Other niche players in AD drug development
Our research suggests lead compounds from Cassava Sciences ($SAVA) and Anavex ($AVXL) are both likely to succeed due to a set of shared molecular targets. Simufilam and 2-73 should have similar affinities towards sigma-1 receptor, filamin A, and a subset of muscarinic acetylcholine receptors based on our modeling analysis. There are some differentiating molecular targets that we might disclose in the future. There are still two unresolved issues. First is the long-term safety and second are the potential target molecules of respective primary metabolites. Anavex 2-73 is a safer bet in terms of safety as it has been in clinical trials much longer. Overall, Anavex leads Cassava Sciences by at least three years in terms of possible phase 3 results, though Cassava Sciences will conduct a more comprehensive set of phase 3 trials. Unless spectacular, the phase 3 results from Anavex most likely will only get conditional approval of 2-73 with confirmatory trial(s) required. We do project outright approval of 2-73 end of 2022 or beginning of 2023 due to outstanding disease-modifying results from the on-going 450-patient trial. We hold a long position in AVXL.
How about the prospects of drugs from other micro-cap companies? Here we provide a brief speculation on the leading drug candidates from Cortexyme, INmune Bio, Annovis Bio, and AB Sciences S.A.
Cortexyme ($CRTX) will have the first crack with P3 results later this year (October?). The central hypothesis states that neuronal infection by Porphyromonas Gingivalis (gum-disease causing bacteria) leads to neurodegeneration. Its leading drug candidate, Atuzaginstat, is an antibiotic against P. Gingivalis.
Central nervous system (CNS includes brain) is a “privileged” organ that is protected from external “storms” by a “roof” called blood brain barrier (BBB), just like a coastal house. Incessant storms will damage the roof and cause leakage. Bacteria, virus, and metabolic toxins can flood the CNS and cause damage. The causes, of course, are the storms and the “leaky” roof (BBB). However, temporary clean-up by removing water and moldy furniture should still help. Atuzaginstat is one of the cleanup crew who removes the moldy furniture and mops the floor. It is a temporary fix and should exhibit fast relief. The negative result from the 6-month interim analysis is a disappointment. However, there is still a chance of positive data after completion of the trial. I would put a 35% chance of statistic significant results with marginal biological significance. The rise of liver enzymes in the extension study is also a concern. On the other hand, any positive result will cause the stock ($CRTX) to pop before gradual decline to reality. There could be option plays here.
INmune Bio ($INMB), Inc. targets the TNF-a pathway, which is critical for immune response and, to certain extent, inflammation. Its leading drug candidate, XPro1595, sequesters soluble TNF-a. In fact, you can call XPro1595 a poor man’s Humira. Overactive immune response and inflammation belong to the “rain storm” family (not hail storm or blizzard). A weekly injectable will always be a challenge for treating AD. However, I do believe eventually XPro1595 would work in slowing disease progress. Remaining questions exist: how will INmune get the $400 M funding required for a P3 trial? What the landscape will be like even if INmune manages to conduct such a trial (6 to 8 years)? It is much more expensive to manufacture a biologic drug and much more expensive to administer such a drug than a small oral pill. I am hesitant to invest in $INMB at current price. There is a chance of acquisition by a big pharma, as XPro1595 is far superior to aducanumab from $BIIB or donanemab from $LLY. I can envision a $500M price for a buyout, even though it is not very likely as BIG PHARMAs have invested too much in amyloid hypothesis to accept failure.
Annovis Bio ($ANVS) pursues the application of posiphen to treat AD. Structurally, posiphen is an enantiomer of the failed drug, phenserine, and overall an interesting molecule. Wikipedia provides an excellent coverage for both phenserine and posiphen (https://en.wikipedia.org/wiki/Phenserine). The continued pursuit of posiphen is due to its complex interaction with many different molecular targets. Posiphen does produce some intriguing results in small trials in AD and PD. However, there are just too many contradictions to predict that this drug will eventually work in a large trial. The stock price has a nice run, and it is time to lock in the gain and never look back.
AB Science S.A. ($ABSCF) continues to pursue the application of a tyrosine kinase inhibitor, masitinib. It is a quite nonspecific kinase inhibitor that possibly affects the growth and maturation of immune cells. A marginally positive P2 result elicited some interest that quickly evaporated. There is not enough interest or liquid enough in the US market to invest.
Nice drug development review: https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.12050