SAVA - Anavex Cassava Sciences And Panax Ginseng: Seeking Agents To Modify Alzheimer's Disease

2024-01-05 16:55:03 ET

Summary

• Sigma-1 receptor agonists such as Anavex's blarcamesine, Aricept, and possibly Cassava Sciences's simufilam may slow down the early progression of Alzheimer's disease.
• Blarcamesine may have an advantage over other sigma-1 receptor agonists due to its apparent antioxidant capacity, potentially near stabilizing mild Alzheimer's disease for years in some patients.
• The long-term efficacy and safety of blarcamesine and simufilam are still being evaluated in clinical trials, and their chances of approval vary.
• Panax ginseng by working upstream and downstream of sigma-1 receptors and by containing multiple antioxidant compounds provides one of the best opportunities for treating Alzheimer's disease.

Anavex’s ( AVXL ) 2-73/blarcamesine is a sigma-1 receptor agonist; Cassava Sciences’ ( SAVA ) simufilam may be sigma-1 receptor agonists ( based on its chemical structure ). Sigma-1 receptor agonists are generally safe but only temporarily effective against mild Alzheimer’s disease. This alone clouds matters in regards to future approvals. However, the potential antioxidant capacity of blarcamesine, may give it a long-term edge over other sigma-1 receptor agonists such as Aricept, increasing its odds of approval.

Anavex has completed a phase 2b/3 clinical trial for blarcamesine but combined the 30mg and 50mg doses. Perhaps it did so in order to achieve statistical significance. This confuses matters as the 50mg dose is likely the effective dose, although producing more side effects. The United States Food and Drug Administration (FDA) may want a larger trial at the 50mg dose to determine blarcamesine's effectiveness and safety. Anavex is now in the process of seeking approval of blarcamesine by the European Medicines Agency ('EMA').

Cassava Sciences will likely complete its phase 3 clinical trials next year (the first one could potentially be completed by December of this year), so one has to go on results from it open label extension trial and cognition maintenance study. In those trials, participants performed similar to Aricept (donepezil) for Alzheimer’s disease, but better than Aricept for mild cognitive impairment. Depending on the results from the phase 3 clinical trials this difference may be significant.

The Limitations of Sigma-1 Receptor Agonists for Alzheimer's Disease

Sigma-1 receptors reduce acetylcholinesterase activity (i.e. they limit the breakdown of the neurotransmitter needed for the retrieval of short-term memory) and they partially inhibit nitrostative and oxidative stress via protein kinase C early in Alzheimer’s disease. However, as the disease progresses nitration and oxidation curtail acetylcholinesterase and protein kinase C activity. Thus, sigma-1 receptor agonists have little to no impact after a year on mild Alzheimer’s disease and on moderate Alzheimer’s disease from the start. In other words they do not modify Alzheimer’s disease.

Cassava Sciences's Simufilam

On the surface, Cassava Sciences’ simufilam looks like a disease-modifying (or even disease-arresting) treatment for mild Alzheimer’s disease, but the problem is that the mild group included those with mild cognitive impairment who improved by 3 points over the course of 18 months and those with mild Alzheimer’s disease who declined by about 3 points over 18 months. At twelve months, those on simufilam with mild Alzheimer’s disease declined by .5 points which is similar to Aricept and considerably better than placebo (an expected decline of 4 points). Between 12-18 months, a further three point decline is what one would expect for someone with mild Alzheimer’s disease on placebo ( table 3 ).

Simufilam does appear to work better than Aricept for those with mild cognitive impairment than Aricept and better than many ( but not all ) herbal studies for mild cognitive impairment (a 2.4 point improvement at 12 months and a further .6 point improvement at 18 months). In this group, 68 percent of patients improved by an average of 6.8 points. Some people with mild cognitive impairment, though, improve on their own, so it will be interesting to see if (or by how much) these numbers drop with more rigorous testing this time around for biomarkers that may signal a more likely progression to Alzheimer's disease.

Anavex's Blarcamesine

Anavex’s blarcamesine also appears to be a disease modifying treatment for mild Alzheimer’s disease, although only in those with a functioning sigma-1 receptor and without COMT (Catechol-o-Methyltransferase) variants ( table 3 ). The latter two comprise about 20 percent of the population. Two of the 8 patients had mild cognitive impairment rather than mild Alzheimer’s disease (MMSE scores of above 24). What stands out, though, is the length of time in which most patients on the highest dose remained close to baseline over 148 weeks. By donating hydrogen atoms and electrons, blarcamesine likely is a scavenger of the nitro-oxidant peroxynitrite and it may also partially reverse oxidation and nitration. The combination of sigma-1 receptor agonist and antioxidant may make blarcamesine a disease-modifying treatment in some individuals. However, one of the possible metabolites of this reaction – gamma butyrolactone – may contribute to the confusion and dizziness experienced by those on the highest dose.

Panax Ginseng

Panax ginseng has two advantages over current treatments for Alzheimer’s disease: it inhibits oxidative stress both upstream and downstream of sigma-1 receptors and it contains multiple effective antioxidants ( saponins , polysaccharides , and a variety of other compounds ). As such it can increase acetylcholine levels, partially restore the regeneration of neurons, and decrease neuronal cell death. It may largely stabilize mild Alzheimer’s disease and may at least decrease the decline in those with moderate Alzheimer’s disease ( Chinese herb study ).

Chances of Approval for Blarcamesine and Simufilam

At this point, it appears that blarcamesine’s best chance of approval for Alzheimer’s disease is with the European Medicines Agency. This may be helped by a 48 week open label extension trial which should be completed later this year (providing 96 weeks of data). Indeed longer term data may be critical because blarcamesine like simufilam may not perform much differently from Aricept at one year in the general population with mild Alzheimer’s disease. The disappointing twelve week pediatric Rett results in which blarcamesine did not perform much better than a high-responding placebo group (some of whom may have been on other medications including supplements) highlights the problem of short-term trials in which other medications may be providing an equivalent (or perhaps better) result than the trial drug.

If Anavex can prove that blarcamesine is a disease-modifying treatment for mild Alzheimer’s disease and that some of its safety issues can be modified (such as night time dosing to reduce dizziness), it has a chance to gain approval in Europe and in the United States. I remain optimistic about the stock but with more caveats than before.

Simufilam does not appear to be a disease-modifying treatment for Alzheimer’s disease although with a better safety profile than acetylcholinesterase inhibitors such as Aricept (the direct inhibition of acetylcholine may be responsible for various side effects caused by this class of drug) and anti-amyloid antibody drugs (which can produce brain bleeds and brain swelling, a few of which have been fatal). I am not sure, though, if the just as effective but safer argument will carry the day with the FDA. Simufilam’s impact on mild cognitive impairment, depending on the results from the phase 3 clinical trials, may need a longer period of time to determine (such as three year trial). The company’s attempt to raise money through warrants could put downward pressure on the stock (via dilution) depending on how many of these warrants are exercised, although potentially raise considerable amounts of money for completing its trials. I remain pessimistic about simufilam at least after the onset of Alzheimer’s disease.

Antioxidants Critical for the Treatment of Alzheimer's Disease

The effective treatment of Alzheimer’s disease likely requires achieving three ends: slowing the production of oxidants, removing oxidants, and repairing some of the damage caused by oxidants. There are a number of compounds that do all three, but only a few are currently being tested in clinical trials for Alzheimer’s disease (blarcamesine may be one of them). Panax ginseng appears to be one of the best at accomplishing all three goals and thus may stabilize mild Alzheimer’s disease over long periods of time and at least slow down the decline in moderate Alzheimer’s disease.

The switch from anti-amyloid, anti-tau, and anti-inflammatory treatments of Alzheimer’s disease to direct antioxidant treatments of Alzheimer’s disease is occurring very slowly. But this switch is probably critical for finding disease-modifying treatments for the disease.

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