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2 key points to parse in Adam's tweet:
"Big is not necessarily legit. micro rarely so."
Is there anything in history of $NTRP to prove exception to the rule?
Before today's mailbag, AdamF had the following comment about NTRP on March 21st:
An earlier study conducted in 2015 tested a single dose of bryostatin in six Alzheimer's patients. The drug was found to be safe but there was no change in cognition in the bryostatin-treated patients compared to placebo-treated patients, according to Neurotrope. A handful of Alzheimer's patients have also been treated with bryostatin under compassionate use regulations.
kid2:
"2 or 3 CU patients could demonstrate that there is efficacy."
"But let's then ask the Street what it thinks. Why is the MC at 145m for an indication that has potential sales of billions of dollars if the results of the Ph2b trial have a very good chance of being positive? Let's cut through the bs. Look at tute participation."
"A cure for AD is staring them right in the eye and they fail to act?"
"It is not a sure thing; it is less than a sure thing"
"...and if anything reflects this uncertainty it is the MC--the potential value that the Street gives it."
"Those three CU mean squat to The Street."
"Dr. Akron's words mean squat to the Street."
My understanding is it was the 95-year-old patient on the presentation slide, in the Bahamas, 3 years before Jenni Spencer.
No idea who conducted the compassionate-use administration.
Can you give the link to your article? No time to search.
Thanks
Theburg:
You make the most important point here.
There are side-effects for every drug developed for a particular disease. That's why the FDA and data safety monitoring boards have to weigh the risks of that drug against the benefits, to determine whether the drug should be used for that patient population.
Further, even if there is an increased risk of seizure or psychosis, there are anti-seizure meds and anti-psychotic meds.
Best comparable disease to severe Alzheimer's is a deadly cancer. Ask a chemotherapy patient how many anti-emetic drugs and anti-pain meds they take, in order to have the chance to live.
We will have a much better picture of the risk-reward of Bryostatin in a few weeks. I'm very encouraged that the DSMB, who saw all of the adverse events in the Bryostatin 2b trial, allowed the trial to continue.
Coach:
I agree. Her mother had documented seizures, as did Jenni, and so far we haven't heard other cases.
Further, seizures appear to be a common occurance in early-onset familial AD, which Jenni and her mother had:
In early-onset familial AD (EOFAD), seizures and epilepsy occur more often than in sporadic AD. For example, seizures have been described in 37 to 58 percent of patients with the PSEN1 E280A mutation (23), in 30 percent with presenilin 2 mutations (24), and in 57 percent of patients with amyloid precursor protein (APP) duplications (25).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482722/
I haven't re-listened to verify but I think he meant after approval of the open-label extension study by the FDA, they would start administering to the 150 patients. I don't think he meant after FDA approval of bryostatin,as you are stating
Good points. Thanks for the pickup on slide 13.
With a range of 11-99 in SIB, it seems like they were interested in almost all-comers. If I recall, they wanted patients to be able to answer at least one SIB question.
Severe Impairment Battery (Bryostatin phase 2b primary endpoint):
http://www.pearsonclinical.co.uk/Psychology/AdultCognitionNeuropsychologyandLanguage/AdultGeneralAbilities/SevereImpairmentBattery(SIB)/ForThisProduct/FrequentlyAskedQuestions.aspx
- There are 40 items and it takes approximately 20 minutes to complete.
- The range of possible scores is 0-100.
- It is composed of very simple one-step commands which are presented in conjunction with gestural cues. Example questions include:
‘What’s your name?’
‘Please write your name here’
‘What do you call the thing you drink coffee from?’
- ...it is possible to grade the severity of impairment by rating those who score less than 63 on the SIB (corresponding to less than 4 on the MMSE) as ‘very severely impaired’."
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Since MMSE score of less than 4 is excluded from the Bryostatin trial, patients will need to have a minimum of 63 on the SIB in order to participate.
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For comparison to another trial:
From the presentation today, slide 16 shows results from the Memantine trial in moderate-to-severe AD:
- At week 12, the Memantine arm improved by an average of 1 point on the SIB score compared to baseline.
- At week 12, the placebo arm decreased by an average of 5 points on the SIB scale compared to baseline.
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Today's presentation:
https://www.veracast.com/opco/healthcare2017/main/events/1045_neurot/pdf/Neurotrope_(NTRP).pdf
I believe Dr. Alkon stated today that throughout the Phase 2b trial, Bryostatin successfully passed all Data Safety Monitoring Board reviews; meaning that there were no individual adverse events or pattern of adverse events that caused enough concern to halt the trial.
100 of the 150 patients were treated with low-dose or high-dose Bryostatin for 12 weeks (7 doses, I believe).
In this NIH article on Early-Onset Familial Alzheimer's, there is a description of symptoms in AD:
https://www.ncbi.nlm.nih.gov/books/NBK1236/
"AD typically begins with subtle memory failure that becomes more severe and is eventually incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, hallucinations, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism."
Jenni's mother, with the same genetic defect, was known to have seizures by the age of 35. Jenni, I believe, started on Bryostatin at age 37.
Theburg:
Right. My post was really aimed at kid2 who said yesterday in post #2188, "One that I had been following, I was even in for a while, was GNMX, which released AD data today "
Theburg:
GNMX trial was in ADHD. kid2 mentioned it because it is a recent example of a trial that many were positive on, but the trial still failed.
I agree with you. Just because past AD trials have failed, that doesn't have any readthru to NTRP situation, because NTRP has an entirely different MOA.
Phase 2a was single dose, for safety/tolerability.
If you would listen to the BIOCeo presentation, you would hear Dr. Alkon say that it took 2-3 weeks of dosing before they saw the effect of Bryostatin in the compassionate-use patients. That sounds like at least 3 doses to me. One dose won't do it.
If you review other medicines, there are several classes of antidepressants that take 2-3 weeks of daily dosing to take effect. Not the same mechanism of action or dosing, I know, but just to give an example that all meds don't work immediately or after 1 dose.
So, I repeat, the Phase 2a single dose safety trial was NOT EXPECTED to have an effect.
That is what the Phase 2b trial is for...multiple doses over 12 weeks.
Further, the 3 Bryostatin compassionate-use patients--who experienced improvements "...that were almost miraculous"--were severe AD patients.
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"However, due to damage to upstream receptors in most people with Alzheimer's disease, protein kinase C alpha activity decreases as the disease progresses (study). So it is not likely that bryostatin can be used to help most people at least not past a certain stage"
This statement may make sense to someone "in theory", but it most definitely doesn't make sense in the context of the 3 real-world Bryostatin compassionate-use patients with severe AD.
SF:
I agree.
I'm with the good doctor (paraphrasing): "What we saw with compassionate-use patients gave us confidence we could do things with severe AD"
More from the Feb'17 BIOCeo presentation by Dr. Alkon, RE: Compassionate-Use patients slide (paraphrasing):
- Patients were very thoroughly characterized
- Saw Major reversal of disease
- Not just reduction of decline
- In each patient, saw evidence of flipping
- Things that were almost miraculous
- Confidence we could do things with severe AD
Thanks again for presenting the PUFA info.
From the BIOCeo conference (Dr. Alkon, paraphasing):
"We have a platform of drugs, 40 or so other compounds, more potent, more specific, to be used as 2nd and 3rd generation drugs."
I really hope they're moving these drugs through pre-clinical research.
Kid2:
You state: "...91% of all clinical trials crash-and burn...Worse for AD: 99.6%".
Here's why I believe our chances are better than 50-50:
[Dr. Alkon at BIOCeo Feb'17, discussing compassionate-use patients:] "No other reports have ever shown comparable benefits in such severely demented patients — albeit in the absence of age-matched controls."
Yes, it's a small n. Yes it's not controlled. BUT, I don't think controls are as important with moderate-to severe AD. I believe the odds are very low that you would see a placebo effect in this patient population, and certainly not with the majority of the patients (3 out of 4, the 4th dropped out).
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There is also scientific basis, as outlined by Dr. Alkon at BIOCeo that success with Bryostatin is a real possibility (paraphrasing):
- There is a WEAK correlation between psychometric indices and plaques/tangles. (Clive Holmes research: even though Amyloid was eliminated, as verified on autopsy, patient's AD didn't improve)
- Very powerful correlation between density of synapses to AD.
- From research, what really happens in progression of AD: when PKC-E is deficient, gradual loss of synapses, followed by beta-amyloid and tau deposits later. This is why the current drugs targeting beta-amyloid/tau cannot reverse AD, and can only slow the decline. The damage is already done by the time beta-amyloid/tau proliferate.
- Fresh frozen human brains post-death measured for PKC Epsilon (researchers blinded to which people had AD). PKC-E reciprocally associated with beta-amyloid and tau tangles. They could tell which people had AD based on PKC-E levels!
- Direct linkage (96%) of risk gene (APOE4) to AD. THIS GENE BLOCKS PKC-E!
- PKC-E triggers entire structural assembly: synaptogenesis, takes care of beta-amyloid and tau, and preserves neurons. PKC-E is multi-modal.
- Bryostatin elevates PKC-E, which activates synaptogenesis, as proven in mouse models and quite possibly occurred in the 3 compassionate use patients. Further, in mouse models, Bryostatin also reverses beta-amyloid/tau, and preserves neurons.
- Results were seen in 2-3 weeks in compassionate-use patients. Phase 2B patients receive IV Bryostatin for 12 weeks (7 times, I believe).
Below is the slide from the BIOCeo presentation in February 2017, describing the compassionate-use patients. Jenny Spencer (JS), the woman in the Gazette Mail article, is patient #2. (might want to pin this post?)
-----------------------------------------------------------------
Compassionate Use Patients: Overview
Bryostatin Compassionate Use Program:
Severe Alzheimer’s Disease
[Dr. Alkon:] "No other reports have ever shown comparable benefits in such severely demented patients — albeit in the absence of age-matched controls."
Patient 1 – 95 y/o male (JT) – disoriented, intermittent coma, non-verbal
Course: Became alert, attentive; remembered date, place, time; mind active, engaged, watching TV, requested to return to work.
Patient 2 – 38 y/o female (JS) – familial Early-Onset AD due to PSEN1 mutation, Non-verbal, drooling, unable to swallow (fed with gastrostomy), attention grossly impaired, spasticity, inability to move
Course: Return of some language and vocalization, swallowing, increased attentiveness to environment & persons, increased range of motion
Patient 3 – 76 y/o white ? (FC)
Course: MMSE: 2-3, improved to 10-12; recognizes, vocalizes words. ADCS-ADL-severity score: 18 improved to 33; hallucinations: reduced; Return of complex motor skills — e.g. swimming, billiards.
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By the way, from biggercapital on twitter, it's my understanding that there were 4 treated with compassionate-use, so 3 out 4 showed impressive results.
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The February BIOCeo webcast is a must-listen:
https://www.veracast.com/webcasts/bio/ceoinvestor2017/18111483071.cfm
Irrelevent
runncoach:
Great post. You should pin this to the top. In fact, there are probably about 10 posts (you, Flash, SF, maple, etc.) that should be pinned to the top!
I added too early yesterday at $19, but I think the games that happened the past few days are fund/funds adding shares as a precursor to the NASDAQ uplist. I plan to add again below $15.
Maple:
Thanks for your research on PUFA. This may not be important to the April release of Bryostatin data, but it IS important if Dr. Alkon's scientific research pans out.
Follow-on drugs and patent estate will be very important going forward. A 2-year lead on competitors in the PKC-e, synaptic growth and the genetic source (apoe3/apoe4) of brain function/dysfunction will be critical over the next few years, so it's very relevant.
Most of us here know what/who are relevant on this board. For starters, #1 in relevance is Dr. Alkon. I just re-listened to his February presentation yesterday, and came away more convinced than ever.
To those that suggest that Neurotrope wants to just keep collecting funds and doing research: no way!
Dr. Alkon is 75, and has spent years of productive research at the NIH, and it's time to cash in those research chips.
I think he would be ecstatic to see Bryostatin succeed, Neurotrope succeed, and, if Bryostatin can successfully reverse AD, he might even be a candidate for one of those European awards.
SF:
It is the feb 13 conference, pinned above. About Minute 25:30, "severe AD patients", "major reversal of disease within 2-3 weeks". Amazing. Doesn't need a scientific conference for presentation. Having dr. Alkon presenting, with over 300 peer reviewed papers, several books on scientific basis of AD, gives the scientific stamp of approval.
Sure, might get an orchestrated spike by those in control. If you're quicker than the other retail trying to cash out, you might actually make some money. Isn't that how those types of fluffy news releases usually get treated? A spike and a selloff back to where you started?
Not what I'm expecting with NTRP, if Phase 2b results meet primary and/or secondary endpoints in a double-blind, placebo-controlled trial in Alzheimer's. Very unlikely to spike and return back to a $200M market cap. It will trade well north of $200M.
Yes, I read the right 10-k, and it noted the grants for P2/extension. I was talking about the planned P2/P3, with funds being promised, apparently verbally.
Be interesting to see how much projected costs are for the planned P2/P3, and how much the Aussie gov't will kick in. Guess we'll have to wait for future SEC filings some time down the road.
Funny, I looked at the 10-K, and I didn't see any mention that Aussie government will pay for the Phase 2/3.
Is there a link to a signed contract between Aussie gov't and AVXL?
Do we have a protocol for the trial? Or is it open-label Phase 2/3?
But, it might take a year for $AVXL to raise funds, so don't expect anything soon.
So glad to hear these 3 achieved remission of what could have been depression. Perhaps $AVXL should run a phase 3 in depression?
My best guess is you have to get out of bed to swim, or play pool.
Seriously, you should have a listen.
You really should listen to Dr. Alkon's presentation on the 3 Bryostatin compassionate-use patients. Significant improvements. Worth a listen!
GentleGiant:
Good insight on the delivery, but if IV is the only viable delivery, I still believe Bryostatin could be a huge success. Many cancer drugs, which are life-saving, are delivered by IV, and I would put a successful Alzheimer's drug in the same arena as a cancer drug (life-saving).
From another angle, the annual cost of moderate-to-severe AD care is huge, and some analysts believe these AD costs will break Medicare in a few decades. So any drug that lowers the total medical and care costs of AD will be successful, regardless of type of delivery.
In the long run, I don't think a company like Neurotrope has the ability to bring this drug through trials and FDA alone, so I think the endgame will be a partnership with a large Pharma or a buyout. Dr. Alkon has already signaled that with a successful drug, they are willing to partner.
SF:
That is good news!
Thanks for posting.
SF:
What is DCP-LA? One of the bryologs? Or another NTRP compound in development?
The CEO is a woman. Have you listened to any of the NTRP presentations?
GentleGiant:
It wasn't really a "shareholder stock expansion".
The authorized number of shares were increased, approved by shareholder vote 10 days ago and released in an 8k this past Friday night.
No immediate impact on the value of each share (no dilution), but it does give management the flexibility of selling shares to raise money in the future.
F1ash:
Thanks for pointing out the 300 peer-reviewed publications, which supports the argument that Dr. Alkon was objectively presenting the 3 compassionate-use patients at the Leerink conference. I don't think he would be one to embellish the patient data or observations.
F1ash:
SIB is definitely the way to go in the Neurotrope trial, leading to more meaningful information, given the impairment of moderate-to-severe AD.
My understanding is that non-verbal cues CAN be given in the SIB, which makes it extremely important that the trial be double-blinded, which this Phase 2b trial is.
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Edit: and there are still the secondary endpoints of MMSE, activities of daily living, etc.