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HCWainwright important points:
**Regarding possible Rett revenue, the following is a near quote from Dr.Missling, not exactly word for word, but very close:
Rett Syndrome and FTD and FragileX are not to be neglected. You can make a quick back of envelope calculation about how much revenue could be because rare diseases allow for higher prices.
(My comment-The company has been existing totally on share dilution for many years. This may change with rare disease approvals.)
**Rett Avatar TLD this year.
**Excellence patients increased from 84 to 96 patients, as regulatory agency requested additional age group grouping.
(My comment-Confirmation the company is actively discussing Excellence with regulatory. I don't like it when the goal posts are moved.)
**Alz on autopilot to conclude next year.
Not checking?? Avatar already EXCEEDED Enrollment! See PR and CC from 8/12.
Georgejj,I suspect your take is correct. I looked into Cecchi a while back. I think DrM has had a good relationship with Cog, for quite a while now, and he trusts Cecchi to write the patent. Be clear though that Anavex owns the patent and the rights to it. It is NOT owned by Cecchi!
Orphan Drug Pricing and the SeekingAlpha article pricing
Below is an article excerpt, giving a succinct description of why orphan drugs are priced higher than normal drugs:
Granite, yes the author eliesbik, did a good job of presenting the information. Nice to have someone with graphic design involved sleuthing a possible pharma scandal LOL. Hey we have lots of good contributors here from many fields. Nice.
Yes, I guess the bottom line is, what are the final explanations!
frrol, you are the first one to vocalize a concern I have with an interim peek. I appreciated your comment "we do a lot of subgrouping", and will expound on it below.
Regarding Hampel's peer reviewed AD A2-73 phase 2a publication. Recall the famous Figure 3a, showing the "Group" change in ADCS-ADL over 148 weeks.
Group2 seems to INCLUDE the super responders in Group1, yet Group2 is 15 points lower. The only difference appears to be that Group1 has APOE3 alleles. What that means is that all NON APOE3 alleled patients perform worse that the super responders in Group1. OK, so? Well if you solve for this unknown group, then these NON APOE3 alleled patients are really pulling the average down, and the drop of only 15 points is thanks to the super-responders keeping the average only down 15 pts!! That is my interpretation of the plot, and maybe where your comment leads.
Another concern about an interim look at the patient data, is the placebo patient data is mixed, or averaged in with all the other patients, just like we saw in the paragraph above. So the placebo patients will pull the scores down too.
Oh yes, then there are all the patients with the Sigmar1 variant and the COMT variant. They will likely be non responders and pull the scores down too!
Interim peeks do NOT unblind the patient data, so it all gets averaged together as described above.
Finally,the data analysis will take a lot of time. I strongly suspect that the trial would end, while they were still analyzing the "interim peek" data,...then they could stop the "peek" analysis and start on the actual unblinded final data analysis.
For these reasons (and MORE) I am opposed to an interim peek. Dr.M will need to have ALL the data AND unblinded, and then he will be able to present a clear (as you say) "subgrouped" explanation for the patients that are super responders, and maybe some "tweeners", and the non-responders. It will then be VERY CLEAR.
I know of one cancer therapy trial, that was unblinded and it shed no light on efficacy at all imho. That trial is what I would call "dirty" for various reasons, but the result is what I outlined above.
frrol, I am not sure if the above is what you were alluding to, so if you have additional light to shed on this, please do. I totally agree with all the points you made about not peeking!
My take on the ScienceIntegrityDigest article "Cassava Sciences: Of Stocks and Blots". I have experience with image processing and "photoshopping". Many of the images in the article certainly look suspect, as the author points out. Tell tale signs of editing are, changes in background texture, color, clarity, or the appearance of lines and rectangles. For example, rectangles are caused by selecting part of a picture, with the most common selection type (a rectangle), copying it from one image, and pasting it in another image. Usually the background of the two images will be slightly different, which causes your eye to "see" a rectangle around the copied part. Similarly, the lines are also an indication of a larger copy and paste. The articles example of these issues are pretty obvious.
The article's Figure 8 has a harder to detect issue. It took me a while to see it. But the dark horizontal brownish "bar" at the bottom of the blue boxes, has a unique shape in both pictures. At first I was not sure there was an issue, because the spots above the "bar" were not visible in both pictures. But upon further review, some of the spots that are plainly visible in the lower box "anti-Ab42" are in the same position in the upper box "anti-NFT". Many of the spots from the lower box are not obviously visible in the upper box. It seems they have been deleted and/or reduced in contrast. However, there are still SOME SPOTS visible above and to the right of the "bar", though not all are visible. The confirmation of the issue, is that you can see a FEW spots that are in identical positions on both. This is to unlikely to happen randomly. Analogous to no people having exactly the same fingerprint. The issue then is what happened to the other spots that have been apparently deleted and or reduced in contrast?
I have no experience with Western blots at all, I viewed the article from an image processing perspective. The author did a good job commenting on the blots and the pictures. I wish she had not included the "Other papers with image concerns", because it was not clear how much that related to Sava or not. She definitely knew what she was talking about.
That said, possible explanations for some of the issues might be that the preparer was trying to emphasize some spot, so they increased contrast, brightness, etc. around certain spots. I do not know if this is common, or accepted practice with Western blots. But if I owned Sava shares, I would want to find this out asap. Because if not, somebody has a lot of splainin to do.
Thanks to all who posted the link to the article.
Georgejj interesting bit of research. 110:8 Thanks
Yep, those are two companies that will never do business together again!
Terrible visuals. SAVA blames Quanterix, Quanterix rebuts that they "did not interpret the reults or prepare the charts". Quanterix says they did some work for SAVA in the past. Wow, Sava throwing the company SAVA SELECTED and HIRED, under the bus. And the client pushes back STRONGLY. Not normal business behavior.
Maybe there is a perfectly reasonable explanation, and the science is good. But the mess is not being handled as though that is the case.
I would not want to be SAVA CEO and have to face WS/FDA/maybe SEC. Sava CEO has been wanting the company to be bought out. Add to the list /other CEO's that might have been considering buying SAVA.
(No SAVA fanboys here today.)
Good link Red
Here's A2-73s murine treatment score for FragileX Syndrome:
This is the 30000 foot, view of the results of the Murine Fragile X study. I like to evaluate efficacy by how far does a drug returns the afflicted back to normal. This will be given as a percentage, with 100% being the afflicted was returned to complete normalcy. Oh yes, the afflicted in this case were, of course, mice.
The efficacy (% of normal) was based on these three tests:
1) Hyperactivity - Open Field Test................100%
2) Fear Freezing Response - Fear Conditioning.....100%
3) Perseverance and Anxiety - Marble Burying......50%
Also shown above is the percentage that each was improved, compared to normalcy. Hyperactivity and Freezing were totally returned to normal, while "Marble Burying" returned half way to normal.
Weighting each of the three equally, an overall efficacy score would be:
For these three tests, the mice on A-73 returned 83.3% back to normal!
The primary biomarker was BDNF(brain-derived neurotropic factor). BDNF levels effect cognitive and sensorimotor deficits.
BDNF returned 93% back to normal!
I am not sure why two other biomarkers were included (pGSK3B and Rac1) as they did not show much change. Maybe they were just included to show they were not affected. If anyone has insight here, please post. The previous (unreviewed) manuscript (posted by TTT?) showed pAkt and pERK. I think these two were excluded because BDNF is already a function of them.
CONCLUSIONS:
It is clear why Fragile X expert, Dr.Hagerman, is very enthusiastic about getting A2-73 trials going for humans, with a hopeful improvements of 83.3%! As quoted in the article "...this neurodevelopment disorder continues to have an unmet therapeutic need.".
The efficacy numbers are amazingly good. The biomarker improvement supports and validates the efficacy.
This study adds to the growing body of evidence, validating A2-73 as a powerful new drug.
The usual caveats exist, this is a murine study(not humans), there were not a lot of mice used, there were limited efficacy tests, etc.
Most important info from call...(imho)...
---------
The Jones Trading analyst asked, regarding the Avatar rett study, do we have an idea when you are having FDA conversation, and if the trial size needs to change to become a pivotal trial, and also some color on the Avatar and Excellence dosing levels.
Dr.Missling: We are in the dialogue right now with the agency and would like to provide update later. Regarding doses we have a dose that is >5mg, but want to keep details blinded, as we do not want inadvertent unblinding of dosing.
---------
Rett adult approval is the critical, first path, to A2-73 commercialization. It sounds like Dr.M is probably discussing U.S. data and pivotal use of upcoming Avatar!
Investor, those were the sort of things I was expecting to hear on the Thursday CC, because of the PR's "Company’s growth strategy" line.
Hopefully/maybe, we get some more great info on the CC!
It sounds like things are coming together.
Thanks for the report!
Anavex set SP at $21...via DTC deal. May well be the defacto price until news.
Hey tell that to the folks with NWBO. 10 year trial and data has been locked for a year!
(Or numbers like that) lol
Remember it is only an 11 month trial and he is confident. If it were a multi year, expensive trial, with not much confidence, then it might be worth an interim peek.
Interpretation of the Parkinson PR good news:
The relevant paragraphs of the PR are quoted at the bottom of this post.
The first paragraph (ANAVEX®2-73 activates the sigma-1...)lays out proof that the there is good correlation between biomarkers and clinical efficacy. This is presented as the biomarker increase of SIGMAR1 activation and the resulting efficacy data. This appears to be strengthening the case for approval, given the Biogen approval for Adu, which was strongly based on biomarkers. It appears pharma is taking that approval as a signal from the FDA, that biomarkers have increased importance as far as approval.
The second paragraph (Parkinson's Disease-related Scores) presents amazing results for the high dose arm for the Unified Parkinson’s Disease Rating Scale test. This MDS-UPDRS test is a standardized test for measuring Parkinsons disease. The high dose arm improved 18.9 % over the 14 week trial. This is twice as much needed to be a meaningful clinical change. This is a great improvement, similar to the increase in memory presented at CTAD. Next Anavex suggests A2-73 is capable of slowing and reversing symptoms, and that is an urgent unmet medical need. Using this wording "unmet medical need" means that they will be pursuing FDA Fast Track Designation. By stating there are also improvements seen over SOC levodopa, Anavex can pursue FDA Breakthrough Therapy Designation!
The third paragraph (Dementia-related Scores), reviews the data presented at CTAD. Note the trial used the standard CDR system Episodic Memory test, but Anavex converted these test results to standard Alzheimer Disease test (ADAS-COG) scores. Some on ihub have suggested that test score conversion is not possible, unlike shown by the PR.
The PR ends with this great quote by Dr.Missling, “We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS indication with unmet medical need. This data further strengthens the foundation of ANAVEX®2-73 as a cross-platform CNS drug.”
The PR supports his statement, and continues to make the case that A2-73 is a cross-platform CNS drug!
georgejj, herArmy posted video of her walking unassisted!! This was a posted a few hours ago. Hooray for her!!! She went from a wheelchair to a walker, to now, first indepedent steps in a long time. Simply fantastic. Makes my weekend. God bless her and all Rett patients.
See you at the ASM next year!
For a beer and toast!!
(sounds like a restaurant in NYC)
Most important sentence from the PR....
Boi, I think he was hoping to be able to announce full rett adult enrollment and full alz enrollment today also. Maybe that was reason for the late May 25 ASM. But it didnt work out. Soon.
Pete, OVER enrollment may be announced tomorrow for Avatar and the Alz trial... stay tuned.
Dr.Missling plotted A2-73 data versus data from other trials, just like I did a few months back. My Anavex 2-73 plot was NOT approved either!
Nice to know I am in good company
Badger, personally, I want to see Phase 3, PD and/or PDD trials registered and recruiting! Where are these trials??? These are the next steps for Parkinsons.
I would LIKE to see the final data from the first Pdd trial, but its no big deal to me as the science I saw already, was good enough. Completed pivotal P3 trials are what is needed for revenue and big sp.
Rett is where the money is right now, and we should be concentrating on getting the ball across the finish line. One is running behind(avatar) but will hopefully finish soon, and the larger Excellence...well has two sites up. I don't understand Excellence with 2 sites.
Lots of sites up for Alz, need full enrollment, should be close, then wait a year.
Dr.M realizes the importance of pivotal P3s, he needs to get some done for revenue and big sp.
Anyway, my view and humble opinion. Hopefully, we will get good news from the annual shareholder meeting...or sooner.
Wolf, Yeah the whole sector looks down. The PR delays struck me. Probably combination of both though. At least we can control the trial times to some extent by the number of sites. Continuous delays upset everybody! As we sit on a pile of money...and only two sites for Excellence.
Price drop because...
PR said:
KayakWench et al, last month, I was doing some DD on Radiogel. I called the company, and I also asked here, who would take over if something happened to Dr.Korenko.
FYI all, the question was answered in the annual report last week (3/24/2021), from page 16:
Raja, does this make it easier:
From clinicaltrials.gov.
Avatar started with two sites in the same city, then added two major cities in UK. Still not complete. Original estimated completion is off by 20 months and counting.
Excellence, same Rett, different age group, but over twice as many enrollees needed. To complete by July and still only has two sites!
There should be something here about learning from mistakes or the past. ARRGGH
Has anyone heard of more trial sites opening up for Excellence? We are sitting on a lot of trial money ($75M) that could be put to use, trying to meet estimated completion dates.
Raja, I am feeling your pain on this one.
Harald Hampel first author mentioned. Still helping us!
Thanks Harald.
Investor, fair enough. It is certainly indicative, as Anavex was comfortable enough with the data (small sample size, no placebo) etc, to plot their data. I mapped Lilly's data to it. It was intended to be a back of the napkin, visual view of where Lilly stood with respect to A273, and I think it serves that purpose well. We rarely get perfect/easy data, and I maintain, Lilly's trial and Anavex's trial were very similar trials (patient ages, inclusion parameters..) and this close of an apples to apples comparison, is actually rare to find.
Agreed, when we see full data from Anavex's current trial, and full data from the Lilly trial we will MAY have a very accurate comparison. I feel it will still look similar to what I presented.
If it is not useful to some, then that is certainly fine, and understandable.
Simple stuff. Still waiting for the math error in my plot.
Can't find it yet? Anvaex 273 still clearly better. See the fine plot vs lilly drug.
Ray, the plot is correct, donanemab is 32% less than the Low concentration shown. So I am still waiting to see where the math is wrong!
Red, I like to compare Anavex drugs, to the competition, whenever possible.
If I ever see Anavex being beaten, I will be VERY concerned.
I am not so quick to discount Lilly. I think they have much better efficacy data than Biogen, and even Biogen has managed to keep their drug moving forward.
Yes, Lilly definitely has safety issues, as you mentioned (I had them in my original chart post as well). I do not remember the Biogen safety severities or percentages. Might make an interesting comparison.
I think we are ahead of Lilly time-wise. Our Alz should read out mid next year.
The sad thing about the these other big Alz trials, is that they compete and remove patients from possible Anavex trials. Biogen trials are huge, and they do not think twice about adding patients.
Regarding beating the dead horse, several people corrected some of my wording, so that is helpful. Questions arise because of communication issues, no arguing that!!
ACTUAL FACTS
1. A CHART BASED ON "MATHEMATICALLY FALSE" DATA IS MEANINGLESS!!!!!!!!
There is no false data. Simple data scaling! Very good chart!
2. SLOWED DECLINE BY 32% COMPARED TO PLACEBO DOES NOT EQUATE TO A 68% DECLINE FROM BASELINE!!!!!
As I replied to Powerwalker, it would be better worded as "declined 68% of placebos decline"
3. THE MMSE IS NOT THE ADAS-COG AND THE ADAS-COG IS NOT THE ADCS-ADL!!!!!!!!
It is called correlation! They are accepted to be correlatable. See https://n.neurology.org/content/90/15_Supplement/P5.178
The relationship between Mini-Mental State Examination (MMSE) & Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) using real world data in US & Europe
From said article:
Conclusions: There is a strong association between the MMSE and ADAS-cog, indicating that where disease burden has been measured for one of these severity assessments, similar conclusions may be drawn for the other.
4. THE CHART SHOULD READ HIGH/LOW CONCENTRATION FOR A2-73 NOT HIGH/LOW DOSE!!!!!!
Ok, true that. Thanks for your contribution. I can fix that wording in my image.
Ray, that makes the error even less!! The max ADAS-COG score is 70, and MMSE is 30. So if you have an ADAS-COG difference of 2, then when it is scaled to the MMSE plot it will be 0.85. The errors scale down!
leo, and where did I subtract ratios??
Power, yes agreed, "declined 68% of placebos decline", is more complete wording. Thanks. That does not affect the plot, and related math scaling.
froll, Explanation here. I presume you are referring to this discussion:
Slowed decline by 32 percent compared to placebo, means it still declined 68%.
"MEANS IT STILL DECLINED 68%" COMPARED TO WHAT??????
I replied baseline. Placebo readings are always referring to the baseline, for the test. The Anavex test and the Lilly test, each had their own baseline scores. True enough. But I maintain they are more close enough for this LARGE, published, difference in readings. Because both tests had there own inclusion criteria for the test scores, but they are very similar, as the trials were both meant to test for mild Alz. Here is the inclusion criteria:
20 to 28 inclusion scores Lilly
16 to 28 inclusion scores Anavex
These are nearly identical!
Statistically, the actual average baseline scores then, should be within a few points of each other...which would have very little affect on the final result plot.
If Lilly made a claim that was close to Anavex's, then the small baseline discrepancy would have been significant, and I would not have made any claims.
Given the similarities in ages, baselines, intended test, etc., I mapped the Lilly data to the Anavex plot.
Cant actually say what the error is though? Still waiting. I will provide a clue...there is no error!
A simple matter of scaling the Lilly numbers, and charting them on the Anavex chart. High school stuff.