I'd say promotion comes from:
1. Missling/AVXL
2. Some lower end investment analysts
3. An overenthusiastic retail segment whipped into a frenzy by #1 and #2.


I gained a distrust of Missling's presentation of the science and the data early on. He spoke grandly about AVXL's approach and how it might reverse AD while not providing any real substance about how the approach was unique. Specifically, he spoke about S1R agonism as if AVXL was the first to ever try it. Then when he actually had data he oversold it...esp. the early cherry picked data. Anyone remember the whole "A2-73 is 4x better than SOC" mantra?...total garbage.

Some investment firms (Maxim comes to mind though I think there was another also) gave very shallow analyses with astronomic projections around the time of uplisting. Reading those reports gave only the sense of promotion not legit investment advice. I think there were accusations that these reports were paid for...by whom I wouldn't care to guess but the quality of the work seemed to mesh well with the accusation. Even the more recent, and higher quality report, from Noble had a nice review of S1R pharmacology and then really missed the mark when describing the available data in a very confused way.

The retail segment appears to be overzealous. Maybe they are right as the A2-73 prospects are not 0 and if can be shown to work the huge market/need will justify all the optimism. OTOH, I think there is a good reason the market has left a huge upside gap and I think more skepticism in current results is warranted. For biotechs in general and AVXL in particular, taking the company line without a critical eye is a recipe for disaster.

I don't know of any even with proven treatments. Certainly none for indefinite time frames because nothing exists that has been shown (or even close) to reverse AD.

First, I'm not sure I agree or know that MMSE is the best measure, just that it was the most important one that was available in this study. Qualitative reporting is fine at this stage..but not very useful or weighed very heavily in terms of approval decisions.


I'm not sure what expections I'm setting. I'm merely commenting on expectations/results AVXL is describing in patients dosed as they were dosed. I can't say how "full strength" dosing would change things.

I didn't know this..in fact I'm a bit surprised if true. I think one of the bigger disappointments of this trial is that they didn't show an indication of possible synergy as per the mouse data but I don't think a non-placebo trial can really disprove it and I'd expect they will need to have significant numbers of patients on DZP for their subsequent trials so I consider it an open (though now somewhat more doubtful) proposition.

Prospective only at this point. See my preceding post for more specifics.

My only response to criticisms of the comparison group would be "direct your criticism to AVXL" they chose it. That being said, IMO its an incredibly useful compilation of available data and a reasonably complete sample of available data.

I do not mean to impugn the actions of any of the researchers and I apologize if I seemed to imply that. That being said I think they are as vulnerable to subconscious influence as any human. I am not as generous in my view of AVXL's management. As to your final sentence I am not an investor and have not been for over 6 months. I have been in and out of AVXL about 5 times for short periods...I feel like its a highly promoted and highly retail driven stock. As such I expect some wide swings I can profit from. That being said I have been too afraid each time I've had a position (3 long, 2 short via puts) such that it limited my profits. I don't know if I'll ever take another position but it probably won't be because I believe in the management.

Hi Seventhwave,

I am not overly impressed with partial revelation of data. In addition 2 of the group had the bulk of their improvement in the first 5 weeks (a total of 24 days of treatment in that timespan) with gains of 4 and 6 points followed by another point or so gain (if I remember correctly).

I think it was Flash1 who provided a reference and made the point that this proportion was not out of line. I have the reference but need to run...check his posts.

gotta run...will come back to other questions

I have no doubt that is true. OTOH, they have only their own compounds in order to try to do that and if they are not successful with 2-73 they are unlikely to be able to try any of their others. Given they only get paid as long as AVXL survives they have a financial interest in pushing this to the utmost even if they see prospects waning. No matter what prospects they see they also have a vested interest in promoting the positive aspects to the exclusion of negative so they can secure funding in the cheapest way possible in order to minimize debt/dilution. In the extreme some companies may even over-promote and mislead to achieve their ends.

FWIW, I have been skeptical of their data presentation/integrity for a long time.

They have a better understanding of the statistics than what is put out for public consumption. Their motivations may also not perfectly align with investors.

I don't think you fully understand how the process works. The FDA does not "pass" them or not. They may give input on what AVXL needs to show in order to gain approval and give input on study methods that would be most acceptable to them for approval but they would never say "nope, secondary efficacy data in this uncontrolled safety study wasn't good enough, go do it again". The decision to move to the next step (and spend money on it) will be AVXL's call.

The point here is that AVXL is making a claim. To me it seems a dubious claim based on the data used for the claim. I'm simply throwing it out to the board to try to explain this claim but thus far all answers seem to be in other directions.

At the same time, I wouldn't underestimate the importance of this claim. IMO the MMSE was the most important of all measures they tried to assess with ADLs in second place.

They were indeed for varying methods but were at least all for "mild-moderate" impairment. That being said, this is the group AVXL chose for comparison and what they based their claims on....as such we should at least be able to make sense of their findings.

Furthermore, I'd be shocked if they didn't also try to pull out some that were best matched for comparison....despite that they seem to have chosen to use the whole group anyway.

Well any measure is subject to error which does not alter the fact that "MMSE is the only widely used, global cognitive measure they have". Hopefully they will have more/others if they can get their next study off the ground.

Whatever the possible shortcomings of the measure, AVXL is trying to claim a statistically significant improvement in performance relative to this historical control despite their performance seeming to be quite solidly in the middle of "no treatment" results and their proposed level of improvement suggesting a historical control performance that falls outside the range of the entire group of 20 prior trials. Statisticians got an explanation? Anyone?

Anavex used more than the MMSE in evaluating the P2a, the trial was on non-optimized dosage, as that was part of the purpose of the trail and statistics don't explain the "unexpected results", the super-responders.

Whether any of that is relevant remains to be seen. However, it is AVXL that is claiming "stabilization" FOR THE WHOLE GROUP and claiming a benefit over THIS group of historical placebo for MMSE. In addition, they will succeed or fail based on COGNITIVE and functional measures not on anecdotes. MMSE is the only widely used, global cognitive measure they have and as such it is of particular importance.

Whether or not they might perform better with different dosing or whether or not some subgroup may be responding vs. normal variation is really not addressed by this study and remains to be proven or disproven. However, AVXL making this claim regarding MMSE related to the current data and IMO, that claim is worthy of examination on its own merits.

Historical placebo control data referenced by AVXL for their bootstrap analysis came from Thomas et al 2016 (see p29 of CTAD slide presentation). That reference pooled performance over time for placebo groups in 20 different trials. Here is how placebo did in those 20 trials for MMSE:



Also in that reference they modeled the "average" performance using a few different methods. Those results are here:


If you want to compare A2-73's performance it was -3 at 52 weeks and -2 at 57 weeks (that graph is in months so of course you'd use time points at 12 and 12.2 months).

As most will recall, AVXL's bootstrap analysis suggested that 2-73's performance was 1.8 points better than these historical controls. Thus, if you may want to plot A2-73's performance - 1.8 leading to -4.8 and -3.8 at 52 and 57 weeks respectively.

Now, you might want to ask why A2-73's performance looks like its right in the middle of the historical controls and why 1.8 worse than that falls outside the range of ALL 20 of the prior trials. Maybe some of the board's statisticians could weigh in on that one.

I saw that study on the "high-throughput" months ago and have been trying to find out since if its in any way similar to Biogen's testing (no success).

If its similar it just would mean 2-73 is one of hundreds of "promising compounds". Maybe Biogen's is somehow more in depth or more telling. I don't know...but it should give pause to the "partership is imminent" crowd.

Nice recap and excellent references.

That being said, most of the data relates to S1R in general. Clearly its an exciting and developing field. However, there are many S1R agonists available and some have been tested in AD with marginal results. I disagree that A2-73 is a selective agonist...it clearly is not selective given the activity at other receptors as you listed. I also still do not see significant differences in Ca++ modulation. While some S1Rs are VGCC blockers I don't think that will be relevant for neuronal ER.

The Lahmy article does provide some theoretical basis for the one aspect that's already been discussed. Namely, the potential that S1R + muscarinic modulation in combination may provide a benefit that selective agents can not. I consider that fairly weak but its something at least and worth following. At the same time, those looking at the avalanche of excitement around S1R pharmacology as somehow specific to A2-73 should narrow their focus tremendously.

Hi Mycroft, thanks for the thoughtful post.

Reduction of intracellular Ca++ is typically thought to be a therapeutic (neuroprotective) effect of S1R's in general so I am not sure less of an effect in this regard would be a good thing. That being said, if you have a reference that shows a differential effect I'd love to hear about it.

Here is a nice review that discusses the neuroprotective effect of reduced intracellular calcium. A2-73 is mentioned but not in the type of detail we are discussing: http://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1004&context=tuccop_pubs

Blu_2 mentioned that A2-73 was hitting the sweet spot for affinity. Would like to know what he means by that and again, any reference would be very helpful.

At the onset it was just safety at various doasages, then they started adapting

So I guess now you agree with me that those early amazing (nonphysiologic) gains made in the first 5 weeks by some in the "strong six" could not possibly be treatment related.

Those "strong" graphs get a lot weaker without those big gains.

On a quick look you seem to have taken the worst case of the error bars from each of the data points (for all patients) as published by Anavex for the 57 week CTAD update.

I'm glad you actually looked. I did not use any extreme data from the error bars...only the actual data points. I don't think reading error was a significant source of variation but if there is variation it would not be in a systematic direction and would not significantly alter that graph. For the ADL data its straight from what they charted. For MMSE I removed their manipulation of the timeline (which was utterly unjustified) and instead graphed from the onset of any treatment. As a result you may be misreading (from my intention not in an overall sense) the MMSE graph because there would be a shift introduced.

You are repeatedly showing an anecdote as your convincing evidence...looks like extrapolation to me.

You asked for "any evidence"...and I gave it to you...but now you don't seem to know what to do with that evidence other than say someone you don't know told you everything was ok.

I know...I'm sure most will get past that.

What about the data?

So you want us to accept your made up charts rather than the company's peer reviewed charts?

I want you to do 3 things:
1. Realize that AVXL does not have truly peer reviewed charts...they need to publish for that
2. Go back to THEIR charts, use their numbers, and plot it for yourself. (at that point you'll see the reason they plotted things separately AND you'll see the obvious manipulation of scale and timelines)
3. Realize the hazards of extrapolating from anecdotes

I'm still waiting for evidence that ANY other AZ drug has allowed the quality of life improvement that we've seen in the piano player, the painter, the golfer and the mass transit drive, and of course, Mr. Heaven.

Data and facts confirm it...


Any evidence? How about the evidence that the treatment group was not any better than the historical control group? Those are AVXL's numbers in those graphs...just put the numbers they provided in with the same scales and used a reasonable timeline. I think you can see why they didn't want to display it this way themselves.

As for over-reliance on an anecdote... there are many reasons that can explain a single case. Many have pointed out fluctuation is expected as is stabilization/improvement for some. The pt may have been misdiagnosed. The baseline may have been skewed and after entry the patient's depression resolved, subdural hematoma resorbed, may have started taking vitamins, may have started taking thyroid hormone replacement, and more.

FooBar - I don't think the charts look grim. I think they show a pretty robust effect. It also suggests the testing Biogen is doing is more likely to be successful (though the import of that is something I think is WAY overestimated in the current crowd). Strange that high dose A2-73 by itself may be a bit toxic relative to ocntrol.

Where I think there is cause for pause is when one asks "why is A2-73 different than other S1R's" of which there are many. That is where I am always looking for AVXL to try to show solid differentiation and I don't see it.

The DM/quinidine trial by Cummings for agitation actually shows a very strong trend toward MMSE improvement (vs. placebo!)...which also may bode well for A2-73...though one could argue that treating the agitation could be the reason for the MMSE improvement.

FooBar - that's an interesting poster. However, I don't think it says A2-73 does a BETTER job protecting oligos than DM does. There are no direct comparisons of the data that I see and their main point is that the effects are similar because they are both S1R agonists and NMDA antagonists.

Given this similarity, AVXL investors might also be interested in how DM (with quinidine) does for Alzheimer's. You can see the effect on MMSE if you look at the D/Q agitation study by Cummings (an AVXL Board member I think).

"Not much chance of failure with AVXL though"

Over what time frame are you thinking this is true. At some point 2-73 will become binary fail/succeed though there are levels of the latter.

Does this pertain only to 2-73 or the entire library of compounds that may keep hope alive for many years even if 2-73 fails?

The improvement of "6" on the MMSE seems significant


Thanks for some real data to sink our teeth into. Very helpful. As for the improvement of "6" did you notice that 5 of those points of improvement occurred in the first 5 weeks (24 days of treatment with varying doses/routes, 12 days of washout non-treatment). Do you think such an improvement could really be ascribed to the treatment?

One subject had a 6 point gain...5 of those points occurred in the first 5 weeks so he/she had 24 days of undetermined dose with 12 days of washout in that period. Despite the miraculous gain of 5 points with "treatment" the trend did not continue. Think maybe there could be an alternate explanation to A2-73? Maybe the subject was not in peak testing shape at baseline?

Dropouts of worst performers CAN explain a rise in P300.

Please educate me on my silly S-1 question.

I believe that story...what is suspect is that A2-73 was the reason for improvement. Given that the full study group tracked the historical placebo response, for every subject doing better there are others doing worse.

Anecdotes are pretty shaky grounds for belief.

The strong 6 is just AVXL's penchant for looking at cherry-picked data. This is a very small study to begin with...any subgroup look is folly.

The P300 data is a bogus measure. P300 latency is what has been shown to have a correlation to treatment effect. No study has ever shown that for the amplitude. Don't forget the wild claims of P300 gains that completely dissolved by week 31 only to reappear at week 57. The sharp gains in the week 52-57 interval reek of statistical tricks rather than something physiologic...not surprisingly, AVXL doesn't give enough information on their analysis to evaluate the reasons but I suspect the dropouts of subjects occurred during that period. Dropouts would be expected to performing poorly...did AVXL just use it as an excuse to drop them from the averages?

Not sure what you see as unique. AVXL has never explained whey their sigma 1 agonist is somehow more useful or has a different mechanism of action than the many others on the market (including Aricept).

In fact, the weaker affinity for Sigma 1 than Aricept might suggest less of an effect. Despite all the claims of "stabilization" their data to date for MMSE and ADLs seems to bear this out. Regardless of their highly flawed "boot strap" analysis, A2-73 is acting a lot like placebo if you use legit time parameters for analysis.

If AVXL used $8M of their ATM since September how much do they have remaining they can access?