Replies to post #508554 on Anavex Life Sciences Corp (AVXL)

[Hosai]

Well I sort of agree, my post did say that ABCLEAR3 wasn't pre-specified (though p value very low and the gene interactions very plausible). However, it comes from ITT data that on its own is better than the MABS ITT data in terms of ADAS COG and CDR SB.. The pre-specified sigma WT data is a bit stronger still. Potentially conditional approval could be given for the pre-specified sigma wt group with a phase 4 on ABCLEAR 3 in meantime. Arguably though perhaps shouldn't need to be a sub-group when beating the MABS on ADAS COG and CDR SB the ones regulators care most about. Plus showing the effect growing into the OLE delayed start analysis.

"In contrast, the mAbs had also modest but clear ITT clinical efficacy and robust A/T/N signals across large, replicated trials."

As I said in a previous post I wouldn't necc say "replicated" as the MABS phase 2 results had quite a lot of failures - Lecanumab primary endpoint not stat sig. Secondary CDR SB also not stat sig. ADAS cog successful at one dose not another.
Donanemab P2 primary endpoint slim pass (0.04), failed most of its seconndary endpoints including adas cog and cdr sb - didn't give p values.
Both trials also showed extra brain volume loss and non stat sig Nf-L data so arguably not great on the 'n' part of A/T/N (this part was repeated in their phase 3s).
Obv I would agree their phase 3 trials were a fair amount bigger than Blarcamesine 2b/3 then again it is harder to get low p values in a smaller trial.

[boi568]

The effect on the traditional biomarkers is bound to be stronger in a symptomatic drug like the mabs than an upstream, long term drug like blarcamesine.

The mabs immediately go to work attacking the plaques, while blarcamesine is instead permanently reducing the neurological degeneration that will create plaques months and years into the future.

You can see the delayed clinical effect in the 2b/3 ADAS-Cog13 graphs, and you can see blarcamesine's unique long range, disease modifying effects in the 144/192 weeks OLE analysis.

The time frames for the mabs is more immediate and of lesser duration, but its immediacy does result in stronger traditional biomarker results. Basically, that's because those biomarkers are set to efficiently detect plaque reduction (mabs) rather than long term disease modification (blarcamesine). This is another function of AD being defined as a plaque disease, and another reason why placing weight on these tests will tilt the playing field toward approving more ineffective AD drugs over better options. I can hope the EMA catches this, as well.

[crescentmotor]

Even within that subgroup {ABCLEAR3], there is no established amyloid or tau biomarker effect.

Blarcamesine's MOA is designed to enhance autophagy, a process upstream from conventional pathologies that later result in aggregated ß-amyloid or fibrillary tangles. So far as I have seen, amyloid or tau biomarker readings were primarily used for patient selection baseline criteria to establish the existence of AD. Can you show me where changes in the baseline amyloid or tau readings were prespecified as clinical trial primary outcomes in AVXL's 2b/III trial? I only remember them being cited as "other endpoints". I'm not sure changes in these biomarkers are even related to Blarcamesine's MOA in patients benefitting from treatment because Blarcamesine would not be expected to reverse prior damage; however, the placebo group readings would be expected to increase with the passage of time.