Anavex Life Sciences Corp (AVXL)

[Doc328]

Schizophrenia studies have historically had a lot of difficulties with high dropout rates. Therefore, this study needs to be as short as possible while giving enough time to show benefit. Although my personal preference would be 6 weeks instead of 4 weeks, the KarXT phase 2 and phase 3 trials was extremely successful at 5 weeks (using the sandard PANSS endpoint difference in means and showing p<0.0001 significance). While an 8 weeks study would give more time for separation, there could be another 15% dropout in this population during the additional month, further reducing the chance that a multiple ascending dose trial will show benefit. The KarXT phase 3 study showed early benefit as soon as 2 weeks, so 5 weeks was plenty of time (and 5 weeks was better than 2).

I think antibiotics needs to start the study as rapidly as possible. Muscarinic agents for schizophrenia are "hot" after 2 very nice acquisitions for billions of dollars each. Karuna's KArXT is an M1 and M4 agonist(counterbalanced by a peripheral M1 antagonist, trospium, that effectively reduces the significant cholinergic s.e.'s of xanomeline) and Cerevel's emradicine, an M4 positive allosteric agent (PAM).

A371 has a related but distinct MOA - M1 PAM and S1R agonist. Anavex licensed A371 10 years ago so it's about time to actually test in an indication.

For timeline expectation/comparison: KarXT did the phase 1a (SAD) 2016 and 1b (MAD) 2018, quickly enrolled and completed the 180 patent P2, reporting November 2019 and reporting the +/- 256 patient phase 3 (with amazing P2, they did not need a super-sized P3 with power calc's). They will be approved September 2024 --- BMS bought a drug for 14B that is far further along and much more de-risked than A371.

So I am not concerned about the length of the schizophrenia study, but I do hope that Missling does not skimp too much on the size of the trial.

In hindsight, I've thought the AD P2b/3 and EXCELLENCE trials were too short

The 273 AD study was indeed too short at 48 weeks and will be one of the reasons that it is not can to be accepted by regulatory agents (a more major point is that the study failed using standard criteria)

Rett at 12 weeks had precedence with the trofinetide trial, though in my opinion both are too short and neither of them seemed to have much of a benefit over placebo, definitely not 1/2 million a year of benefit