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Good to hear, coach. Hope everything returns to normal for you ASAP.
Does anyone know if Huntington's Disease is a potential disease target for Bryostatin?
I'm reading in wikipedia that HDAC inhibitors are being investigated in this disease, and I think coach posted something about HDAC being involved in Alzheimer's.
https://en.wikipedia.org/wiki/Huntington%27s_disease )
"Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.[133]"
That's good to hear that kids have been dosed. Thanks. We may be able to avoid dose-escalation in cohorts, which can significantly delay the progress of a trial.
I think what could really push this thing forward is the fragile X Society. Incredibly well organized group of motivated parents who will have no problem pushing the FDA to expedite any potential cures. They can gain a lot of media coverage. Even though results are likely a ways off, I'm very excited to get this kicked off. I posted well over a year ago that I felt Fragile X might be an easier route to approval.
The main benefits of Orphan Drug Status:
- Marketing exclusivity for 7 years
- Protocol assistance offered by FDA
- Tax credits of 50% of the clinical drug testing cost awarded upon approval
- Research grants—FDA awarded approximately 75 grants in 2013
- Waiver of NDA/BLA application fee—this is a $2.2 million value
http://pharmaceuticalcommerce.com/opinion/common-misconceptions-about-the-orphan-drug-designation/ (see part 7)
Your key points are important and worth re-stating:
- FDA isn't concerned with bryostatin safety.
- Safety data in > 1500 patients
- Long-term safety data (2 years in some patients)
- Activating PKC-e levels back to normal to re-activate nerve growth factors using Bryostatin [a macrocyclic lactone] has been proven in animal models and the current phase 2 trial is designed to prove this.
Further, bryostatin is a macrocyclic lactone, which is NOT an IGF (a polypeptide hormone similar to insulin).
Two entirely different classes of medicines, with different side-effects.
IGF and it’s side-effects are irrelevant to bryostatin
This abstract analyzes post-marketing data from GH use in PEDIATRIC population.
There is a reason that THE FDA requires companies to test many drugs in pediatric trials before they can be used in that population—the reaction of some drugs in a developing, immature body can be very different and have different side effects than in an adult patient. It’s apples and oranges to extrapolate pediatric side-effects to adult side-effects.
The average age of the targeted population for bryostatin will probably be about 65-70!
There is the possibility that the FDA will require a post-marketing study on theoretical risks (this is common for many drugs), but I can’t foresee this as a reason to deny approval of a drug that may reverse a deadly disease—Alzheimer’s.
I've already looked. Trajectory of patients in AVXL's last trial follows the same MMSE decline as historical placebo.
Predicting approval based on cherry-picking results from a non-placebo controlled trial is a recipe for disaster.
NTRP, in spite of drug-to-drug interaction, still saw an improvement of SIB scores in the on-drug arms in a placebo-controlled trial. Sub-group analysis of non-memantine patients saw statistically significant improvement (p=.012) in SIB scores in bryostatin patients.
NTRP is running a trial to prove that Bryostatin reverses Alzheimer's in moderate-to-severe patients. I don't see any indication in their trial results that AVXL reverses AD.
There was a small cap company with successful phase 2 trial results, that traded up to a $2B market cap (MC) right before they announced their phase 3 trial failed. (I can't remember the name of the company, but they are doing gene therapy now).
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Removing all other factors (synthetic bryostatin, macro economy, another successful competitor, etc), my best guess (with successful phase 2 results) is we should trade in the $500M-$1B MC range within a few months after results.
Leading up to results from a phase 3 trial, we should trade in the $1B-$3B MC range (because we can actually improve AD, not just slow the decline).
If we get a partner with significant upfront and royalty, double each of the above numbers.
With successful Phase 3 results, we should be trading > $10B MC with or without a partner.
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Success in trials for other indications should increase the above numbers by at least 50%.
An awful lot of conjecture in your statements:
"...are likely to..."
"...and could contribute to Alzheimer's..."
Metformin, one of the lynchpins of diabetes treatment, causes severe diarrhea in some patients.
Gotta tell all those people trying to live better lives with Metformin that they need to quit the drug due to its side-effects!
But wait, what does untreated diabetes lead to?
Heart disease and a higher risk for heart attack and stroke
Eye and vision problems, including blindness
Kidney disease that can lead to kidney failure
Neuropathy (nerve damage)
Infections
Dental problems
Amputations due to infections in the feet.
Good luck telling people they shouldn't use their life-saving drugs due to minor side-effects.
Damn...I guess I should stop hiking. I'm in my 50s, and I get myalgias every time I go hiking. Must be unhealthy for me. But, Advil certainly helps.
Myalgias is a known side-effect for statins, which are for high cholesterol--not a life-threatening illness like Alzheimer's! Quick, everyone quit your statins...it would be a sin to have to take Advil for those pesky side-effects! Ignore the fact that you'll likely die earlier of a heart attack from clogged arteries.
I picked up on one quote from the 10q :
Additional analyses compared 20 µg dose patients who were on baseline therapy of Aricept vs. patients off Aricept. No significant differences were observed.
This Aricept analysis further bolsters the finding that it is the NMDA receptor (the same receptor used by memantine) that is key to the activity of Bryostatin.
That is, other Alzheimer's drugs that don't interact with the NMDA receptor do not interfere with Bryostatin.
Also, patients on other drugs that use the NMDA receptor (dexomethorphan, etc) are excluded from the current Bryostatin trial.
Thanks
Great to see 17 sites are ready to enroll!
I thought I read somewhere there will be 30 clinical trial sites, so that's about 3 patients per site, to get to 100 patients enrolled.
Washout period of 30 days to clear memantine adds a little time to how long each patient takes to get all treatments and follow-up.
Further, this is important:
"More conservatively, the post-hoc analyses assessed statistical significance with two-sided p-values ≤ 0·05"
Part of the reason we were hit so hard when we released phase 2 results last may was because we only used one-sided p-value.
I'm really feeling good about this data and the upcoming trial.
I'm in awe. Stats guy they consulted with is worth his/her weight in gold.
I think those are good assumptions.
Seems like most patients who are diagnosed with moderate-to-severe AD should be eligible to receive Bryostatin, if approved.
I'm VERY excited about the poster.
And, I'm finally understanding the significance of what the stats expert (hired by NTRP earlier this year) did to help analyze the data and come up with a protocol that is more likely to succeed than the previous protocol.
Here's the primary endpoint of the previous P2 study:
The primary statistical objective for efficacy was to estimate the effect of bryostatin on the mean change in the total SIB score after 12 weeks of treatment, assessed at Week 13 (day 91).
Here's the primary endpoint of the current P2 study:
Efficacy: change in the Severe Impairment Battery (SIB) score obtained between the average 13 and 15-week scores and the baseline score
From the poster today:
Moreover, to avoid large potential intra-patient SIB variation over time, for the post-hoc analyses, we considered the change in average score collected during week 13-15 from baseline as the endpoint.
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The stats expert must have noticed 2 things:
1) Even though there is significant improvement in SIB score over time, there is a large variability when comparing one test to another test in individual patients. Large variability in the pooled data is damaging to the final p-value analysis. By taking the average of week 13 and week 15, this dampens the variability, and HELPS meet statistical significance.
2) The average score at week 15 is a higher average score than the week 13 score, so the statistical analysis will also take advantage of the higher scores when taking the average of 13-week and 15-week.
And, to prove it, they took the previous trial non-memantine data and plugged it into the current trial primary endpoint!
This gives us a much better chance at meeting statistical significance next July.
AWESOME!
Good points. Thanks for the help clarifying.
That was my point, although not well-stated: increasing PKC-e levels back to normal levels, so that the healthy process of repairs and clean-up can take place.
Thanks
Things I'd like to see in this week's (July 25th) poster presentation:
- Blood markers: A direct correlation between increasing PKC-e and improving SIB scores.
- The percentage of non-memantine patients helped by Bryostatin. If most trial patients are helped, it means most moderate-to-severe AD patients will be eligible to receive Bryostatin.
- The range of improvement in SIB score in non-memantine pts. If the range of improvement in SIB scores is narrow and consistent, this indicates healthcare professionals administering Bryostatin won't have to individualize the treatment dose and schedule. Also, this gives greater confidence in the company requiring only 100 patients in the confirmatory trial.
- Further clarification on the reason for stratification by MMSE score (4-9, 10-15).
I agree--just delaying the inevitable by a few months.
I'm not sure how much more effective the combo of memantine/donepizil is, but it can't be significant, because biopharma is still searching for the holy grail.
Here is a link to a post by runncoach:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=139207917
and a fix to the link to an overlay of Bryostatin post hoc vs Memantine:
$NTRP Overlay of Bryostatin sub-group analysis onto graph of Memantine vs Placebo results (SIB Scores). Hoping to see the same results in upcoming confirmatory trial. pic.twitter.com/c79XDbYwD3
— InTheTrenches 🙏🍀 (@InTheTrenches2) March 12, 2018
What's remarkable about the Bryostatin post-hoc data is that patients improved at every point that the SIB test was given. Even one month after the last IV Bryostatin treatment was given, the SIB score improved.
The final improvement was +6 points.
From memory: In Memantine trials, I believe Memantine improved SIB score by 1 point in the first ~4 weeks vs. a decline in SIB of 1(?) point for placebo.
However, Memantine and placebo arms declined in a similar trajectory by the end of the trial (6 months). That is, at the end of the 6 month trial, both Memantine and placebo had declined in SIB score but Memantine had declined less.
I believe Donepizil, the other approved drug, is viewed slightly more favorably. It was approved before Memantine. It is similar to Memantine, in that AD patients on Donepizil still decline in SIB score in the long-run, but less than placebo.
Also, the 2 drugs together work better than either separately, but some AD patients can't tolerate the side-effects of one or the other.
AF really needs to read yesterday's press release in the context of the detailed phase 2 Bryostatin results at clinicaltrials.gov (post-hoc data on 20ug Bryostatin non-memantine patients).
The 20ug non-memantine data is clear and convincing; with proper enrollment numbers, this should lead to a statistically successful trial.
From the first patient enrollment PR yesterday:
- "...patients in the bryostatin 20ug dose group not receiving concurrent memantine treatment exhibited a SIB score improvement from baseline of over 6 points. There was no corresponding treatment effect for memantine-treated patients."
- Alkon: "The potentially important persistence of the bryostatin-induced improvement in the SIB scores in our recently completed Phase 2 trial, even one month after completion of all dosing, is an effect that we hope to repeat in this confirmatory trial."
- Alkon: "Our hope is that this might translate into long lasting cognitive function benefit in advanced AD patients, and earlier stage patients..."
- Ryan: "...very positive feedback from key opinion leaders..."
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IMO, AF is mistaken in his analysis of Bryostatin.
You may be right that it's institutional.
We frequently see the market maker leave a wide spread, with a large ask (several 1000 shares) much higher than the current bid.
Over the past several months, the only way for an institution to build a large position is to pay up to the ask, which is often .50 or more higher.
Definite possibility it's institutional buying today.
Nice move on above average volume.
Looks like a surge in buying at 11:20.
I agree. Doesn't seem to be any sign of reversing Alzheimer's.
About 850 total patients. So about 140 patients in each arm of the trial (5 different doses + placebo).
If I recall, Memantine showed stat. significance with fewer patients in each of their arms. This indicates to me that there is a smaller improvement in this Eisai/BIIB drug than Memantine. And Memantine doesn't really do much in terms of improving the lives of patients over the long-term.
But, it is a positive for the Amyloid theory.
For further discussion:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=142012043
Certainly a controversial issue. My main concern is that I wouldn't want to see the ultimate goal of approval of Bryostatin get derailed because of conflicts with Right-To-Try Act.
I'm very sorry to hear about your family members. That must have been heartbreaking to be so close to that kind of suffering.
A new update on an old theory on the cause of Alzheimer's (Herpes virus).
https://www.statnews.com/2018/06/21/herpes-viruses-alzheimers-disease-role/
George Perry (director of NTRP) is asked for a comment. His name keeps coming up; regarded as a "key opinion leader" (KOL) on Alzheimer's.
An informed opinion on the Right To Try Act:
The #RightToTry Act was problematic from day one. No one should be surprised that many companies won’t participate (eg, $SRPT) and those that do are driven by the ability to recoup cost (which could be very expensive). These issues and more were raised prior to RTT becoming law
— Michael D. Becker (@Becker_MichaelD) June 20, 2018
We've often wondered if those in a "more" severe condition had scores that improved more or less all things equal than those with "less" severe diagnosis. Maybe we'll see some clue of that when we get the data at AAIC next month although with a much smaller sample population.
Yes, I agree. They may have seen a signal that one group is performing better than the other, but the numbers are too small to see a clear distinction.
But, it's important enough to the stats guys to pre-specify a look at the data with this stratification.
[ From a google search of "what is the purpose of stratifying random sampling" ]
"Why would you use stratified random sampling?
Stratified random sampling is used when the researcher wants to highlight a specific subgroup within the population. This technique is useful in such researches because it ensures the presence of the key subgroup within the sample."
Thanks for posting, Biostudent! We are close to first enrollment.
Interesting:
- Eligible subjects will be stratified based on Mini Mental State Exam (MMSE-2) scores 4-9 vs. 10-15 and will be randomized 1:1 to one of two treatment arms: 20µg bryostatin or placebo for twelve weeks (7 doses).
- Subjects who are memantine naïve or have been off memantine for at least 30 days prior to initial treatment with study drug (30 day "wash" period).
Just a guess, but I think this CTO has to do with the contract manufacturing agreement for synthetic Bryostatin OR possibly an extension of our agreement to use Bryostatin in neurological disorders.
Why? Scanning this document:
https://media2.mofo.com/documents/faq-confidential-treatment-requests.pdf
I see this statement:
"As a rule of thumb, the Staff has indicated that confidential treatment beyond the minimum term of an agreement usually is inappropriate, as the value of the information typically is associated with the effective period of an agreement."
The SEC document says the CTO expires in 10 years. So, it must be some type of long-term (10-year) agreement.
Perhaps the pricing and/or the royalty and/or the milestones we will pay to our contract manufacturer?
[ I just now see that Whatsupp confirmed this--thanks, Whatsupp! ]
"...but that is the most clear example I may have seen of confirmation bias..."
I couldn't agree more. And Billion$ have been poured into the research/development of this confirmation bias, and will continue to be poured into trials testing these amyloid-beta drugs at an earlier stage of the disease...
...until the true hypothesis is confirmed in about a year.