Replies to post #508376 on Anavex Life Sciences Corp (AVXL)

[abew4me]

Excellent question!

Hope Doc takes the time to answer in detail.

[Doc328]

I probably should have added 20-25 MM to my cash burn estimate for an OLE for AD.

Doc, could you help us understand why you think PDD/PD P3 is less likely to succeed compared with AD/Schizo/Rett?

The AChEI's like donepezil and rivastigmine did better at AD than PDD so success likelihood is probably a little lower for PDD. The indication may just be harder to prove benefit - or study might just need to be longer. The P2 did not meet the primary endpoint (pre-specified CDR Battery subscales (not the sub-subscales they tried to pass off as the actual endpoint)) and the study was short at 12 weeks, so it is too insignificant to serve as a 2b/3. PD looked potentially interesting with significant changes noted on the MDS-UPDRS. However, they needed to use the less vigorous Wilcoxan rank statistics implying data was skewed or many outliers. Who knows what was in the SAP. The study would be a little chea;er than AD as less complex and could be shorter. If only looking at PD (i.e MDS-UPDRS endpoint), could be 6 months plus OLE. If company can get AD approval, they may be able to get by with a single PDD phase 3. But without AD approval, they may need to do 2. They just don't have the funds without excessive dilution. Hence I doubt they do PDD trial start in next couple years unless they drop AD.

PR says they’ll be “providing relevant biomarker data” for the re-exam

I'll do a separate post for this

The one clean precedent I can find is panitumumab (Vectibix) in mCRC:

Nice example that is somewhat relevant - the exception that proves the rule?. I researched this further. There are important factors that prevent a perfect correlation with A273.
- caveat: cancer drugs are often looked at differently and this is from 15 years ago. This drug had multiple studies.
- Most tumors are KRAS WT.
- FDA:It was actually first approved by FDA in 2006 with accelerated approval using PFS as a surrogate marker (OS was primary endpoint). The company quickly started 2 P3 trials. As these were enrolling, further analysis of the P2 showed that KRAS WT tumors showed benefit but the KRAS variant tumors did not. The 2 P3 were already enrolling (ultimately > 1100 patients). The SAPs were amended to reflect KRAS startus before the readout (so post-hoc for the P2 and amended SAP for the P3's). So all 3 studies enrolled 'all-comers' with the P3's evaluating (and publishing in 2009) reflecting booth the all comers and the variants. The label was modified in 2009 to reflect the KRAS status based on this amended SAP analysis of the P3's and approval was changed from accelerated (all-comers) to full (KRAS WT) a couple years later. .
- The EMA, usually slower than FDA, granted initial/conditional authorization in 2007, The P2 genetic analysis came out during the MAA evaluation. Therefore the initial conditional authorization was for KRAS WT and then updated to reflect KRAS status later after the P3 trials confirmed the KRAS subset finding.
- I do not know if they needed to do an oral argument but it was approved without a re-examination-- as A273 will apparently need. .
- A273 had the S1R WT/Q2P data, and the limited biomarker data and MRI data at the time of the MAA (November 2024). The drug is not already approved in the US. There are no additional studies already in progress.

[Doc328]

But on the A/T/N biomarker spectrum (Aß42/40, p-tau181, p-tau231, NfL), Blarcamesine still has no reported p-tau181, p-tau231, or NfL data.

So:
Can they really claim “disease-modifying” or “upstream to amyloid and tau” if the tau markers don’t show any convincing correlation?
If CHMP is benchmarking against donanemab/lecanemab on A/T/N, how big a hole is that for Blar?

There are still folks hoping the post-hoc ABCLEAR3 genetics can rescue the re-exam. I’m curious how you view that in light of how rare post-hoc biomarkers actually move the needle at EMA.

I don't think the AB42/40 data will save the day. As you have pointed out pTau181 and NfL were not significant in the entire population. I had previously pointed out the very low N for the biomarkers. For some unknown reason, many patients who stayed in the entire 48 week trial never got the biomarker blood-work (simple blood test can get all 3 biomarkers in one panel from Labcorp and pTau 231 from Quest or other labs). Compared to the ADAS-Cog N of 313 patients completing 48 weeks - only 197 did the 'significant' AB42/40 biomarker at week 48. Because only baseline and 48 weeks, Anavex cannot use MMRM/LSM to finesse this dataset -- what happened to these patients and are they representative. Now imagine if you were to cut N down a further 30% for ABCLEAR1 or 50% for ABCLEAR 3. pTau231 has even fewer patients.

Although higher N, there were still an unexplained reduction of N for NfL and pTau181 - and these biomarkers failed - likely due to very large variance. Was the test even done at the same lab?

See the n values below