Anavex Life Sciences Corp (AVXL)

[sokol]

I think that the RSBQ AU may be a better endpoint than RSBQ alone, which has been criticized by experts. See https://www.clinicaltrialsarena.com/analysis/rett-syndrome-endpoints/. In pharmacology, the dose response curve shows the relationship between the amount of a drug taken and its effects on the patient. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug. The Clinical Global Impression – Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. Isn't it best that the clinician assess whether the Rett patient's condition has improved or worsened at points in time in conjunction with the patient's concentration of the drug (AVXL 2-73)? Is this method better than RSBQ alone, which has be criticized by experts as I mention above?

The following (excuse any of my typos) is from slide 8 of the conference call that attempted to explain the Avatar data:

.......
"Appropriate Primary End Point for Rett Syndrome

Statistical significance alone not sufficient for determining whether an individual patient has experienced a meaningful clinical benefit

As a standalone caregiver reported primary outcome assessment, RSBQ does not appear optimally suited, on its own, for the determination of a clinical trial outcome (could lead to either type one or type two error)

FDA:

Anchor based responder method - linking of scores from one clinical outcome assessment (RSBQ) with scores from a simple reference "anchor" clinical outcome assessment with a clinically meaningful threshold (CGI-I) to facilitate interpretation of what constitutes a meaningful within and between patient change in clinical outcome assessment scores (RSBQ AUC)"
.........

So, according to what Anavex indicates above, RSBQ AUC recommended by the FDA was meant to provide a more meaningful outcome assessment than RSBQ on its own, which might lead to errors in interpretation.

See also: Anavex: The First Impression May Not Be The Right Impression
https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiaisqO9-P1AhVOlWoFHZfDCVgQFnoECAwQAQ&url=https%3A%2F%2Fseekingalpha.com%2Farticle%2F4483849-anavex-the-first-impression-may-not-be-right&usg=AOvVaw0Xrs-NV1fP8s--NvTOLDQT

Of course, this is a difficult subject for me to understand and explain. I have made an attempt to understand this issue and offer bit of an explanation, which may be subject to legitimate criticism. Therefore, I am open to criticism and discussion. Perhaps someone else may find fault with what I say here and may offer a better explanation. In any event, if the FDA did recommend changes in the design of the Avatar clinical trial, it seems to me that, other than the effect on Anavex's share price for the time being, the only things that are important is whether Anavex is providing what the FDA recommended and whether the FDA views the Avatar trial outcome as sufficient to expedite approval of AVXL 2-73 for Rett. In the long run, it does not matter what me, Adam F or anyone else thinks or says.

Following (1-3) is some additional internet research I did in reference to what I have written above.

1.In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of a curve that describes the variation of a drug concentration in blood plasma as a function of time (this can be done using liquid chromatography–mass spectrometry[1]). In practice, the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to estimate AUC.

Interpretation and usefulness of AUC values[edit]
The AUC (from zero to infinity) represents the total drug exposure across time. AUC is a useful metric when trying to determine whether two formulations of the same dose (for example a capsule and a tablet) result in equal amounts of tissue or plasma exposure. Another use is in the therapeutic drug monitoring of drugs with a narrow therapeutic index. For example, gentamicin is an antibiotic that can be nephrotoxic (kidney damaging) and ototoxic (hearing damaging); measurement of gentamicin through concentrations in a patient's plasma and calculation of the AUC is used to guide the dosage of this drug.

AUC becomes useful for knowing the average concentration over a time interval, AUC/t. Also, AUC is referenced when talking about elimination. The amount eliminated by the body (mass) = clearance (volume/time) * AUC (mass*time/volume).

AUC and bioavailability[edit]
In pharmacokinetics, bioavailability generally refers to the fraction of drug that is absorbed systemically and is thus available to produce a biological effect....

https://en.wikipedia.org/wiki/Area_under_the_curve_(pharmacokinetics)

2.The area under the curve (AUC) is commonly used to assess the extent of exposure of a drug.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152796/

The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg*h/L.

This area under the curve is dependant on the rate of elimination of the drug from the body and the dose administered. The total amount of drug eliminated by the body may be assessed by adding up or integrating the amounts eliminated in each time interval, from time zero (time of the administration of the drug) to infinite time. This total amount corresponds to the fraction of the dose administered that reaches the systemic circulation.

The AUC is directly proportional to the dose when the drug follows linear kinetics. The AUC is inversely proportional to the clearance of the drug. That is, the higher the clearance, the less time the drug spends in the systemic circulation and the faster the decline in the plasma drug concentration. Therefore, in such situations, the body exposure to the drug and the area under the concentration-time curve are smaller.

....

3.Clinical implications

During clinical trials, the patient’s plasma drug concentration-time profile can be drawn by measuring the plasma concentration at several time points. The AUC can then be estimated. Knowing the bioavailability and the dose, the clearance of the drug may be calculated by dividing the dose absorbed by the AUC. The clearance calculated is relatively independent on the shape of the concentration-time profile. This method gives precious information on the pharmacokinetic behavior of a drug on trial. It can also be used to study a change in the clearance of a drug in specific clinical conditions, such as disease or concomitant drug administration.

https://sepia2.unil.ch/pharmacology/parameters/areaunderthecurve/#:~:text=The%20area%20under%20the%20plasma,body%20and%20the%20dose%20administered.