In reply, nidan -
First point: (your post)
“Since all this CNS disease have never been effectively treated this is a gray area. We only can define fail. We are now buying time using an old clock.”
We can only define fail. (Quote)
Ok, let’s restate this, (because I think we are in agreement and saying the same thing in different ways. Let’s set them equal and then see what key differences remain - if any), let’s take out the notion that we can only define fail. So, if this is in reference to all/ most previous clinical trials and real world evidence of successfully eradicating or slowing CNS disease, then, I would suggest we can define “fail” as in failure to meet endpoints or to treat a specified body of clinical patients at a sufficiently high statistically meaningful level.
failure to do this simply means we have failed to stop the disease from continuing its path for whole groups of people. Have we altered the path at all at individual levels? This is what precision medicine means.
If we can not know what “success” looks like, we cannot know what “fail” looks like either (logical construct using opposites).
There is a reason that we can not know what these look like and at the same time we can know what these both look like. These diseases present differently on a case by case basis - except for certain generally accepted standard hallmarks, and even those vary in intensity, quantity, and some are even lacking.
Since the disease can show itself in many different ways, with a general decline in cognition as a hallmark, mostly memory, but also, comprehension, retention, interaction/ process speed, and these can be accompanied by an array of other symptoms: sleep patterns (both ways), agitation/mood, appetite, seizures, motor skills, etc., as well as some measurable physical findings: amyloid plaques, tau tangles, high markers in csf, I contend that no two Alzheimer’s patients present in exactly the same way. Same with other CNS Diseases. I hope we agree on this.
So, in order to pass or fail, succeed or be unable to stop the path of disease, ALL LIMITS MUST BE SET AT THE INDIVIDUAL LEVEL.
I hope we can agree on this as well.
Once we agree that this is where the plotting needs to take place, individualized treatments, as opposed to groups, we should be able to agree that this may have already been accomplished by some. For all we know, one or two patients may have benefited from each of the “mabs” which “failed” to gain approval or meet endpoints over a very large trial. It is simply not economically feasible for a company to research and produce individualized treatments. That explains the “old clock” one size fits all approach - but even that clock, if broken, was probably “right” twice a day. (Heck, 10 cups of coffee for some...)
So, along comes Anavex with a precision medicine approach. What will change? (Btw, this same thinking had to be explored in oncology, before CNS arena, and individual treatments were found to be feasible - partly due to high costs for the time and economics involved.)
This is why our MAO is vital. The published papers are worth their salt. These explain how a drug working upstream can improve a variety of symptoms at one time. (Unlike the amyloid clearing drugs which cannot restore mitochondrial function, which enables restoration of cognition, sleep, mood...etc.)
Using the mitochondrial approach as the disease modifying foundation, the tweaks will be on an individual basis (for unique symptoms) and not economically prohibitive.
Precise answer to your question about how do we know when we have failed (as opposed to succeeded, implied, ...opposites):
If Susie has AD and presents with impaired cognition (memory and comprehension and response speed) along with visually determined amyloid plaque and tau, along with mood swings, but no sleep problems or seizures or motor difficulties, then the disease which defines Susie is all of those things. And failure is Susie in this state and worsening. Therefore, not failing, by definition, is Susie in this state but NOT WORSENING, and success is Susie as Susie was before. Success cannot be an entire group of people as Susie was before - they must all be as they were before.
To make this possible, biomarkers must be measured and established at the individual level. (This is Cognision and ERP trial goal - Not to establish a “norm” but to establish everyone’s “norm” - tons of “norms”. So we can know when we reach them again or get closer to them to avoid the concept of “fail”.) Perhaps, in the example, Blarcasemine (A2-73) regimen completely restores Susie to her former self with the exception of sleep. I believe her family would live with this compromise and take an OTC med or find a soothing remedy, but, at that point, Susie is successfully recovered from AD and suffers from insomnia. Or perhaps agitation/anxiety. From this point, management of the problem has several easier, more familiar options.
We can only define fail.
When each patient and caregiver tells you the patient is themself again, you can define the opposite of the disease.
If Blarcasemine is not able to reverse the disease and restore the patient to pre-symptoms, but can stop the worsening of the disease, that can be known and measured as well, both by objective tests as well as caregiver assessment. If the drug is only able to slow the worsening, this would be the most difficult to see and to know, imo. One would have to conjecture (but much harder to prove) what the person would be like without the medicine. That would be the most challenging scenario and could turn a possible success into a failure for lack of ability to prove differently.
I am guessing that this was where the most recent HH tweet would be most useful (although still not a slam dunk, nor a blow out win). If you recall, he tweeted an article about AI machine learning using Gaussian Processes to make projections. I’m assuming this would be projections based upon individual data as to where the individual would be on the disease path without treatment which slows the progression. And this is where the Cognision and biomarkers would be the only discernible way to measure or detect effect.
Next point: (your post)
“AVXL staff surely know what is going on. Patients will eventually make this obvious. This cannot go on for long, IMO. Interim results are everywhere for sure. I always thought that some RETT mom would let us know.”
Agree - AVXL staff know what’s going on.
I NEVER expected leaks from any RETT mom or other trials. I’ve posted my experience about never knowing about a local boy who could WALK while on an experimental drug - I do not expect leaks, period, emphatically. Nor would I want them if they could jeopardize the blinding of our trials.
Next point: (your post)
“Somehow the investment calendar and the science calendar have to get in synch.”
You bet your ass! However, one thing for certain, two things for sure: If WE (the mb posters who study this tirelessly and compile far reaching DD) can’t sync the price to the science accurately yet, how the heck could the market ever hope to??!?
That’s why I believe Missling and co. are going straight to a deal, launch site for effecting orbit included, and cutting out the middle man. The day to day is boring and meaningless. Imo, if every ocean were filled with ink and the endless sky were a giant parchment, every Technical Analyst could chart our minute - hour - day - week price 24/7 from inception until this sells and won’t make a bit of difference (except trading points), cause in the end this will be kept off the streets. (Not saying TA is bad - just will not see this meteor hit).
Much respect, nidan. Apologize about the length - there is a process evolving here which I think we agree on and also for the need to quantify, standardize, and see logical steps taking place, which I do.
The rest of the message is: We’re Golden - Got This!