Cassava Sciences (SAVA) presented the phase 2b data on its lead drug, Sumifilam, from its re-analysis. The results look impressive from the view of biomarkers, although the new analysis is not blinded. Initial analysis by an independent company in a blinded fashion showed no effect from treatment.

The impact on memory through 28 days showed some improvement but not statistically significant (tip for Hedges’ g value: 20%, no one sees the difference; 50%, some can see a difference; 80%, most can see a difference). There are not enough details in the press release for more solid assessment. It would be nice to know all the responses from each patient. Nevertheless, the results will propel SAVA to initiate phase 3 registration trial once funding is secured. The likely scenario is through a partnership by giving up 30% of company for $300 million. The price target is $35 upon securing a partnership.

In the same space, Anavex (AVXL) targets sigma-1 receptor with two candidates, 2-73 and 3-71. There is some impressive data for a sub-group of patients who has been on 2-73 for over four years without symptom deterioration. More importantly, 2-73 has been in a registration trial for AD for over two years and most likely is ahead of SAVA three years.

Now the question is: which company has the more promising drug?

Sumifilam (PTI-125) is developed by Cassava Sciences to target filamin A, which is a central structural protein for inflammatory responses. Anavex has developed 2-73 and 3-71 to target sigma-1 receptor, a critical protein for various stress responses as well as BBB maintenance. Sumifilam, Anavex 2-73, or Anavex 3-71 are all from thinly published scientific literature and outside the mainstream amyloid-cascade hypothesis. That is the likely reason for their meager market-cap. However, these findings do shed new light on AD studies as amyloid theory has been questioned more recently.

Then what are the valid molecular targets for these compounds? We have conducted extensive analysis by structural comparison and docking to sigma-1 receptor and filamin A. The conclusion is that all three compounds most likely have the same sets of molecular targets (chemical structure in Figure 1, and visualization for similarities from Figure 2).

Figure 1: Structural Comparison of Leading Compounds.

1. All three compounds are agonists of sigma-1 receptor, with affinities in descending order: 3-71 > Sumifilam > 2-73. The tertiary amine with a methyl group is essential for the binding as it mimics the head-group of choline. After all, sigma-1 receptor is a low-affinity choline receptor first. Stimulating sigma-1 receptor is critical for the restoration of blood-brain-barrier (BBB). A leaky/damaged BBB is a common feature among AD patients. The primary metabolite of 2-73 has similar affinity towards sigma-receptor to that of Sumifilam.

2. All three compounds have high affinities towards filamin A. Docking studies indicate that the affinities are in comparable range for all three with 3-71 slightly weaker. Binding to filamin A is critical for reducing inflammation.

3. Additional molecular targets have also been identified (not disclosed here). All three compounds bind to those targets.

Figure 2. The Shared structure of the three compounds. The tertiary amine (6-member ring) and 5-member ring structures bind to sigma-1 receptor.

Despite the different approaches from SAVA and AVXL, it is interesting to note that both arrive at similar molecules for treating AD. This bodes well for both companies with AVXL in the lead for about 3 years. We project AVXL to be in the $40~45 range per share within a year with positive Rett result, partially positive result from Parkinson trial (positive only for those patients with certain genetic markers) and the completion of recruitment for AD trial.

Results from Cassava Sciences: https://www.cassavasciences.com/static-files/f7e26ba8-7e56-4ff5-8bc1-fe1614fa4eba

Anavex corporate presentation: https://www.anavex.com/wp-content/uploads/2020/02/Anavex-Presentation-February-2020.pdf

Clinical trials of 2-73 and 3-71 from Anavex: https://clinicaltrials.gov/ct2/results?cond=&term=&type=&rslt=&age_v=&gndr=&intr=&titles=&outc=&spons=anavex&lead=&id=&cntry=&state=&city=&dist=&locn=&rsub=&strd_s=&strd_e=&prcd_s=&prcd_e=&sfpd_s=&sfpd_e=&rfpd_s=&rfpd_e=&lupd_s=&lupd_e=&sort=