Anavex Life Sciences Corp (AVXL)

[F1ash]

”My understanding is that has not been a positive trend in any prior clinical trial, only scattered patients. This might be because prior trials did not use the same statistical analysis. Posthoc analysis as used after the trial weakens the evidence. With AD, patients vary by the day—it is critical to set the statistical rules before not after the study. “

George

George Perry, Ph.D.
Dean and Professor
Semmes Foundation Distinguished University Chair in Neurobiology
College of Sciences

In reply to:


... I am writing you today to see if you can help me clarify some of the remarks you made during your interview with Dr. Missling from Anavex on October 13th.

The audio is at the following link and your portion begins around the 33 minute mark.

http://www.wsw.com/webcast/cc/avxl2/index.aspx


Someone else transcribed the remarks I am referencing (so please pardon and feel free to correct any inaccuracies)

“"Further it is important to note that the data that is shown, I'm talking about the statistics thing, that this approach actually has been effective in benefiting patients, they are actually improving. That has not been shown in any prior studies, even at the phase 2, it has always been instead a focus on the rate of change in decline. The sort of Aricept type model, which does benefit patients and families, but the results are very narrow and limited. “


My question is : Are you saying that in Previous trials that no trial has shown a “statistical” (or an Average/Mean) trend line of all participants in the trial that increased at 12 months (57 weeks for Anavex’s data) or are you saying that no individual patients ever improved in the previous trials?

As I’m pretty sure you are aware, Anavex had a group of “strong responders” whose MMSE scores actually increased during this study. Is that something that has never happened before?

Slide 31
http://www.anavex.com/my_uploads/CTAD-Anavex-December-2016.pdf

I follow a message board and there are a large number of individuals there who are under the impression that that type of thing (5 “strong responders” who’s MMSE scores actually increased after one year) has never happened before. The comments you made on the 13th seems to reinforce their belief.

I did some research on my own and came up with these two pieces of research that “seem” to show that it’s pretty common to have a subgroup that actually improves even after one year even though the Average/mean for the entire group actually decreased.

July 1999
Variability in Annual Mini-Mental State Examination Score in Patients With Probable Alzheimer Disease

https://jamanetwork.com/journals/jamaneurology/fullarticle/775209

(Figure 3)

https://jamanetwork.com/data/Journals/NEUR/6482/noc8161f3.png

(Figure 4)
https://jamanetwork.com/data/Journals/NEUR/6482/noc8161f4.png

“Figure 4 shows the overall rate of change for each patient. This was estimated as the difference between the last and first MMSE scores, divided by the number of years between testing. Follow-up intervals ranged from 1 to 6 years. For patients with only 1 year of follow-up, MMSE score changes ranged from a decline of 23 points to an improvement of 7 points. As follow-up interval increased, the range of score changes narrowed, but even after 4 years, 13 (15.8%) of the 82 patients returning had no meaningful decline.”



And this:

https://alzres.biomedcentral.com/articles/10.1186/alzrt210

“Figure 2
CIBIC, changes in global performance. The changes in global performance (CIBIC) from the start of ChEI treatment over three years in mild AD. CIBIC score 1 to 3 was considered as improvement, 4 as unchanged and 5 to 7 as deterioration. Among the remaining patients in the study, 61% exhibited global improvement or no changes after one year, 43% after two years and 33% after three years of ChEI therapy. AD, Alzheimer’s disease; ChEI, cholinesterase inhibitor; CIBIC, Clinician’s Interview-Based Impression of Change.”

http://media.springernature.com/full/springer-static/image/art%3A10.1186%2Falzrt210/MediaObjects/13195_2013_Article_270_Fig2_HTML.jpg


I don’t feel I’m qualified to properly access if I’m misunderstand you or I’m misunderstanding the other papers I referenced above.

Here is Anavex’s graph of MMSE and ADCS-ADL for (ALL PATIENTS)

http://www.anavex.com/my_uploads/Anavex-September-2017-Presentation-.pdf

It looks to me like the MMSE actually decreased from 21 to 19 for all patients and the ADCS-ADL decreased from 70 to 65. If I’m reading the graphs correctly, isn’t that about what one would have expected to happen?

I’m also unclear on what they mean by “All Patients” since they apparently had 5 dropouts during the period the graph represents. Shouldn’t they have labeled the graph “Per Protocol” or “Intent to Treat” and accounted for how the dropouts were represented?

I look forward to any clarification you can provide me and I would also like your permission to share your response on that message board so we can all be on the same page.


Again thanks for your time and I look forward to reading your response.