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Thanks Joseph.
Quote: "By the way, after the last press release she said that traditional approval is a possibility; in fact, unless the SAP set up a route for AA based on the biomarkers we're claiming, she sees traditional as more likely than AA."
That's quite a statement considering most of our WDGT group has given Anavex a near zero chance of traditional approval.
How did she come to this conclusion without any additional data other than what was in the 9/14 Press Release?
Good. So you agree that it is important to point out (as Hoskuld did in his post) that Biogen was successful in getting surrogates approved by the FDA as new biomarkers.
Don't you think Anavex will be presenting new biomarkers for the FDA to consider when they present their NDA from the P2b/3 trial?
OK. But he was correct in saying that they had never been used before as surrogate endpoints.
What part of his post is "BS"?
Hoskuld's post: When Biogen was less of a big deal than Anavex is now...it got Avonex approved based on surrogate endpoints that had never been used before (T1 and T2 lesion reduction on MRIs.) Brain volume and beta amyloid (which has been used as biomarker) are at least as compelling as Biogen's MS biomarkers - and accompanied by unprecedented 45% reduction in cognitive decline over 48 weeks.
Doc328's post: Can't BS your way with MS studies. I know these inside and out. Avonex was approved based on TWO phase 3 studies. The first one used time to progression of disability as the primary outcome. First on the hierarchy was Kaplan Meier analysis and supplementary analysis was mean change. High significance was reached on both. Exacerbation (relapse) rate was the highest secondary endpoint and then MRI measures (T1 Gd lesions and T2 volume) were additional endpoints - significant with the additional clinical and imaging endpoints as well. The second study was a clinically isolated syndrome (very early MS) study and used time to second exacerbation (Kaplan Meier stats) as the primary endpoint -- very significant p on this clinical measure. MRI measures were the top of the hierarchy for SECONDARY endpoints and it was significant as well.
Just because you can break down Biogen's specific methodology of the Avonex endpoints doesn't mean he was wrong in saying that they were approved based on surrogate endpoints that had never been used before. Please point out anything that contradicts his claim.
Thanks.
AGREED! And that's why I strongly believe that Anavex will get Rett approved first...and repurpose A2-73 for their AD application.
By that time, the OLE should be completed and they can add that data as a P4 confirmation trial to the NDA too.
Agreed. You can also add Dr. Missling as an insider. There's no doubt that he too has all of the data at his fingertips.
That being said, it is no surprise that Doc328 only holds 1,000 shares of AVXL -- while Dr. Missling holds 1.23 Million shares...with 232,000 of those shares added just 4 months ago when his options were converted. (He could've just as easily sold those 232,000 shares for over $1.4 Million when they were issued...but he didn't!)
Love him or hate him, you can't dispute that Dr. Missling is putting his money where his mouth is. IMO, it's pretty obvious that he (with all of the data at his fingertips) believes that the FDA will approve the NDA when it is submitted for AD and Rett.
A quick calculation of Dr. Missling's shares shows that he has over $8 Million riding on the success of our Rett and AD trials...and if you include his options, he has over $800 Million riding on it. Those are some pretty big meatballs!
Go Gators!
...and frankly, I don't understand why you think it is bullish to delay new trials just because they used the verbiage "landmark" and "did demonstrate" in their Press Release.
Please elaborate...
You said there was a bullish and a bearish explanation for the delays...but you gave only the bullish scenario. What is your bearish explanation?
Yup. The last thing the FDA needs is to be accused of approving a drug BECAUSE the former FDA Head of Clinical Trials (Dr. Kun Jin) was influencing his former colleagues.
Good post.
Additionally, if you "follow the science" you would also realize that the Avatar (adult) trial has dramatically increased the odds of success for the Excellence (pediatric) trial. TGD has stated several times that the heavy lifting has already been done...due to the success of the adult Rett trials. (Paraphrasing)
I sleep very soundly at night knowing that A2-73 has already proven itself with two adult trials under our belt.
Have a good weekend.
abe
Well done, Joseph. (This is a great omen!)
Per the LLM Artificial Intelligence: "Here are some examples of situations where a clinical drug trial might be deemed successful even if one of two co-primary endpoints is not statistically significant:
A trial of a new drug for the treatment of Alzheimer's disease might be deemed successful if the drug shows a statistically significant improvement on one co-primary endpoint, such as cognitive function, and a clinically meaningful but not statistically significant improvement on the other co-primary endpoint, such as functional ability. "
Was Cymabay's previous (P3) trial results comparable with our P2b/3 AD results?
I realize their drug is for cirrhosis, but it would be interesting to compare their results nonetheless.
Looks like Basparks was right about NWBO. It's been on a tear for the past month...up over 100%. (Up 50% in just the last 5 days alone!)
I think he's also correct that AVXL will get AA from the FDA. Once Anavex announces the TLR for the Rett Excellence trial, I think our share price will jump over $10.00 pretty easily.
Holding tight.
I'm going to give it a push UP to $6.95 by repurchasing 10,153 shares right now.
Third member of FDA advisory panel resigns over Alzheimer's drug approval
https://www.nbcnews.com/news/us-news/third-member-fda-advisory-panel-resigns-over-alzheimer-s-drug-n1270428
FDA broke own protocols in approving Biogen Alzheimer’s drug, congressional report says
https://www.nbcnews.com/health/health-news/fda-broke-protocols-approving-biogen-alzheimers-drug-congressional-rep-rcna63662
Quote: "This is very important and relevant guidance to address multiplicity. Until the last 5-6 years, almost all AD trials were in mild AD and with clinical rather than PET entry criteria. As the anti-amyloid drugs showed some activity in the mildest patients but no activity in the moderate patients, trials evolved to test either MCI (with proof of amyloid) only or Mild Ad / MCI (with proof of amyloid). ADAS-Cog is more sensitive to follow progression of mild AD than it is for MCI. Therefore, some studies the past 5 years have used CDR-SB (lecanemab among others as example) or iADRS (donanemab as only example). iADRS is basically the subset of ADAS-Cog found to be most sensitive for MCI and mild AD combined with the ADCS-iADL scale (a modified instrumental ADL for MCI and milder AD). Therefore the 2017 example for AD in the draft guidance became a poor example and not included in the final guidance to industry."
Good for you, Doc!
Is it fair to say that Anavex's (Dr. Jin's) newly released TLR for the 2b/3 results has a stronger chance of FDA approval than you initially thought?
Yes. I remember that. Well done, boi.
And correct me if I'm wrong, but statistically speaking, isn't one co-primary endpoint at .025 and the secondary also at .025 is just as strong as both co-primaries at .05 and the secondary at .05?
I saw an order to buy 60,000 shares at $6.97. (That's almost half a million dollars)
Nice to see the buyers are stepping in with big orders.
No. Not at all...because they continue to affirm that they've achieved ADCS-ADL on their website as per their "met all endpoints" position.
And frankly, I don't believe Dr. Kun Jin would allow today's Press Release without acknowledging that one of the endpoints didn't make it...if that was the case.
Secondly, we know that they've submitted the data for publication in a peer-reviewed journal...so it makes sense that an embargo would require them to withhold specific data from the public.
NO. They will wait until A2-73 is approved for Rett first, then repurpose the drug for AD. This will also allow for the OLE to be completed and expedite the entire NDA process for AD approval.
Anavex's website still shows that they met all end points. (see below)
ANAVEX®2-73 (blarcamesine) Meets Co-Primary and Key Secondary Endpoints for Patients with Early Alzheimer’s Disease
• ANAVEX®2-73 (blarcamesine) treatment slowed decline of cognition and function in patients with early Alzheimer’s disease over 48 weeks
• ANAVEX®2-73 (blarcamesine) treatment reduced cognitive decline by 45%, measured by ADAS-Cog, as compared to placebo, representing a treatment difference in mean score change of -1.85 points (p=0.033) over 48 weeks
• Patients treated with ANAVEX®2-73 had 1.84 times higher odds, or likelihood, to improve cognitively compared to placebo, with an ADAS-Cog score threshold of -0.5 points or better [Odds Ratio = 1.84 (p = 0.015)] and had 2.67 times higher odds, or likelihood, to improve function with an
ADCS-ADL score threshold of +3.5 points or better compared to placebo [Odds Ratio = 2.67 (p = 0.0255)]
• Compared to placebo, ANAVEX®2-73 (blarcamesine) reduced clinical decline of cognition and function by 27% with mean score difference of -0.42 points (p=0.040) as measured by CDR-SB
• ANAVEX®2-73 (blarcamesine) was generally safe and well tolerated Next Steps
• Publish full analyses, including MRI data, prespecified biomarkers of response as well as Whole Exome Sequencing DNA data and full mRNA exome expression data collection data on biomarkers of neurodegeneration in a peer-reviewed medical journal
• Continue open-label extension study ATTENTION-AD to follow participants over 96 weeks
• Meet with regulatory authorities to discuss data with aim to bring this therapy to patients in Europe, Asia-Pacific, and the U.S., including potential Accelerated Approval Pathway based on newly available preliminary efficacy results of surrogate biomarkers
Odds Ratio of ADAS-Cog meaningful improvement in cognition at threshold of -0.5 points or less (90% CI)
Improvement
-1 0 1 2 3
ODDS RATIO
Odds Ratio of ADCS-ADL meaningful improvement in function at threshold of +3.5 points or higher (90% CI)
P = 0.015
1.839 (1.17, 2.94)
-0.5 0
1 2
3 4 5 6
ODDS RATIO
Improvement
P = 0.0255
2.67 (1.17, 6.13)
17
https://www.anavex.com/_files/ugd/79bcf7_97da6311c3b643bea8e9a6659bb51422.pdf
And do you think that information was left out of the press release...
1) purposely?
2) negligently?
Choose wisely grasshopper!
Indeed...and to paraphrase TGD at the Annual Shareholder's Meeting: You will enjoy reading the results when they are released in the 2nd half of this year.
And thus, I fully expect the peer-reviewed results to validate what Dr. Kun Jin has concluded in today's press release.
2+2=4
Joseph.
I don't have an answer for your specific question...but I take comfort in knowing that the FDA's former lead statistician was probably the one that finalized all of the numbers that were published in today's press release...Dr. Kun Jin
Anavex Life Sciences Appoints Former FDA Lead Neurology Statistician as VP Head of Biostatistics
https://www.anavex.com/post/anavex-life-sciences-appoints-former-fda-lead-neurology-statistician-as-vp-head-of-biostatistics
Good post.
The other option is to wait until Rett is approved and repurpose the drug for AD.
Submitting the P2b/3 trial results with a FDA-approved drug should be sufficient to substitute the need for a second P3/4 trial.
Remember, the FDA can approve an NDA (New Drug Application) with one successful P3 trial and the repurposing of an FDA-approved drug.
So, if the FDA approves A2-73 for Rett, that would qualify for the first half of our Alzheimer's application. The other half would be our P2b/3 AD trial.
IMO, this is the main reason why Anavex wants the FDA to approve Rett first. Once it is approved, they can expedite the entire process for our Alzheimer's application by simply repurposing A2-73. (Qualifying for the $100M voucher is a bonus)
I'm not worried at all because our FDA guys know what they're doing...especially Dr. Jin.
A simple phone call to IR should easily clear this up. This should be public information so why wait until Sept/Oct?
Good post.
Raja..."I would have preferred a PR, sometime in June-July which stated ' Seeking FDA Approval'. (Not very difficult to do, since the company stated the they met both the primary and secondary end points)."
If they're going to repurpose A2-73 for AD, they'll have to wait for Rett approval. Once that happens, I believe they will indeed make the statement: "seeking FDA approval".
Raja...quote:
A) 9 months and counting since CTAD (especially after assuring that there would be more data to share, sooner than later. Each of us can interpret this delay to suit our ego/convenience by making assumptions accordingly).
B) If one considers the time since the AD trial was done and dusted, it has been more than a year.
So, what has changed since the CTAD data release 9 months ago?
Anavex Life Sciences Corp. Appoints Dr. Kun Jin as Head of Biostatistics
March 09, 2023
Anavex Life Sciences Corp. announced the appointment of Kun Jin, Ph.D., as Head of Biostatistics. Dr. Jin will draw on his extensive experience, including recently as the Statistical Team Leader at the U.S. Food and Drug Administration (FDA).
Dr. Jin provided statistical review coverage and expertise for neurological drug products for the Center for Drug Evaluation and Research (CDER), and performed timely and quality reviews of marketing applications, including New Drug Applications (NDA), Biologic License Applications (BLA), and Investigational New Drug (IND) applications. Under the leadership of Dr. Jin, the neuropharmacological statistical team has completed several hundred statistical reviews of NDAs, BLAs, and efficacy supplements. Prior to joining Anavex, Dr. Jin had a distinguished career of more than 27 years at the FDA.
During his tenure at the agency, Dr. Jin has contributed extensively to statistical review issues and trial designs surrounding the regulatory approval of drugs for the treatment of neurological diseases including Alzheimers disease, Parkinsons disease, migraine, epilepsy, and multiple sclerosis, as well as rare diseases, such as ALS and DMD. Dr. Jin was the lead author in top theoretical statistics, biostatistics, and molecular genetics journals. He was also a winner in a worldwide innovation competition on clinical cardiology data processing (Predicting Acute Hypotensive Episodes).
Dr. Jin has extensive research experience in Alzheimers clinical trials. He has been an invited speaker and has authored publications on topics in Alzheimers disease endpoints and trial designs. He conducted FDA/CDER The Oak Ridge Institute for Science and Education (ORISE) Summer Fellowship projects, built the Integrative Alzheimers Trial Database, FDA/CDER Regulatory Science and Review (RSR) Project and the results have been communicated at Accelerate Cures/Treatments for All Dementias (ACT-AD), Drug Information Association (DIA), and Joint Statistical Meetings (JSM).
Before joining the FDA, Dr. Jin was Assistant Professor at the Division of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Dr. Jin received his Ph.D. in Statistics from the University of California at Berkeley, California.
Such a ridiculous accusation. You just earned an emphatic IGNORE.
Bye-bye
Great story. Thanks for sharing Hoskuld.
It's important to see how NWBO's stock price was manipulated down (~35%) to frustrate the weak-handed investors who sold their shares for a big loss...while the strong-handed investors kept their shares and positioned themselves to reap the rewards of a possible approval.
I've seen this happen numerous times with other companies just before good news is announced. You can practically set your watch to it...IMO, of course.
"The Company anticipates submitting the MAA in approximately the next 30-45 days. The Company plans to request that the MHRA review the MAA under the 150-business day process that the MHRA [equivalent to the U.S. FDA] has established to accelerate the availability of new medicines for patients in the U.K."
https://www.prnewswire.com/news-releases/northwest-biotherapeutics-announces-completion-of-prerequisites-and-plans-for-submission-of-marketing-authorization-application-301912602.html
Yeah, I get it.
But if they have 6 P3s planned for trials (and no P2s), they must be pretty comfortable with the data they've acquired for dosages.
That's up to the Anavex team to decide whether or not they want to conduct a separate P2 trial for dosage.
IMO, they have enough data with all of the P1s, P2s, and P3 trials (which includes pediatric and adults) to determine dosages for most every age group.
The question is whether those dosages can be applied to other diseases? IMO, yes.
Well, let me try to explain repurposing a drug in simpler terms...
Let's assume that the FDA approves A2-73 for Rett. That means that the FDA has approved a specific dosage for that specific disease.
Now, Anavex has to prove to the FDA that A2-73 is also effective for Fragile X - which is a new disease that is listed in our pipeline. And the only way to prove that it is effective for Fragile X is by conducting a separate P3 trial that is double-blind, placebo-controlled, multi-centered with enough n to satisfy the FDA. (We can skip the P1 and P2 trials because the FDA already knows the drug is safe via the Rett approval)
So, for every new disease that is listed in our pipeline, we will need to conduct a P3 trial to prove its efficacy.
Fortunately, we already conducted a P2b/3 trial for Alzheimer's Disease so Anavex can use that study for the P3 requirement. (When you repurpose an FDA-approved drug and submit a P3 trial, the FDA will consider it for an NDA)
BTW, we only conducted a P2 trial for PDD, so we will need to conduct a P3 trial for that disease.
I hope that makes sense to you.
Yup. The only way that you can skip the required P1 and P2 trials and go directly to a P3 trial is if you are going to repurpose a drug for another disease.
IMO, this is confirmation that Anavex will in fact be repurposing A2-73 after it is approved for Rett...which is exactly what I had outlined in my previous post a few weeks ago. (See below)
*****************************************************************************************************
abew4me
Post# 426544
Wednesday, August 09, 2023
Yes. I think they'll present the OLE as an alternative to a full-blown confirmatory trial because their NDA (New Drug Application) will be focused on repurposing A2-73.
This has been Anavex's plan from the beginning (IMO)...but the Covid virus delayed the approval of Rett. Now everything is back on track!
Drug repurposing, or repositioning, is a strategy aimed at identifying new uses for already approved drugs, which fall outside their original medical indication. This strategy has led not only to the successful preclinical and clinical testing in multiple neurological disorders, but also to the reevaluation of disused drugs, epitomized by the remarkable case of thalidomide.
In recent years drug repurposing has covered a wide range of neurological disorders, from neurodegenerative and neuropsychiatric to drug abuse-related disorders.
Alzheimer’s disease and Parkinson's disease, for example, are the two most common neurodegenerative diseases, for which only symptomatic therapies are available, while neuroprotective drugs are still an urgent unmet need. They are therefore in the top list of neurological disorders for the investigation of repurposed drugs, targeting both the disease neuropathology and symptoms.
**************************************************************************************************
The FDA can approve an NDA (New Drug Application) with one successful P3 trial and the repurposing of an FDA-approved drug.
So, if the FDA approves A2-73 for Rett, that would qualify for the first half of our Alzheimer's application. The other half would be our P2b/3 AD trial.
IMO, this is the main reason why Anavex wants the FDA to approve Rett first. Once it is approved, they can expedite the entire process for our Alzheimer's application by simply repurposing A2-73. (Qualifying for the $100M voucher is a bonus)
Our FDA guys know what they're doing...especially Dr. Jin.
TGD and his team know what they're doing. Just sit back and enjoy the ride.
"The S1R plays an important role in neuronal health and it is an established therapeutic target for neurodegenerative and neuropsychiatric disorders."
Very Nice!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455549/