Replies to post #146648 on Anavex Life Sciences Corp (AVXL)

[Talon38]

Doc, I bow to your medical expertise and experience however, the sum total of treatment progress with Alzheimer's is abysmal. The disease is a death sentence and takes a tremendous toll on family and caregivers yet, we continue to spend huge monetary and scientific capital on failure prone research. To make a crude analogy we are trying to save survivors of a ship wreck in the North Atlantic by throwing them life preservers.... we keep throwing preservers to those in the water and they continue to die of exposure. I believe that the current FDA "adaptive/precision" drug development is aimed at "Triage" i.e. save those closest to the life boat by pulling them aboard. We can't save them all but if we do save the XYZ patients we have made progress and the research goes on into early detection, genomic specificity, and combination solutions. Seamless adaptive trials with RWE and continual data feedback seems heresy in light of the large scale, and time consuming trial methodology heretofore. However, Scott Gottlieb and Janet Woodcock appear to be moving the neurodegenerative drug development toward their Cancer Center of Excellence model.

[bas2020]

Let's say a study compared two doses and placebo but the high dose was found to have many dropouts due to toxicity. It would be reasonable for the independent data monitoring committee to pass this info on to the company. They then would likely drop the high dose (and move all high dose patients to the lower dose) and continue the study, and possibly increase the numbers to be enrolled in the now only dose and the placebo.

In A2-73's case, higher dose (i.e. blood concentration) has shown to be more efficacious, which makes this drug much more promising.

[XenaLives]

The trial will probably focus on the super responders but that does not mean that the others did not have a benefit. They all chose to continue with the trial. I believe the data from that continuation will shed additional light on the effects of the drug, and I believe there is a very strong chance that that data will indicate an improvement over SOC for the total population over a three year period... this is due mostly to the fact that the bar is set so low, it won't take much to show superiority.

I also believe that there will be multiple biomarkers, not just "XYZ postitive".

The problem, and it is a big problem, is that there are only a few super-responders and no placebo. I don't see how they can get any meaningful result. They may just find markers for slow AD rather than treatment effect. Anavex would have been much better served by a larger phase II with a placebo arm. The FDA is very content to have companies do Precision medicine trials -- however, if they only investigate patients who are XYZ positive then the approval will only be for XYZ patients not for everyone with AD and insurance will not cover those who are not in the genetic category. As a great example, one of the new lung cancer drugs is approved for ALK+ NSCLC, not everyone with NSCLC nor every lung cancer

RWE evidence will also be collected in the P2/3. It is being collected in the P2b extension. Avonex vs Tysabri is a bad comparison. The current SOC has little to no effect after a few months for Alzheimer's patients.

I believe that it will more like - "We know you'll sleep better and you blood pressure problem will get better, your mood will probably improve too. We don't know how much you will benefit cognitively, but it will be better than Donepezil, so let's give it a try.'

Real world experience trials are very commonly done in Phase IV and doctors kind of ignore the results as they are uncontrolled and/or nonrandomized and often too small or too variable and we always wonder if patients were selected to be in one group or another based on disease aggressiveness or other factors. As an example, if there was real world nonrandomized comparison of Avonex (weaker) vs Tysabri (stronger), chances are I would put my aggressive MS patients on Tysabri and less aggressive patients on Avonex.

I don't get your point here - this will be a pre planned adaptve P2/3. Changing protocols in a P3 is a non sequitur.

One has to be careful changing a protocol mid-study. In Phase III's there are independent data monitoring committees (independent doctors who are not recruiting patients plus statisticians). Let's say a study compared two doses and placebo but the high dose was found to have many dropouts due to toxicity. It would be reasonable for the independent data monitoring committee to pass this info on to the company. They then would likely drop the high dose (and move all high dose patients to the lower dose) and continue the study, and possibly increase the numbers to be enrolled in the now only dose and the placebo. The advantage of adapting is the study goes on and timeframes can be kept but the disadvantage is they now have less likelihood for success (assuming higher dose was more effective). Biogen just adapted their amyloid drug study by adding more patients

[nidan7500]

[quoteBiogen just adapted their amyloid drug study by adding more patients ][/quote]

Thanks doc. Like the man said. "Tip of the iceberg". Very much appreciate your contribution I understand you to say that this is going to take a while and there is no, "one size fits all" solution.

[LakeshoreLeo1953]

You tried.

Analytic discussion is not common.

Most significant takeaway must be universal and
well defined approval.

Presuming to assure "super responder" results
(whether realized or not)
WOULD likely restrict (lacking further study)
authorization to that sub group.

Not quite the Sliced Bread solution predicated by
many share price guesses.