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Finding an effective treatment for Alzheimer’s disease reminds me of the classical game labyrinth: no matter how long and how hard one tries, the ball always falls through a hole rather than making it to the end.
Annovis (NYSE:ANVS) CEO Maria Maccecchini has a very logical approach to attacking Alzheimer’s disease and other neurological disease: inhibit the formation of neurotoxic proteins such as amyloid, alpha-synuclein, and huntingtin in the first place and you can effectively treat these diseases. The fly in the ointment, though, is that these neurotoxic proteins are only part of the problem. The U.S. Food and Drug administration has already approved two anti-amyloid drugs (Aducanumab and Leqembi) and is on the verge of approving a third (donanemab) so if drug candidates that inhibit the formation of amyloid (Alzheon’s ALZ-801 and Annovis’s buntanetap) prove safer and just as effective as anti-amyloid antibodies then perhaps they will be approved as well. But such an approval is not a given even if the results are somewhat positive. Investment in Annovis, as really with any “Alzheimer’s company”, is a risky proposition.
Unless the FDA requires additional trials, Annovis has raised enough money to reach the end (financial situation). The unanswered question is how the FDA looks at non-anti-amyloid antibody Alzheimer’s drugs if the results are similar to that of anti-amyloid antibody drugs but likely safer. Is it a case of more the merrier or does the FDA feel it has now done its job of approving the first new drugs for Alzheimer’s disease in two decades? Was the approval of the anti-amyloid drugs a perfect storm of close relations between the FDA and Biogen, the clamoring of some patients and the Alzheimer’s Association (among others), and a pent up desire to approve something new for the disease or can other less well-placed and supported companies expect the same regulatory results? There is not clear cut answer to these questions.
Annovis is on the verge of releasing data from two six month trials: a phase 3 clinical trials for Parkinson’s disease and a phase 2/3 trial for Alzheimer’s disease. Annovis had “promised” a readout for the Parkinson’s trial by the end of January, but this has been now been delayed as the company said it needed more time to “clean” the data. Annovis’s CEO probably should have used a different term other than clean or explained what clean meant as some might suspect that some data was being altered or removed. This was not the case as the results remained blinded. The announcement, though, spooked some investors.
The results for Parkinson’s trial may be available next month and the results from the Alzheimer’s disease may still be on schedule for March. The following is an analysis of what one might expect from the Alzheimer’s disease readout, which of course is speculative.
Annovis’ buntanetap may slow down the progression of Alzheimer’s disease in some cases, but for reasons explained below it is not likely to substantially affect the progression of the disease. Some of the general comments made below also apply to alpha-synuclein in Parkinson’s disease; most notably that it probably also plays a secondary role in the disease.
Amyloid is Not the Primary Trigger for Alzheimer’s disease
With the exception of a rare amyloid precursor protein mutation, the primary triggers for Alzheimer’s disease are unrelated to amyloid. Among the multitude of factors that can potentially cause Alzheimer’s disease are: a diet high in sugar and other carbohydrates, high fructose corn syrup, salt, cholesterol, saturated fats, and nitrated meats and low in antioxidants in vegetables, fruits, teas, and spices, exposure to environmental toxins such as air pollutants, water contaminants, heavy metals, industrial solvents, pesticides, and herbicides, heavy smoking or drinking, psychological stress, brain injuries, and genetic mutations. These primary triggers can lead to the formation of amyloid, which in some cases can accelerate disease progression. Annovis buntanetap suppresses the formation of the amyloid precursor protein but this may only modestly slow down the progression of mild Alzheimer’s disease since it does not alter the primary factors that led to disease in the first place.
Amyloid is only a Secondary Trigger in APOE4 carriers
Amyloid appears to only reach high enough levels in APOE4 carriers to act as a secondary trigger for Alzheimer’s disease. Anti-amyloid drugs that remove amyloid or prevent it from aggregating have only slowed down the disease in APOE4 carriers (Ban2401/Leqembi, Aduhelm, donanemab, tramiprosate). This will also likely true for buntanetap which as mentioned above suppresses the formation of the amyloid precursor protein.
Anti-Amyloid Drugs Only Slow Down the Progression of Alzheimer’s Disease Early On (and then only in APOE4 carriers)
This is now acknowledged by even the most ardent supporters of the amyloid hypothesis for Alzheimer’s disease. Their explanation is that once the disease has progressed too far nothing can be done to treat it. There is a kernel of truth in this perspective as Alzheimer’s disease becomes more difficult to treat as it progresses, but the problem with anti-amyloid treatments is that they only work for mild Alzheimer’s disease, because they only slow down oxidation and nitration during the early stages of the disease (amyloid and protein kinase C, nitration of protein kinase C).
One more point to note, in recent short-term Alzheimer’s trials including that run by Annovis, the placebo group also performed well. The reason for this is that a large percentage of those taking placebo were also taking either Aricept (or another acetylcholinesterase inhibitor) or Namenda. The former may keep those with mild Alzheimer’s disease near baseline for a year whereas the latter may lead to improvements in moderate Alzheimer’s disease between six months and one year (example). Six month trials therefore may not be long enough to determine the efficacy of an Alzheimer’s disease drug candidate.
In mild Alzheimer’s disease and in APOE4 carriers, anti-amyloid drugs appear to act synergistically with acetylcholinesterase inhibitors such that they provide a modest additional benefit when taken in conjunction with such inhibitors. Depending on how long it takes for anti-amyloid treatments to reach peak efficacy, it may be that the drug outperforms acetylcholinesterase inhibitors alone for a longer period of time (such as up to 18 months), but in the end anti-amyloid drugs likely are no better than either acetylcholinesterase inhibitors or placebo, because even in APOE4 carriers, amyloid plays less and less of a role as the disease progresses.
As an anti-amyloid drug, buntanetap, then, is not likely to significantly affect the course of the disease. It may have an antioxidant impact, in addition to suppressing the secretion of the amyloid precursor protein, by binding to an aberrant iron regulatory protein element/iron response element, which in turns reduces levels of iron in the brain (explanation). Iron does have an impact of oxidative stress in Alzheimer’s disease, although copper does as well. Moreover, iron dysregulation itself is a consequence of nitration, and it is not clear how much or how well buntanetap corrects this problem.
The best-laid plans, then. A drug candidate that looks like a direct frontal assault on Alzheimer’s disease and Parkinson’s disease instead seems to be working around the edges. It is impossible to know its exact effectiveness at this point which leads to the hold recommendation.
