryostatin-1 in patients suffering from moderately severe Alzheimer's disease ("AD"). To date, the Company has now dosed 58 of its target 100 patients. Seventeen sites continue to be live.
Additionally, the independent Data Safety Monitoring Board ("DSMB") overseeing the trial convened to assess the safety of Bryostatin through an interim analysis and confirmed that 40 advanced AD patients have been dosed with Bryostatin without any significant safety issues.
Alan Tuchman M.D ., Chief Executive Officer, stated, "With the spotlight firmly on Alzheimer's disease following the recent FDA approval of Aducanumab, we are encouraged to see the level of evidence for Bryostatin -1 continues to grow. The DSMB assessment further validates the significant safety profile of Bryostatin, as opposed to safety issues observed with other candidate Alzheimer's drugs now being developed."
"Our two previous pilot trials demonstrated safety while also showing a 4.8 improvement over baseline of the Severe Impairment Battery Score. We are pleased that our ongoing six-month Phase 2b trial sponsored by the NIH, has also displayed signs of safety thus far, consistent with our two previous trials," stated Dr. Daniel Alkon , President and Chief Scientific Officer. "Efficacy and safety continue to be our primary objectives in the clinical trials of Bryostatin to treat advanced AD patients."
About Synaptogenix, Inc.
Synaptogenix is a clinical-stage biopharmaceutical company that has historically worked to develop novel therapies for neurodegenerative diseases. Synaptogenix has conducted clinical and preclinical studies of its lead therapeutic candidate, Bryostatin-1, in Alzheimer's disease. Preclinical studies have also demonstrated Bryostatin's regenerative mechanisms of action for the rare disease, Fragile X syndrome, and for other neurodegenerative disorders such as multiple sclerosis, stroke, and traumatic brain injury. The U.S. Food and Drug Administration has granted Orphan Drug Designation to Synaptogenix for Bryostatin-1 as a treatment for Fragile X syndrome. 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.
Additional information about Synaptogenix, Inc. may be found on its website: www.synaptogen.com .
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 clinical trial of Bryostatin-1 and further studies, and continued development of use of Bryostatin-1 for AD 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 its 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 its business plans or strategies. These and other factors are identified and described in more detail in the Company's filings with the Securities and Exchange Commission. The Company does not undertake to update these forward-looking statements.
Contact information:
Investors and Media
Investor Relations
Brett Maas
Hayden IR
brett@haydenir.com
(646)536-7331
Robert Weinstein
Chief Financial Officer
Synaptogenix, Inc.
rweinstein@synaptogen.com
CisionView original content: http://www.prnewswire.com/news-releases/synaptogenix-announces-phase-2b-nih-sponsored-alzheimers-disease-trial-update-301308982.html
SOURCE Synaptogenix, Inc.
News Provided by PR Newswire via QuoteMedia
I don't get it either.
Acting director Janet Woodcock was also involved in a controversial approval of Sarepta's drug for Duchenne Muscular Dystrophy (DMD). That one also had controversial data (used historical data? walk test sketchy?). Still, I thought the Sarepta drug approval was an ok decision: Advisory committee was split on the vote. It's a very rare disease with only a few hundred cases/yr diagnosed. And DMD patients are diagnosed very young, with death usually occurring by mid-20s.
Good article. Thanks.
On the surface, it appears the FDA was in a no-win situation with AD advocates on one side and FDA/Pharma oversight groups on the other.
I'm more in the camp of the oversight groups:
The FDA had an easy out to deny approval, with their own advisory committee voting 10-0 against approving aducanumab.
Further, the FDA caved to Biogen in their requirements of a confirmatory trial: NINE years to complete. Plenty of time to cash in on a drug windfall that seemed unlikely to be approved for the past several months.
Finally, I was all for GILD's initial pricing on its HCV drug, about $60,000 for a treatment/cure. But aducanumab, at $56,000/year, doesn't seem remotely close to the cost benefit of GILD's HCV drug.
----------------
On a positive note, near-term should be good for CNS drug companies and biotech stocks in general.
Aducanumab (BIIB) approved.
Hope some of the money starts flowing to SNPX
Since the 1-for-4 reverse merger, SNPXD is now a low-float, low market cap stock.
Doesn't take much for share price appreciation with these types of stocks. For an example, see PIRS. Just signed a deal with a relatively small upfront ($20M), and share price increased almost 2.5X.
I added to SNPXD this morning.
Also, ANVS trial wasn't statistically significant versus placebo (only statistically significant versus baseline, which we know doesn't count)!
Thanks Cyosol for updating the Intro. Very helpful.
Thanks for the update from this conference, Coach.
Of all the other potential indications for Bryostatin, I'm most interested in a traumatic brain injury (TBI) treatment. Imagine a drug that can treat athletes who sustain a concussion, or soldiers returning from frontlines with TBI. An area of treatment, with unmet need, for our younger population!
I think that proposal (#2) is post-merger/reverse split.
NTRP previously had ~25M shares outstanding.
1 for 5 split occurred on merger with Metuchen, so PTPI now has ~5M shares outstanding, and holds Metuchen assets and Bryostatin assets.
Spinco (NBI) is created and receives Bryostatin assets, and shareholders of record on November 30 receive 1 share of NBI for each share of PTPI held.
NBI will have ~5M shares outstanding, which is 1/5 of Neurotrope outstanding shares before merger with Metuchen.
Bioequivalence (for synthetic) and bioavailability (if we switch to an oral formulation) studies are typically small phase 1 trials.
As an example, NTRP ran pre-clinicals for Traumatic Brain Injury (TBI).
Since TBI is a new indication, NTRP may need to apply for an exploratory dose-escalating trial to determine the max-tolerated (safety; PHASE 1) effective dose, since this dose/sequence may be different than what was determined for Alzheimer's.
FDA may require a new PHASE 1 trial for the synthetic Bryostatin 1 anyway.
Here's a good candidate for NTRP to run an exploratory trial:
Run a PHASE 1 trial using synthetic Bryostatin 1 on one of the other neurological indications...
Thank you.
If there is readthrough from the preclinical Fragile-X abstract you posted to the Alzheimer's trial, then readout in 2022 will be something to look forward to.
I do hope NTRP mgt considers doing a few small phase 1 trials in other indications in the interim time.
Hope this quote from the Fragile-X preclinical work has some read-through to NTRP's Phase 2 Alzheimer's trial:
"Interestingly, a short period of treatment (5 weeks) only produced very limited or no therapeutic effects on the autistic and cognitive phenotypes in the Fmr1 KO2 mice, while a longer treatment (13 weeks) with the same dose of bryostatin-1 effectively rescued the autistic and non-spatial learning deficit cognitive phenotypes. It is possible that longer-term treatment would result in further improvement in these fragile X phenotypes. This effect is clearly different from other treatment strategies tested to date, in that the drug shows little acute effect, but strong long-term effects."
Coach:
The only other reason for the buy is to keep the stock above $1 for listing purposes.
But, in the end, there is really only 1 reason an insider buys: to make money. They sell for many reasons, but only 1 reason to buy.
Just saw a review (from someone I respect) of the AVXL call/PR:
"
$AVXL call summary for you:
1. We hit great cognitive endpoints (no one knows which)
2. A 10 minute introduction to Parkinson's disease
3. Question: can you elaborate on efficacy? -Yes all the efficacy endpoints were amazing
4. Were secondary endpoints met? -We have too much data so we don't know
5. To conclude, I hope you are as excited as us about the data today
"
It would be great if someone can post the AVXL p-values??
---
NTRP made the mistake after the first phase 2 trial of claiming success based on ONE-SIDED p-value, instead of the industry standard TWO-SIDED. But at least the one-sided statistical analysis was pre-specified AND we had a p-value to discuss.
I didn't listen to AVXL's conference call.
Were any p-values given for the primary endpoint or the subset analysis?
Was the subset analysis pre-specified or post hoc? If they didn't say it was pre-specified, then I assume it was post hoc. (A secondary endpoint would be considered pre-specified)
Did they say how many other post hoc analyses were run? I think it was doc that pointed out on the NTRP data that if you run enough post hoc analyses, you're bound to find a subset that works, and success in a subset is still a fail.
In any case, very disappointing if they didn't give a p-value on the primary endpoint.
The only conclusion one can draw if they don't give the primary endpoint p-value is that it's a failed trial.
I do wish them better luck in the next trial. Another tough disease. I don't believe NTRP has anything active in PDD; AXGT reported positive results over a week ago and will report more results within the next several weeks. However, their trial was uncontrolled and small n.
Can't vouch for the accuracy of this tweet:
Data any minute now: $CVM - 164 days since trial completion$AVXL - 124 days$NWBO - 1885 days
— Jssr (@juliaskripkaser) October 12, 2020
Best guess is traders used the patent PR a few days ago to run up the price of CANF, followed by other traders (who bought higher) deciding to unwind their positions today.
Hope we hear something soon on the COVID trial in Israel.
Trying to analyze this PR, to see if there's any read-through from the initial 40-pt trial in Israel.
Facts:
- Israeli company, so they have better contacts with researchers/hospitals there. Made sense to run the initial trial in Israel: faster startup, enrollment, and results.
- Even if they enrolled all 40 patients on the first day of enrollment (April 13th), the 28 days of treatment/follow-up ended this past Monday. More likely, they are about half way through the initial trial (full read-out early-to-mid June?). It would be questionable to report results on an incomplete trial at this time.
- But, this 40-pt Israeli trial, randomized 1:1, is open-label, so they know the results as they go.
----------
If they aren't seeing good results, it would make no sense to apply for a larger randomized, controlled trial in the US. This company is running on a small budget, and would not pursue a follow-on trial with ambiguous or negative results.
IMO, they are seeing good interim results in the initial trial.
Any other takes?
What I've seen on NTRP is an attempt to advocate for the science. Hope this continues.
S-3 filing after hours, but this was just to renew the expiring $100M shelf.
It's been 3 months since any significant news ($18M offering).
Seems quite possible NTRP was close to a deal, but the COVID pandemic put things on ice.
Possible we may have to wait another few months before a deal is struck?
Exactly. As you say, priority #1 is an acquisition/merger.
Priority #2 is analyzing/advancing Bryostatin results and/or advancing a new Bryolog.
With 7-10 years of cash in the bank, cash concerns aren't even a blip on the radar, until the company decides it's future with an acquisition and/or new trial with Bryostatin.
c'mon coach...your priorities are messed up if you're not concerned about something that might happen 10 years in the future.
lol
The pre-specified raw data on the Bryostatin treatment group looks stellar.
The next trial will come down to understanding that placebo effect.
Is it due to a more invasive treatment (IV)?
Is it due to comorbidity of depression?
Is it due to some long-term positive effect from going cold-turkey on Memantine?
Or other?
But, it's fortunate that the company called for the pre-specified analysis in their statistics plan.
You are right--it is BOTH pre-specified and post-hoc.
Was the recent release of subgroup results post-hoc? Or is it pre-specified?
My understanding is the recent analysis was pre-specified: stratigraphic analysis of 2 subgroups (moderate and severe).
Red:
Can you give us details on who the CRO was for each trial, and where you find ratings for each?
Thank you
Good summary. Your suggestion to extend the trial should be high on the list of things the company undertakes. I was a bit surprised that the company didn't extend the trial longer last time (as I think you were).
Seems like a few things that need to be addressed:
- Why is placebo doing so well? How to get that group to "behave" more like other trials.
- How to get a better balance in the trial (unusual imbalance in the randomization).
I would still like to see if there is any long-term benefit to going through a washout of memantine. There might be some insight if the company released a subgroup analysis (on-drug vs placebo) of those who weren't on memantine prior to entering the trial.
In addition to extending the trial, both of these issues (placebo and imbalance) should benefit from a larger N (perhaps 300 patients?).
If bryostatin works, I think the key is to activate those pathways (BDNF, etc) in vivo, by activating PKC-e repetitively.
If those neuro-restorative pathways aren't activated, the disease will continue attacking the newly introduced synapses and neurons. At least that's how the theory goes.