2023-03-10 09:18:38 ET
Summary
- Aricept, blarcamesine, simufilam, and panax ginseng by acting as acetylcholinesterase inhibitors and as indirect antioxidants, positively affecting cognition during the early stages of Alzheimer's disease.
- Simufilam performs about the same as Aricept for mild cognitive impairment and mild Alzheimer's disease; neither has much effect on moderate Alzheimer's disease.
- Panax gineng and probably blarcamesine act as direct antioxidants, which leads to cognitive improvements in mild cognitive impairment and mild Alzheimer's disease that are maintained for at least two years.
- Blarcamesine has a better chance at accelerated approval by the FDA than simufilam because it appears to produce somewhat better results for mild cognitive impairment and mild Alzheimer's disease.
- Investment in Cassava Sciences is risky. I believe the effectiveness of simufilam for the treatment of Alzheimer's disease has been overstated.
The following is an evaluation of the efficacy of Cassava Sciences' ( SAVA ) simufilam, Aricept, Anavex's ( AVXL ) blarcamesine, and panax ginseng for the treatment of early stage Alzheimer's disease and moderate Alzheimer's disease. Attention will be paid to the pathways affected by each, the trial results, and the challenges faced by Cassava Sciences and Anavex in gaining FDA approval for their drug candidates. For reasons explained at the end of this article, I am more optimistic that blarcamesine will be approved than simufilam, but neither is assured. Anavex has still not released its 50mg data which makes it difficult to know exactly how effective blarcamesine is. Cassava Sciences will need to complete its phase 3 trials to determine how much more effective simufilam is versus a placebo group in which the same number of patients are also taking Aricept. In regards to panax ginseng, this natural product produced significantly better results for those with mild Alzheimer's disease when it was used alone versus when it was used in combination with other "Chinese herbs" and conventional therapy. There is a need for further clinical trials (including large, placebo controlled trials) to determine its actual effectiveness for the treatment of Alzheimer's disease.
I will begin each section with an essential quote followed by the steps that lead to disease progression.
Malinow's team [Malinow is a professor of neuroscience at the University of California San Diego] found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn't inhibit brain function unless PKC alpha is active ( source of quote ).
Pathway
Overactivation of G-protein coupled receptor and/or Receptor Tyrosine Kinases
?
Phospholipase C
?
Diacylglycerol and Intracellular Calcium released into the cytoplasm
?
Protein Kinase C
?
NMDA [N-methyl-D-aspartate] Receptor
?
Inducible Nitric Oxide and Superoxide Anions ? Hydrogen Peroxide
?
Peroxynitrite (ONOO-)
All of the treatments discussed in this article probably affect points in this pathway for early Alzheimer's disease, as outlined below.
Panax ginseng inhibits phospholipase C and thus the activation of Protein Kinase C.
As sigma-1 agonists, Aricept (donepezil) and blarcamesine inhibit intracellular calcium release into the cytoplasm which limits the activation of Protein Kinase C. Simufilam is likely also a sigma-1 receptor agonist ( more precise study ).
Panax ginseng, Aricept, blarcamesine and probably simufilam by inhibiting intracellular calcium release also decrease acetylcholinesterase activity , thus temporarily maintaining levels of acetylcholine needed for the retrieval of short-term memory. Moreover, all four may reduce oxidative and nitrostative stress via protein kinase C activation of NMDA receptors enough to at least stabilize mild Alzheimer's disease for a year or more. However, panax ginseng and probably blarcamesine by additionally acting as direct antioxidants may lead to improvements in mild Alzheimer's that are sustained for at least two years.
Comparing Simufilam to Aricept
Simufilam at one year (all scores in this article are mean baselines and mean changes):
- -2.4 improvement from a baseline ADAS-Cog of 15 (amnestic mild cognitive impairment)
- .5 decline from a baseline ADAS-Cog of 19.1 (mild Alzheimer's disease)
- 4.4 decline from a baseline ADAS-Cog of 25.7 (mild to moderate Alzheimer's disease)
( press release )
Note: Higher ADAS-Cog [Alzheimer's Disease Assessment Scale] scores mean more cognitive impairment.
For Amnestic Mild Cognitive Impairment
Only a few indeterminate studies exist for the effects of Aricept on amnestic mild cognitive impairment at one year. These ranged from an improvement of - .7 points to an improvement of - 2.27 points . Importantly, though, while Aricept may delay advancement of mild cognitive impairment to mild Alzheimer's disease for about a year, it does not alter the advancement to mild Alzheimer's disease much beyond that ( study ). Whether this will also be the case with simufilam remains to be seen.
For Mild Alzheimer's Disease
Late onset Alzheimer's patients taking Aricept had a .5 decline from an ADAS-Cog baseline of 21 at one year whereas those taking simufilam had a .5 decline from a baseline of 19.2. The Aricept group at baseline had slightly more cognitive decline than the simufilam group, but separated out faster declining early onset patients ( tables one and two) . The larger picture is that there is only a slight difference between the effects of Aricept and simufilam.
For Moderate Alzheimer's Disease
In one clinical trial in which patients on Aricept declined by 4.08 points at one year. The impact of Aricept and simufilam on moderate Alzheimer's disease appears similar, neither performs much better than the historic placebo decline at one year (about a six to seven point decline in ADAS-Cog11 scores for moderate Alzheimer's disease)( table four ).
Herbs versus Aricept
A series of herbs produced nearly the same improvements as Aricept for amnestic mild cognitive impairment at six months (- 4.23 versus -4.31 improvement in ADAS-Cog11 scores respectively with baselines around 15). Those on Chinese herbs plus conventional therapy and those only on conventional therapy remained near baseline for mild Alzheimer's disease at one year (most in both groups were on Aricept). But at two years those with mild Alzheimer's disease on Chinese herbs plus conventional therapy remained near baseline while those on conventional therapy alone declined close to the historic decline in placebo groups. Those with moderate Alzheimer's disease taking herbs and conventional medicine stayed above baseline for a year, but declined by nearly 8 points the next year, whereas those on conventional therapy declined by about 6 points annually over two years.
Blarcamesine and Panax Ginseng
The results for the 50mg dose of blarcamesine have not been released but if the 30mg dose acted like a true placebo (as it did in the phase 2a trial), the outcome would likely be the following:
- -3.3 point improvement at 48 weeks from a baseline score of 19 (after the ADAS-Cog13 score of 28.75 is converted into an ADAS-Cog11 score) ( table one ).
The calculations for this are somewhat complicated: one multiplies the ADAS-Cog13 score by about two-thirds to get ADAS11 score. If the 30mg group worsened by an expected placebo decline of 9 points for ADAS-Cog13, the 50mg group would have had to improve by about -5 points to get to the approximate 2 point mean decline in the combined groups ( phase 2b/3 trial results ). A -5 point improvement in ADAS-Cog 13 scores translates into about a -3.3 improvement in ADAS-Cog 11 scores (-5 X .66=-3.3). For its phase 2a trial at 57 weeks, Anavex conservatively calculated that the high concentration group with mild cognitive impairment or mild Alzheimer's disease and without a "negative" sigma-1 receptor variant improved by - 3.4 points . These patients remained near baseline for three years ( extension results ).
Anavex only included mild cognitive impairment and mild Alzheimer's disease patients in its phase 2b/3 clinical trial because blarcamesine proved to be ineffective against moderate Alzheimer's disease in its phase 2a trial.
In mostly mild Alzheimer's disease patients, panax ginseng produced the following results:
- -9.6 improvement at 48 weeks from a baseline ADAS-Cog11 score of 19.7
( open label trial )
The more direct MMSE [Mini-Mental State Examination] comparisons between panax ginseng trial and blarcamesine (after excluding those with moderate Alzheimer's disease in the phase 2a trial) are as follows:
Blarcamesine
- MMSE improvement at 57 weeks 2 points
- MMSE improvement at 70 weeks 3 points
Panax Ginseng/Korean Red Ginseng
- MMSE improvement at 57 weeks 3.7 point
- MMSE improvement at 70 weeks 2.7 points
The improvements in those taking panax ginseng was largely sustained for two years.
Simufilam, Aricept, Blarcamesine, and Panax Ginseng
Whether simufilam will follow the same pattern as Aricept for mild Alzheimer's disease--small decline for a year followed by a relatively steep decline or that of panax ginseng or blarcamesine-improvement that is largely maintained for at least two years remains to be seen.
Why did blarcamesine appear to outperform simufilam and Aricept, if they are all sigma-1 receptor agonists? The answer probably does not lie in binding affinity or efficacy. Aricept binds to sigma-1 receptors at much lower concentrations than simufilam and blarcamesine but it also binds to acetylcholinesterases.
Furthermore, all three compounds seem to have similar degrees of receptor occupancy/efficacy. The greater benefit provided by blarcamesine (a tetrahydrofuran derivative) over a longer period of time may be due to its potential role as a scavenger of hydrogen peroxide (which is a problem early in Alzheimer's disease ) and peroxynitrite (the scavenging of both requires the donation of electrons and hydrogen atoms ).
Unlike Anavex, Cassava Sciences did include at least a few patients with moderate Alzheimer's disease, although its inclusion range for mild Alzheimer's disease (MMSE 21-26) was slightly higher than Anavex's (MMSE 20-27) and the mean ADAS-Cog score after conversion was nearly the same as Anavex's.
At this point, then, it looks like blarcamesine is somewhat more effective than simufilam and Aricept after one year in mild cognitive impairment and mild Alzheimer's disease.
Sigma-1 receptors agonists (such as Aricept, blarcamesine, and probably simufilam) do not help those with moderate Alzheimer's disease in part because of the nitration of protein kinase C abrogates their beneficial effects.
Moderate to Severe Alzheimer's Disease
"The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite ( source of quote ).
Pathway
NMDA receptor overactivation (due to the lack of transport of glutamate)
?
Calcium Influx
?
ERK (Extracellular Regulatory Kinase)
?
P38 MAPK (Mitogen Activated Protein Kinase)
?
NFkB (Nuclear Factor kappa-Beta) and NADPH (Reduced Niotinamide adenine dinucleotide phosphate) Oxidase
?
Inducible Nitric Oxide Synthase
?
Inducible Nitric Oxide and Superoxide Anion
?
Peroxynitrite (ONOO-)
?
Depletion of Critical Neurotransmitters
Interference with neurotransmissions (due to hyperphosphorylation and nitration of tau proteins)
Lack of regeneration of neurons, synapses, and axons
DNA damage
Neuroinflammation
Lipid Peroxidation
Mitochondrial Dysfunction
Death of neurons
(partially derived from chart one and chart two )
Potential of Panax Ginseng and Other Chinese Herbs for the Treatment of Moderate Alzheimer's Disease
Panax ginseng inhibits the formation of peroxynitrite after calcium influx, scavenges peroxynitrite , and partially reverses the peroxynitrite-mediated oxidation and nitration of proteins that directly or indirectly produces many of the problems in Alzheimer's disease listed above.
Below are the results from the Chinese herb plus conventional therapy study for moderate disease patients (I multiplied the MMSE scores by 2.33 to get the ADAS-Cog11 scores; another conversion measure multiples MMSE scores by 1.7):
Moderate Alzheimer's Disease
- Chinese herbs plus conventional therapy ADAS-Cog change at one year -1.2
- ADAS-Cog change at two years 6.6
Conventional Therapy (almost all the patients were on Aricept)
- ADAS-cog change at one year 5.6
- ADAS-cog change at two years 11.7
Panax ginseng alone appeared to work better for mild Alzheimer's disease than a combination of Chinese herbs (which included panax ginseng) plus conventional therapy, but it is not clear if this pattern would be replicated for moderate Alzheimer's disease.
The Good, the Bad, and the Uncertain
Questions to be asked for simufilam
Can simufilam significantly distinguish itself from placebo when an equal number of patients in the drug arm and the placebo arm are taking Aricept? The limited data at one year suggests that simufilam produces results similar to Aricept. It is possible that if Cassava Sciences' removed those with sigma-1 receptor variants as Anavex did that it would show more benefit than Aricept. Simufilam appears to have fewer side effects than Aricept but the costs would be considerably higher. The FDA might be hard pressed to approve a drug whose superiority over Aricept may be slight if at all. On the other hand, it might do so to give an alternative to those who experience side effects from Aricept (or from other acetylcholinesterase inhibitors).
Will simufilam slow down the progression of Alzheimer's disease beyond one year? The 18 month cognitive maintenance study is not likely to produce the answer because those on simufilam may consist largely of patients who have the least cognitive impairment. The 18 month phase 3 placebo controlled, randomized trial may provide a partial answer. By potentially addressing the problem of amyloid toxicity, simufilam could produce similar benefits for APOE4 carriers at 18 months as Aduhelm and Leqembi (i.e. modestly slowing down the progression of the disease) but without the serious side effects. However, given that simufilam does not appear to act as a direct antioxidant, long-term stabilization for mild cognitive impairment and mild Alzheimer's disease does not seem likely although it is not impossible. For this reason, I remain mildly pessimistic as to the impact of simufilam and the future of Cassava Sciences.
Questions to be asked for blarcamesine
Did the 50mg group improve in a similar fashion to the high concentration group in the phase 2a study? The answer based on some assumptions (such as the 30mg group acting similar to a true placebo) is that they did.
Will the number of patients in the 50mg group be sufficient to gain FDA accelerated approval? The FDA likes to see at least 100 patients in the drug group, although it can make exceptions. The modified intent to treat population in the 50mg group was about 150. There were 18 dropouts and 24 down-titrations due to intolerance to the high dose. So the FDA has to look at three factors: the number of patients, the severity of the adverse effects (principally dizziness and confusion), and the magnitude of the improvement. My own belief is that once the FDA considers all three it will grant accelerated approval and that is why I continue to give Anavex a buy rating.
Conclusion
Many investors in Cassava Sciences are convinced that at least accelerated approval for simufilam is inevitable. Shorts and other critics of Cassava Sciences believe that the company has mislead investors with shoddy science and manipulated data. The over-enthusiastic promotion of Cassava Sciences and the concerted attacks against it have in part explained the whipsaw action of the stock. Favorably distinguishing the effects of simufilam from both Aricept and blarcamesine (and in a less tunnel-vision world from panax ginseng) may not be in the cards. I am, therefore, bearish on the chances of FDA approving Cassava Sciences' simufilam. These days, though, the distance for Cassava Sciences to fall is much less than it once was, whereas an upside of 100 points or more upon unambiguously positive phase three clinical trial results cannot be completely ruled out.
For further details see:
A Comparison Between Cassava Sciences' Simufilam, Aricept, Anavex's Blarcamesine, And Panax Ginseng For The Treatment Of Alzheimer's Disease