Replies to post #316438 on Anavex Life Sciences Corp (AVXL)

[RipperMagoo1]

Are we running out of stickies for this guy yet?

Excellent recap and explanation as always Mayo, thank you.

[RedShoulder]

Mayo this is the best post of the day IMO. Thanks for breaking the details down and the chart reads.

This is quite impressive considering two items, first is this was on low dose, and second these are the adults which usually don't respond as well as the 5-18 age group.

Yet in spite of those disadvantages, they scored extremely well. This bodes well for the following Rett trials on higher dosage, and the Pediatric age 5-18 Patients With Rett Syndrome (EXCELLENCE).

Thanks for taking the time and effort to put this together, very well done.

[Pineapple1]

Adult Low Dose Rett Trial

Great job Mayo, thank you.

Pine

[tradeherpete]

Thank you very much for elaborating the Rett findings.

[attilathehunt]

Great recap! Thank you for taking the time to share.

"It is my opinion that Anavex will receive accelerated approval from regulators for Rett syndrome. "


What is the timetable in your estimation?

Thanks for answering.

[123tom]

Very helpful .thank you

[jmvho]

Mayo - Many thanks for the significant effort to lay this out for the rest of us!

jmvho

[RedShoulder]

I just made this a yellow sticky, as it does an excellent job of covering and explaining the details and graphs on the just released Rett trial top line results news.

https://investorshub.advfn.com/boards/read_msg.aspx?message_id=164514575

[jimmy_mcyoloswag]

Excellent summary and assessment of the data, thank you!

[blue finch]

Thank you for helping us all here

[mrplmer]

Great work

[McMagyar]

Thanks Mayo

[attilathehunt]

Nice job!! Thank you Mayo!

[Investor2014]

Abstract
Rett syndrome is a genetically based neurodevelopmental disorder. While the clinical consequences of Rett syndrome are profound and life-long, currently no approved drug treatments are available specifically targeted to Rett symptoms. High quality outcome measures, specific to the core symptoms of a disorder are a critical component to well-designed clinical trials for individuals with neurodevelopmental disorders. The Clinical Global Impression Scale is a measure of global clinical change with strong face validity that has been widely used as an outcome measure in clinical trials of central nervous system disorders. Despite its favorable assay sensitivity in clinical trials, as a global measure, the Clinical Global Impression Scale is not specific to the signs and symptoms of the disorder under study. Development of key anchors for the scale, specific to the disorder being assessed, holds promise for enhancing the validity and reliability of the measure for disorders such as Rett syndrome.

Improving Treatment Trial Outcomes for Rett Syndrome: the development of Rett-specific anchors for the Clinical Global Impression Scale

One thing to keep in mind is that both RSBQ and CGI-I are observation based scoring rather than biomarker objective. CGI-I is based on expert clinical impressions, whereas RSBQ is based on parent/caregiver observations.

In the CGI-I chart we see the placebo group had 40% responders vs. 60% non-Responders. That is high and much higher that in RSBQ, where 90% of the placebo group was Non-Responders. We could attribute at least a good part of this to observer bias, imo.

Btw. in the CGI-I chart it is a little odd the Responder and Non-Responder patient counts do not add up to 100%. That must be an Anavex typo given the patient numbers do add up.

Below is regarding RSBQ.

Need to know:
Rett syndrome is a progressive neurological disorder in young girls. Two ongoing Phase III trials use Rett Syndrome Behavior Questionnaire (RBSQ) as a primary endpoint. This validated 45-item checklist assesses behavioural and emotional symptoms in Rett syndrome.
But experts took issue with RBSQ as it focuses too heavily on behavioural changes at the expense of physical improvements. They are calling for better efficacy endpoints that are more quantitatively and objectively sensitive for real-world value.
Current outcome measures in Rett syndrome clinical trials lack the sensitivity to measure nuanced changes in disease progression, experts say. Without more sensitive endpoints, ongoing Phase III trials could struggle to objectively quantify symptom improvement.

Two Rett syndrome candidates—Acadia’s trofinetide and Anavex’s ANAVEX2-73—anticipate data from their respective Phase III trials this year. As a coprimary endpoint, both trials use the Rett Syndrome Behavior Questionnaire (RBSQ): a caregiver-focused checklist measuring behavioural and emotional symptoms.

While RSBQ is a validated endpoint, it does not adequately focus on important motor function outcomes, University of Alabama Rett Syndrome Clinic director Dr Alan Percy says. Rett syndrome is a rare neurological disorder characterised by progressive loss of balance, speech, and motor function.

A more holistic outcome measure would better emphasise Rett syndrome’s physical manifestations, including walking and hand use.

Rett syndrome experts grapple with trial endpoints that lack sensitivity

The U.S. Rett trial was relatively small and so is the AVATAR trial. Together and given the identical trial designs and higher dose, if AVATAR confirms and improves on these observation based scores the combined results are strong. I think there are risks, not objectively addressed by having an S1R mRNA biomarker of response to A3-73, and really hope the AVATAR readout when it comes is strong. Even so I still think it is likely we need EXCELLENCE data before filing for approval.