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I think the AD approval chances are good. With AD we have some (arguable) efficacy seen. The theory and science research also supports.
I am less confident about Rett and PD trial approvals. We have no efficacy, except for mouse studies. Mouse studies only reflect 10% to 20% success with humans. On the other side, the theory and science still supports. Unfortunately these two trials are up first.
Hopefully I am being to conservative.
I appreciate the estimates given so far! Thanks for answering some hard questions guys! It seems that, in the last few days, the MB has been refreshingly realistic and analytical, without the wild optimism/negativism.
George, I see only one new U.S. Rett testing location, Missiouri. Only one added since the last update to the trial, (using the link you provided).
Please tell me if I am wrong.
Amateur, yeah, good points, and remember they were all on speed dial. Things are moving along though.
I think Prof.Macfarlane believes in a2-73 and/or is friends eith Dr.Missling, as he seems to be keeping our ball rolling in AU.
Plex, not all trials get the 100% enrollment they need. My guess as to why Rett enrollment is slow is a combination of:
1) It is difficult for caregivers. Gotta schedule and get patient to hospital.etc. Caregiver life is difficult normally!
2) There is not much motivation for the caregiver. See the rett sites, they describe the anavex trial with a2-73 as improves nueron function, or something vague like that. They want a cure! The description does not appear to offer them much for the extra life burden of getting their loved one involved in a 'trial'.
3) There are other trials too!
Getting people into trials and studies is a sales job. That is why drug companies offer open label, after trial, as it is something they can use to help recruit.
Comparison of published A2-73 AZ 57wk data to current AZ trial
5/16/2019
A week ago, Nidan posted a link to a good Nuerology article at mdedge (Feb.2017), which is based on 57 weeks of data for the original A2-73 safety patients. It is based on the Prof.Stephen Macfarlane Anavex presentation. Though this article is a little dated, this is still some of the best data we have at this time for estimating AZ trial success.
https://www.mdedge.com/neurology/article/130412/alzheimers-cognition/can-sigma-1-agonist-stabilize-cognition-and-function
Nuerology article at mdedge
Below is a comparison of the current Alzheimers Phase 2b/3 trial outcomes/endpoints, and the Safety trial 57wk data for the original A2-73 safety patients. The purpose of this post is to connect some of these dots.
Current Phase 2b/3 48wk trial-Primary Outcomes:
1. ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition)
-----57 week Safety trial result-- At week 31, statistically significant improvements of processing speed, attention, and memory, were seen(per article). (Likely the reason for the trial being 48wks!) Also, a similar test called Mini-Mental State Examination(MMSE) was used. “The MMSE declined 45%...less than what we would have expected from the historical control data,” Dr. Macfarlane.
2. ADCS-ADL (Activities of Daily Living)
-----57 week Safety trial result-- "...the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane.
Current Phase 2b/3 48wk trial-Secondary Outcomes
1. Adverse events
-----57 week Safety trial result-- "Nearly all patients (98%) experienced an adverse event. Most events were mild, transitory dizziness or headache...", per the mdedge article.
2. Clinical Dementia Rating Scale Sum of Boxes
-----57 week Safety trial result-- no data.
3. RSCAQ sleep score
-----57 week Safety trial result-- "Any patient who scored on the insomnia measure [of the Hamilton Depression Rating Scale] at baseline had no sleep disturbance at all by weeks 12 and 26,” Stephen Macfarlane.
The upcoming peer review article will likely have similar data (as this was the data collected to 57 weeks), but be for two years and hopefully show further improvements.
Curiously, what appears to be very encouraging Electrophysiologic measurement data (P300), from the 57wk study, was not included in the current trial as an endpoint or even as a measurement. Doc328 and I analyzed the A2-73 for treatment of AZ patent app 20180360796, regarding the electrophysiologic data, and concluded that it did not make sense. Most likely, because the patent info only went to 5 weeks, and was statistically insignificant. This seems like good quantitative data that one would want in go/nogo type trials. Maybe Anavex did not have the confidence, or was not prepared, to include them in the AZ trial. Prof.Macfarlane will probably collect this data on all his patients in AZ (just my guess!).
Yes, I interpretted Dr.Missling to mean just that.
At first I thought that Prof.Macfarlane might have been the key driver in getting the PD trial extended into Australia. Now it looks like Anavex wanted to be sure the Rett AND PD trials achieved full enrollment. It appears the PD trial enrollment might have been slowing after initial good enrollment Also, Rett seems to have needed help with enollment also. I thought it was aleady fully enrolled, as did we not hear that all the enrollees "were on rolodex"?
At any rate I am glad to hear Au is enrolling for these two trials now too. Will help keep the schedule. Good for us, as we are all hoping for results this year!
Prof. Macfarlane may still be a key driver, as his specialties are aged psychiatry and dementia. Glad he is involved.
From several months ago, there was talk of a Rett safety study first, followed by an efficacy study, and questions about young girls being safe with the doses. I think we are seeing that playing out, with the safety and efficacy study for the >18 yr old patients. Later the young girls under 18.
Dont worry about anavex financials. Pogue, if you are correct and we only have 18 months of cash...
If we do not have a successful trial in 18 months, then we will have a lot more to worry about as the stock price and company will be at 0.
If we do have successful trial within 18 months, we will all be very happy ( Benny will be jumping up and down), and no one will be worried that we were $3,351,565 and 99 cents in the red for a quarter or two!
RECENT NEWS and thoughts...
Spain PDD --If linear enrollment...end of July for last enrollment.
Could be the enrollment has slowed down, as is frequently natural, so end of July may very well be optimistic. So published results this year are still possible. As an investor, I am interested in the timing, so would very much like to get some trial results by end of year. As the AU PDD trial is just starting, I dont think they will help in getting results out this year. Especially as roy's HammondCare email said they would get back with him in a month or two!
USA Rett trial enrollment is at 40%. What happened to previous news that...there was 100% Rett enrollment, and they were 'all on rolodex'?
Quarterly financial report today - The questions were much better from the analysts, than in the past.
Regarding the USA vs AVATAR Rett studies, Dr.Missling said he did not think the FDA would require separate study in the USA, but that it would depend on the data and results (but he certainly did not commit to no study needed in USA!). The AU gives back 40% of the cost, he said, so that helps financially.
Dr.Missling did commit to making public, when each trial achieves 100% enrollment.
In an answer to the Roth analyst, Dr.Missling said all the Rett patients are being genetically verified.
In an answer to the BI Research analyst, Dr.Missling said the USA and AU Rett patients will all be >18yrs old. There will probably be a separate study later for younger patients.
General - The message board is doing good job scooping the world on Anavex info!
JonJones..Regarding your question about whether the AU trial found yesterday, is the same trial as in Spain? Probably, but why were different dosages mentioned? Typo? Why no news about this? Why is this being done now, as the Spain trial is ahead of enrollment schedule?
I suspect Prof.Macfarlane is a major reason for this news as they will be testing for his and Hammond Care's specialties.
Like I said, the article raised a lot of questions. Wish there was a PR today.
One of our good MB contributors sent an email and got a response that he/she would be contacted in a month or two about enrolling. Seems to me this will slow down the fast moving Spain trial. Will this delay trial results?
It sure looks to me like Prof.Macfarlane is doing everything he can to be behind A2-73! Which is good news for us.
Wow. Thanks for digging roygbiv.
So it is not at all clear how, if at all, this is tied to the Spain PD trial. Could this be "Hammond Care's Prof.Macfarlane" doing his own study in collaboration with Anavex, independent of Spain? Are the dosages typos? Why no announcement of this 'trial'. Is this a way for Prof. Macfarlane to get his own data?(scientists love raw data) Lots of unanswered questions.
Good news is...
Prof. Macfarlane sure seems willing to go even further out on a limb with this baby bio.
Today news. PD trials opening in AU also.
The previous 'confusing' post was probably a synopsis of this more detailed article.
NOTE: One of Hammond cares charters is to get out info about AZ and dementia care. So they are trying to get info out so people sign up for the PD trial.
From the link Hammond Care News
I like the way they refer to Prof.Macfarlane, as he is HammondCare's...
They probably have a good idea about what is going on with the AD and now PD trials in AU!
Principal investigator for the Melbourne trial is HammondCare’s A/Prof Stephen Macfarlane who is...
ElsaSara, May/June, even better!
Good luck to All
PD full enrollment by end of July.
Roughly as started Nov.1 and halfway on March13.
July add 14 wks ...done mid November.
Ok, the spinoff.com/sigma1 link is the resulting study from the 2015 research grant. I was wondering if the spinoff.com article was recent (more significant) or old, as there was no date on the web page. Glad to know the report is recent!
George, another good article you found, this one about Parkinsons Sigma-1 research at Lund University.
I like their statement that they found marked improvement in mice after only 5 weeks.
Researchers could already be seeing improvements in our PD trial patients!
Basparks, so now everyone can read about Anavex in the report!
Hold on longs!!!
This is the kind of spontaneous publicity that makes people famous. (Navan, The Jerk)
Lima, good summary of what has been happening lately, with minimal speculation
Tnx Jonjones, nice article. That mentioned a Rett website (Girl Power 2 cure) I visited last week, that said "...highly important announcement in mid April..."
Dont know what it is, maybe someone else does. Heres the link
girl power to cure news link https://www.girlpower2cure.org/news/
Xena thanks for the thoughts. I hope you are correct that anavex patents will not be violated for the reasons you gave. Please note that cost of production is only one factor in determining price. It is anavex's only product, so it solely will be supporting all anavex expenses, from production cost, salaries, rent, regulaory expenses, distribution, and so on. Of course the least expense is haircuts!
makemydaze, like the link
Doc328 and I had some discussion about it. He had some very good input. Please follow that chain.
Also, please note that we do not see these ERP or P300 data in current corporate presentations or as AD trial endpoints.
If you are technical, I would be interested in seeing your analysis of the current data. All the best!
Patent protection(?) when an invention is FABULOUS
Owners of Anavex consider this...
Every time someone asks about Anavex patent protection, I think about the AIDS issues of decades past. I remember there was a call to "CURE AIDS" from every corner of the globe. As AIDS spread more and more people were dying.
I remember some compassionate African leaders began saying that when the cure for AIDS was found, they would make a generic form of the drug, for the love of their people. Patents and pharma be damned!
Immediately after that there were rumors in the pharma industry (maybe more than rumors) that upper management decided not to invest in AIDS research, because they would not see any profit from it. The inventions were going to be stolen.
I did not research this, back then, just always remembered it, because it showed that what was taught in free market econ classes is reality.
Patent protection is only valuable when countries respect patents. Today China is famous for ignoring patents, IP, trademarks, etc.
You can see where I am going with this. How many people die from Alzheimers every day? What if a company could cure AD??
(I know someone will say LINKS please. As I said I never researched this, but just now did a few quick googles to prove to myself my memory was correct. Yep Brazil was in the mix too! Google these..
Brazil To Ignore Patent on AIDS Drug 2001
Africa AidS War NY Times 2001)
I would be interested in others thoughts. (no flames needed)
Xena, yes that is the paper. A really good study. In particular table 2 has the data anavex cites for IDN (identification).
Thanks nidan. I dont know much about the publication, not a psychologist, but i think the article referenced, written by YY Lim et al, is a well known and cited article.
Thanks. Agreed, not sure about the timing of the 208 week data making the publication. But anavex will probably give the latest data.
Logically analyzing the publication(?), ASM note, AD trial together with some DD.
A lot of discussion from brichnyc ASM notes particularly about the publication note:
"Major publication will publish data from the Phase 2A trail instead of presenting it at a scientific conf."
But look at his note just before that...
"Will look at data next at 208 week mark for the original patients"
That seems like a major clue that the published data MAY include all the data up through week 208!!
So the doctor is sidestepping the placebo issue and going to publish this Phase 2A AD data...WHY?? Thats crazy, Pharma will yell PLACEBO!!??
Because he has GROUNDBREAKING VERY GOOD data indicating great improvement!!!
So what is this data showing NOW, that would cause Anavex to go out on this limb?? How can we find out?
Lets look at the recent corporate presentations. They show what Anavex is telling potential investors, so it should be the latest and greatest POSITIVE news!
In particular lets look at the AD positive scientific DATA, as this is the science. This is the type of data that will be PUBLISHED!
There is a slide showing higher concentration shows more improvement than lower...OK. This is not suprising for a drug that WORKS.
The heart of the science data is..
1) The nice data slides indicating improved activities of daily living (ADCS ADL) scores and MMSE scores (citing Hampel), showing data out to 57 weeks.
This is accepted, reproduceable tests. Imagine this data updated and plotted to publication time!
2) There are two nice data slides that test AD patients speed (milliseconds) in identifying a red versus a black card. These tests the patients cognition and reflexes and are the AIBL-ROCS and Cogstate IDN tests.
This is hard, reproduceable data, showing patient improvement in coginition and reflexes. These are very interesting slides as they show A2-73 patients demonstrably improving. But these plots only go to 17 weeks and only have two A-2-73 data points.
It appears that in the first five weeks A2-73 patients response improves about 68ms, and maybe 90ms at 17 weeks. But with only two data points, there is not much info, but it appears that over time the patients continue to improve.
It is frustrating that these slides only go to 17 weeks. Who knows how much improvement there is at 52 wks, 148wks or publication time??!
Note that these slides cite YY Lim in the journal Clinical Neuropsychology. Might this be where the Anavex data will be published?
Now lets look at the endpoints of the current AD trial, for hints of what data is being collected and looked at.
1. Primary outcome-> ADAS-Cog.(AD Assessment Scale) Bingo! Adas-cog are COGNITION tests which correspond to MMSE (www.ncbi.nlm.nih.gov/pubmed/26617181) tests. Also we listed cognition tests in 2) above!
2. Primary outcome-> ADCS-ADL (Activities of Daily Living). Bingo! As we listed in 1) above!
Other slides cover autophagy, Sigma-1, and cell homeostatis. The published article will probably tie all this CAUSAL science together with the data, so that the scientific community, and hopefully the public, respond with "OH. I get it. There is a great story here!"
I have tried to stick with the facts and not get to far off into speculation land. It helped me tie a lot of loose ends together. I hope it helps someone else!
You are welcome. Everyone on this board contributes to the DD and helps out.
Hello Peter, glad to see you are still active on the board. I always liked your blog and analysis. Last word was you would not be maintaining the blog anymore. Will you be active on the MB and stop the blog?
Nidan thanks for the book suggestion. Downloaded it, will read it.
No, i have the utmost confidence in Dr.Missling and his strategy and his team.
Just frustrating as an investor having to rely in MB members to get any info at all about shareholder meetings. Haha maybe soon we will have a whole IT department.
Thanks for the reports from the team that attended!
Arghhh! I know anavex is a Small company, with a marginal website. The Wainright presentation monday can be announced on the website today...but no info about the Once A Year shareholder meeting! No transcription of the shareholder meeting! No audio posted of the meeting!
RANT OFF
Longs are causing the SP to go down! Hear me out...
Well to be more precise, the buyers are causing the decline when there is no news.
Buyers keep placing bids several cents (or more) below the last trade price.
When the market is this thin and no one is selling, the MM must sell out of its pile. So it will move down to pick up the decreasing bids!
Anyway, this is a speculation.... comments?
I am not sure about this, but it seems to make sense, with no news.
Flames ON!
Suggest prioritizing the questions, most important first, just in case you cannot get answers to all of them.
I agree, answers that substantiate the science are the most important. Such as did the patients request PDD drug extension, and can TGD say if patients are noticeably improved, even sleep.
Thanks a lot guys and good luck!!
Thanks Tradeher. That gives some context to the PD request. Not really indicative of improvement being seen, but maybe! Imho
My question is does anyone know what the original context was regarding this?
Bourbon, of course we are pleased that the PDD patients will be able to continue taking 2-73 after the trial.
It is quite common for drug companies, and anavex did this, to offer the drug to all patients after the trial is over. This helps recruitment, as the patients all know they will end up with the drug.
So if the PDD Principal Investigator, asked TGD if his patients could continue getting 2-73 after the trial, like the AD first trial, TGD might have said sure. The PI asked, and TGD can say they the PI asked for continued 2-73 for his patients!
That is very different from the PI noticing lots of patients improving and begging TGD for 2-73 for all the patients after the trial.
You see what I mean? The context is most important!
Can you (or anyone) provide the context?
Thanks
Consortiums have typically been very open to accepting of new members. The more the better, as they promote consensus. So I dont read much into anavex joining the ERP one.
That said, consortiums do tend to generate standards and protocols that are then accepted by industry. These standards, if accepted by industry, then can be used by regulatory bodies, in writing new regulations (read FDA). This may be how precision medicine is eventually integrated into fda procedures!
Xena, regarding the Cecchi app, not to speak for Doc328, but here are my comments.
Yes the patent app was applied for in July of 2017. A while ago.
I checked the Anavex website presentations for 2019 and 2018. There is no mention of these P300 tests or the button pressing response test. (The measurements did not make sense for these in the patent app.)
It appears that Doc is correct, these were found to not make sense, and were not included in future presentations. It does seem the narrative has changed to MMSE, Cogstate, autophagy, etc. It may simply be they did not know what exactly would improve, back then, so they tested reasonable things, like P300 and button reaction times. It may be a case of learning as they go, which leads to precision medicine.
Doc328 clears up the patent questions and provides some good background info in his post ...
docs post
Yes, closetinvestor, figure 7 shows the results of a particular measurement "P300 amplitude performance". It only shows data at 1 month for the 2-73 patients (change +38%), but also shows the donepezil data up to 6 months peaking at +34%. So the 2-73 patients improved quickly (1 month) and were slightly better than the donepezil patients at 6 months.
But as Doc328 pointed out, the 2-73 data only goes out to 1 month, so we do not know how they would compare, both at 6 months or 1 year. He noted that
investor provided a link for the 2-73 data up to 1 year, but because it did not make sense, this test was not included in the phase2a/3 trial.
Here is Doc328's
explanation...
Thanks for the patent data explanations and extra background info Doc328.
Yes, there were only 5 weeks of data for 2-73. As you said, these ERP P300 amplitude data does not fit Anavex's narrative. I would say the same may be true of the button pushing response times as well! Thanks again.
Your explanation below..
The patent only compares the 5 week Anavex ERP data to multiple Donepezil timepoints but Anavex has 17, 31, 43 and 52 week data (see Investor2014's post)
From Figure 7 in the patent, looking at the ERP P300 amplitude improvements, A273 beats Aricept at one month. However, from the above link, Aricept/donepezil beats A273 later on (month 3 and 6 DPZ vs. weeks 17 and 31 A273). We don't know how the 2 would compare at +/- one year.
From Investor's link, the A273 data was all over the place, quickly improving at 5 weeks then also as quickly going back to baseline at 17 and 31 weeks and then shooting up above 'healthy control' at 52 weeks. These swings do not make physiologic sense. If Anavex had used the 31 week data in the patent, they would have needed to explain why Donepezil is better than A273. Since Donepezil is not too strong, this is not the narrative that Missling wants. I think these swings might also explain why they opted not to use ERP P300 in the Phase 2a/3...it's just not that great of a biomarker.
Investor, regarding your patent comments. I read it too, in some detail. I guess Cecchi might have been contracted to write it up, or has some affiliation with anavex or a partner.
2-73 patients, in the P300 amplitude tests, did only slightly better than the donepezil patients. But the 2-73 patients improved in 1 month vs the doepezil 6 months. Figure 7.
Also the button pressing tests were at least questionable. The 2-73 patients, for false alarms, were 2x better than healthy control subjects! Hows that? Table 2.
You have any comments on these observations?
Fyi i wrote up my notes in message 186838...
my notes
Xena, I think medical doctors, particularly general praciticioners, are threatened by AI. Because they get a description of symptoms, usually partial, then must try to diagnose the problem. AI is very good at diagnosing issues vs a database, and giving probabilities of each cause. Then doctors frequently prescribe pills, but cannot remember all the possible interactions and side affects. AI could not only diagnose the problems, but also provide pill suggestions with warnings, for each cause.
Until then we have to do our own research. Arghh