Replies to post #445415 on Anavex Life Sciences Corp (AVXL)

[frrol]

It's important not to mislead people. Avatar's problem was not that it was "small". Let's review and take it step by step:

Avatar's endpoints failed at week 7. They evidently passed at week 4, because the AUC scores were good and graphs weren't ever provided. The company used AUC (area-under-curve) as the endpoint gauge to "smooth over" the volatility. This stats technique is valid, but comes with a compromise: it de-emphasizes the patient's end-of-trial drug benefit. For a small mid-stage trial with a volatile endpoint, the technique is justifiable. Even though the company said it was potentially pivotal, it ended up not pivotal because we only passed using AUC, not week-7-change. Smoothing over with AUC is too much of a stats 'trick'. We have to show that patients have stat-sig RSBQ and CGI scores at the CONCLUSION of the trial (week 7), not at an arbitrary time point in the middle that gets us to a stat-sig AUC. If we drew a chart, it would show the drug's line looking good at week 4 but trending right back to the placebo line at week 7. That's no good for drug approval.

Now let's look at Excellence. Excellence was over 90 patients, so AUC was not used; the company used just the end-of-trial values (week-12-change). Nothing is stat-sig. Apparently RSBQ is stat-sig at week 4. Sound familiar? This is just like Avatar. And the problem is not just RSBQ; CGI apparently didn't reach stat-sig anywhere. Nor ADAMS.

So Avatar was not stellar, nor pivotal (self-evident). And Excellence was like Avatar on RSBQ, and worse on CGI and ADAMS. (ADAMS is particularly disappointing, given Avatar's p=.01. We didn't even report Excellence's ADAMS scores.)

BTW does everyone see the parallels with our AUC in Avatar to claim "met endpoint" with using odds risk in the AD 2b/3, and the risks when you do that? Missling has to be watched on endpoints. He can mislead the inexperienced when he's "spinning" results. AUC and odds risk have to be used appropriately, and understood.

[Investor2014]

So now that the Excellence trial failed you are at 55% chance of approval, whereas I was at an about 50% too generous chance before the sort of TLR readout.

I also expected the pediatric Rett trial to be a success. It was not the clear success I expected. I gave a 99% probability. Now I give it 55% and that may require an additional trial.

I am now way below 50% chance without a new trial.

Having 99% chance of approval in biotech investing, and even Boi's expected 80%'ish chance from the EMA filing in AD (and yes I know the {inappropriately applied} stats being used to arrive that conclusion), is imo, experience and understanding pure misguided insanity.

Look at the performance of professional biotech analyst, where even the very best ones comes nowhere near any WGT chance. The biotech investing game is not about believing in one's ability to pick unicorns, but skillfully with an open critical mind winning more than loosing. You don't even need an overall > 50% chance per investment, since the winners often have outsized gains and the losers can't cost more than a 100% of your investment and usually cost somewhat less.

Most, including Anavex, believed that success in paediatric Rett patients would be more likely since the damage from the MeCP2 gene defect would be less severe and the younger patient biology more able to restore balances with the help of A2-73 than the adult patients in the two previous trials. Did it surprise this turned out not to be so?

In the past I pointed out that both adult trials had outsized placebo effects and unfortunately in the Excellence trial placebo effect turned out even higher. Not too surprising when caregiver (RSBQ) and physician (CGI-I) subjective scoring is the only available measure of severity and disease progression.

The placebo imbalance in baseline scores that Kaufmann describes below could have been avoided with a larger trial with randomisation more likely to have ensured a better balance. It will be interesting to perhaps later see the baseline scores and how uniform they are. Keeping in mind how unreliable (up to 300% between scoring of same patient) the subjective scorings are hard to work with and results unreliable especially in a too small trial.

Walter E Kaufmann, MD, Chief Scientific Officer of Anavex commented, “We believe that a high placebo response may have masked the therapeutic effect of this innovative orally available molecule. High placebo responses are well documented especially in pediatric clinical studies. Although data analysis is ongoing, the early conclusion is that the placebo rate could have been higher in the study due to a slight imbalance in disease severity at baseline, across the treatment arms, and the 2 to 1 drug to placebo randomization ratio. We intend to further assess the collective results and discuss with the regulatory authorities next steps.”

We also want to know why n=77 and the reason for the 15 dropouts and how distributed between the placebo and dose arm.

Hopefully deeper analysis also of biomarker correlations will help even that GABA/Glutamate along with SIGMAR1 mRNA expression may not be accepted standard biomarkers in Rett, but could provide support to A2-73 making longer treatment more likely to have increasing beneficial effects over placebo. The OLE and Compassionate use Rett population should help this objective analysis regardless of the Open Label setting.

[sab63090]

Steady T

Thanks, just catching up right now...other issues kept me away!

I'm about 190 posts to review...looks to me like yesterday was a climax in trading with many throwing in the towel...