Cassava’s Simufilam And Acetylcholinesterase Inhibitors (NASDAQ:SAVA)

Despite allegations of manipulation of data and western blots, Cassava Sciences, Inc. (NASDAQ:SAVA) always has seemed to hold an ace card: significant improvements in cognitive function. But the recent results from a second group of 50 trial participants on its Alzheimer’s Disease drug simufilam for at least 12 months calls this into question:

• Group One: 3.2 point improvement as measured by ADAS-Cog scores
• Group Two: .2 point decline as measured by ADAS-Cog scores.

The partial caveat to these numbers is that out of the hundred participants, 63% improved by an average of 5.6 points after one year, while 21% of the participants declined by less than 5 points. The last figure is the roughly expected rate of decline in mild/early stage Alzheimer’s disease patients after one year in the absence of any treatment.

The question, though, is not whether simufilam performs better than no treatment after a year, the question is whether it performs better than acetylcholinesterase inhibitors over this time period. Unfortunately, most studies of acetylcholinesterase inhibitors are for six months or less. A couple of studies, however, indicate a minor improvement in ADAS-Cog scores after using galantamine, and donepezil/Aricept and rivastigmine for one year (approximately one point). In the donepezil or rivastigmine study the number of individuals who showed cognitive improvement as measured by ADAS-Cog scores after one year was 83 percent. However, there was no improvement in some specific measures of cognitive function:

The results obtained suggest that the treatment with cholinergic drugs may improve global function (ADAS-cog) and psychomotor speed (TMT A), however, such treatment is unable to prevent the deterioration of working memory and executive functions (source of quote).

ADAS-Cog scores, then, do not fully capture all aspects of cognitive function.

The first group on simufilam performed better in regards to ADAS-Cog scores than those on acetylcholinesterase inhibitors at one year; the second group performed worse. A number of factors could explain this including differences in initial cognition scores, the ratio of ApoE4 carriers versus non-carriers, the percentage of individuals on acetylcholinesterase inhibitors, and the average length of time on the drug. What at this point, seems to be clear is that the additive benefit of simufilam over acetylcholinesterase inhibitors is relatively small if it exists at all.

Simufilam and acetylcholinesterase inhibitors may be acting as indirect antioxidants and perhaps as weak direct antioxidants against Alzheimer’s disease, but neither appears to scavenge oxidants or reverse the damage that they do to the brain. They may then stabilize Alzheimer’s disease for a period of about a year in some people during the early stages of the disease, and may modestly slow down its progression after that. In short, acetylcholinesterase drugs are not disease modifying drugs and the early data at least suggests that is also the case for simufilam. In the absence of better alternatives over the next couple of years and if the safety profile of simufilam holds up, it could potentially be approved as an alternative to those who experience side effects from acetylcholinesterase medications.

The FDA has already approved one drug – Aduhelm – that is less effective (presentation, p. 23) than acetylcholinesterase inhibitors with a worse safety profile than simufilam. But one of its makers – Biogen (BIIB) – cultivated close ties with FDA regulators. I would not expect the FDA to do anything in regards to simufilam until phase 3 trial results are known in 2024 at the earliest. Given ongoing investigations and the latest lukewarm open label extension results, Cassava Sciences is not on particularly strong footing at the moment. One can hold out in hopes for better results from the cognitive maintenance study or from the two phase 3 clinical trials, but at this point the stock is not worth the risk for the average investor.