A small recap of existing drugs approved for AD
There are four FDA-approved drugs for Alzheimer’s disease, three of which are acetylcholinesterase inhibitors, and one of which is a glutamate antagonist. All four are not disease-modifying; they essentially stimulate the brain temporarily, after which patients’ cognition reverts to their original downward trajectory.
Acetylcholinesterase inhibitors (donepezil, rivastigmine and galantamine, respectively trademarked as Aricept, Exelon and Razadyne) lead to accumulation of choline in the brain, by inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine. They hence express cholinergic action. Acetylcholine is useful in transmitting signals in the brain. As the brains of AD patients have low levels of acetylcholine and neurons related to acetylcholine are affected, the goal of inhibiting the breakdown of acetylcholine in the brain was to accumulate acetylcholine, to allow it to be available in sufficient amounts. Apparently, that works well for about three months, after which patients’ condition worsens faster than in regular AD patients. It is as if acetylcholinesterase inhibitors cover up the underlying decay for a while.
The decay could be shown here, for Donepezil alone:
Or here, for all three approved cholinesterase inhibitors over the course of three years, showing results as of two months after treatment start, which I took the liberty to show in a chart.
The glutamate antagonist memantine, commercialized as Namenda, blocks NMDA-receptors, a glutamate receptor subfamily broadly involved in brain function. Basically, in AD patients, levels of the neurotransmitter glutamate are high, and they overtrigger the NMDA-receptors, leading to degeneration of these receptors. By blocking these receptors, one could lower the overtriggering. Favorable results from an initial 6-month trial led the FDA to approve the drug in October 2003. However, over a longer period, memantine treatment appears symptomatic. Over a 52 week period, no statistical difference has been noted. “In other words, the original placebo group has “caught up” with those who had been on memantine all along.
The above is relevant for the assessment both of ANVS-401 and for Anavex 2-73. I will discuss buntanetap, the new name for ANVS-401 or posiphen, below.
The evolution of Annovis’ market cap and the reasons underlying such evolution
This is the one-year chart for Annovis. One sees a meteoric rise from mid may to end of July 2021 after the announcement of a massive improvements in ADAS-Cog 11 in AD even though the placebo group also significantly improved, and then an absolutely dramatic fall over 2 days after the AAIC conference.
Remark post publication: allegedly no new data had been shared at this conference, as it was the data that would have already been shared in May 2021.
If one were to read the February 2022 presentation of Annovis, one would wonder why the market has reacted in such a way, as in the eyes of Annovis, buntanetap performed excellently, something the market apparently chose not to buy. Some quotes from the February 2022 investor presentation:
In Phase 2a clinical trial, is the only drug to improve cognition in AD and motor function in PD patients.”
BIOMARKERS: reduced as expected
COGNITION AND FUNCTION: improved ADAS-Cog and WAIS in AD patients and UPDRS and WAIS in PD patients”
These are strong statements. Reading them, one would be led to believe that buntanetap is the miracle-drug both in Alzheimer’s and Parkinson’s disease. That also means that, if these statements do not hold true, Annovis may be misleading its investors.
However,an author on Seeking Alpha who had invested in Annovis considered that Annovis had boasted its results a bit much. She concluded that Annovis’ claims were incorrect:
- contrary to the claim that the AD group treated with buntanetap showed trends of improvement in all four ADAS-Cog tests, there were in fact no statistically significant differences between placebo and treatment groups;
- contrary to the claim that the AD group treated with buntanetap showed trends of improvement in all four parts of UPDRS tests, there were in fact no statistically significant differences in any of these parts between placebo and treatment groups;
- MMSE trended positively, but changes were not statistically significant, and placebo groups showed better results:
- in CDR-sum of boxes, the placebo group performed better, numerically speaking;
- contrary to claims that buntanetap decreased a whole array of AD-related biomarkers, it seemed that only the difference in P-Tau reduction reached statistically significant difference.
That must have been quite a feet-back-on-the-ground-moment for many investors. The author on Seeking Alpha noted:
Given these are very small p2a trials (n=14 in AD/PD each) and a short time frame (25 days), these positive-trending results are perhaps as good as the results could be expected to be. […]
It is not certain that in the next trials, presumably larger and for a longer duration, these positive trending p2a data will be repeated or become stronger, e.g. showing statistically significant, placebo-adjusted, treatment benefits.
It is indeed remarkable that Annovis came out with its results, and even had a $ 50 million share offering in the middle of it, over a very short period of time. Annovis reported two measures which, to me, already did not seem so impressive, namely on NfL (Neurofilament light chain) and tau. Buntanetap reported a -13% decline compared to placebo for NfL, and a 10-12% difference in t-tau / p-tau versus placebo.
NfL is interesting as it is considered a relevant biomarker for AD progression and for other neurologic diseases. Larry Friedhoff, the developer of donepezil, stated it as follows in 2019: “These results suggest that a single assessment of this biomarker at a single time could be used to assess drug efficacy.”
As a comparison, INmune Bio reported a reduction of 84% over the course of 12 weeks or 3 months, which is more than six times higher and hence massive), and furthermore reduction of 46% in pTau217 and of 2% in pTau181. Cassava reported a reduction here of 28%/34% at 28 days for respectively 50 mg and 100 mg, and 55% at 6 months.
As its enantiomer, buntanetap is similar to the FDA-rejected phenserine, but how similar?
The Annovis website used to contain rather few details on the origins of its drug buntanetap, previously known as ANVS-401 and otherwise known as posiphen.
Remark post publication: there is however a press release of 5 January 2022 stating that both substances are enantiomers and totally different:
"Buntanetap, previously known as ANVS401 or Posiphen, is sometimes mistaken for phenserine. However, Buntanetap is the pure (+) enantiomer, i.e., mirror image, of (-) phenserine. The two compounds are totally different drugs as they have different efficacy, mechanisms of action, and there is no chiral switching between them or their metabolites. Phenserine is an acetylcholinesterase inhibitor, similar to Aricept or Exelon, while Buntanetap inhibits the translation of neurotoxic aggregating proteins. Both compounds derive from the intramural research program at National Institute of Aging, a division of the U.S. National Institutes of Health. Phenserine was invented in 1995, while Buntanetap in 2002. Both enantiomers were licensed to Axonyx, Inc., which developed phenserine into phase 3 clinical studies. Axonyx merged with Torrey Pines Therapeutics, which licensed Buntanetap to QR Pharma in 2008 that became Annovis Bio in 2019.
In a 2012 publication, it is mentioned that posiphen is the enantiomer of phenserine. For the record, an enantiomer is a mirror molecule that is not identical but often acts similar to its counterpart, and may in some cases have different functions. Annovis claims it is a totally different drug with different efficacy. I find that hard to believe.
And that’s where it becomes interesting, as it appears that phenserine has already had its shot on goal as a potential Alzheimer’s drug. Wikipedia on phenserine mentions more than one interesting fact:
The research of phenserine, initially patented by the National Institute on Aging (NIA), has been suspended since phase III of clinical trials in 2006, conducted right after the drug licenses were issued. The abandonment of the clinical trials led to disapproval by FDA. The retrospective meta-analysis of the phenserine research proposed that its clinical invalidation was arisen from methodological issues that were not impeccably settled before proceeding to the subsequent clinical phases.”
My comment here is that that’s the kind of stuff I do not want to find out as a (potential) investor, which was the case for Annovis when I looked at it. In my eyes, Annovis’ management should have put this out there in a straightforward way from the start of trials.
Where the Annovis website is also silent is on the exact mechanism of action and tries to claim buntanetap is a ‘translational inhibitor of neurotoxic aggregating proteins’ which ‘potentiates the binding of IRE to IRP1’, one reads on Wikipedia that phenserine is an acetylcholinesterase inhibitor. Hence, if buntanetap also is an acetylcholinesterase inhibitor, which I would assume it being phenserine’s enantiomer, then I would understand why Annovis only reported results on a 25 day timeframe, and why the author on Seeking Alpha reported that results over such period of time may be the best they can get. One only needs to zoom in on donepezil’s results over six weeks to see that the massive improvement occurs within the first few weeks (below is a highlight over those six weeks taken from the 159—week figure above). The massive improvement stops halfway at about a month’s time (similar to 25 days), stabilizes for about two weeks, and then starts sliding down even faster than placebo for the course of the remaining period.
Post publication remark: Yet, I may have assumed wrong as pointed out by some readers: posiphen would not be an acetylcholinesterase inhibitor, referring me to the following article: Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, α-synuclein synthesis, interleukin-1β, and cholinergic action
However, that article reads:
The reported acetylcholinesterase (AChE) inhibitory action of 15 (Table 1), in particular (IC50 63.4 ± 4.4 nM), may thereby provide Posiphen (1) indirect cholinergic action, mediated via its metabolism. By contrast, the chiraly pure and separate drug (−)-phenserine (2), the antipodal isomer of Posiphen (1) (Figure 1), provides anticholinesterase activity as its primary action (AChE IC50 24.0±6.0 nM) (Table 1) [21,22], but likewise reduces Aβ levels by lowering the rate of synthesis of APP in an equipotent manner to Posiphen (1) [10,11]."
That's unfortunately not more comforting. The cholinergic action, i.e. inhibition of the neurotransmitter acetylcholine, may take place in a different manner.
Further remark post publication: Annovis' PR company has referred me to the following article, co-authored by management of the company itself: "Posiphen Reduces the Levels of Huntingtin Protein through Translation Suppression". That article states, among others: "Unlike (−)-phenserine, it is not an acetyl-cholinesterase inhibitor [2]. Rather, it is an inhibitor of the translation of specific mRNAs and reduces the levels of at least two proteins, amyloid precursor protein (APP) and α-synuclein (αSYN) [3,4]"
That's interesting, but not compelling, to me.
Phenserine would have been a new type of acetylcholinesterase inhibitor which furthermore would alleviate neurodegeneration, repress neuronal cell death, suppress β-amyloid precursor protein (APP) and Aβ peptide, and attenuate neuroinflammation and excessive activation of microglial cells.
Phenserine at first sight had pretty amazing results on cognition too. I found the May 2008 article 'effect of phenserine treatment on brain functional activity and amyloid in Alzheimer’s disease', showing that. However, the article also states that several studies have shown short-term metabolic increases by cholinesterase inhibitors, including donepezil, galantamine and phenserine. The increases in metabolism are observed over a relatively short interval (3 months) and metabolism returns to pretreatment levels after longer term treatment (6 months).
In the Phase III randomised, placebo-controlled double-blind studies the safety and efficacy of phenserine (10mg and 15mg twice daily) was evaluated in 375 and 450 patients respectively with mild to moderate Alzheimer’s. However, phenserine failed in Phase III development.
There have been several discussions as to why, after phase 3 trials, phenserine was rejected. Many have conjectured it was due to procedural issues rather than lack of drug efficacy. Whatever the case, it failed and the FDA will know why.
I just wonder whether buntanetap isn't an almost copy of the previously rejected phenserine, for whichever reason.
Post publication remark: the company has now given some further insight, claiming both drugs are entirely different, but I find that a clear comparison has not been made, and besides, being an enantiomer, I am a bit wary about a claim that a drug targeting the same devastating and insofar as we know not properly treatable disease would be totally different, while at the same time phenserine apparently did something quite good.
I also found that, following 6 years of phase I and II trials, a company called Axonyx Corporation had licensed phenserine to Daewoong Pharmaceutical and QR Pharma. The latter which later adopted the new corporation name Annovis Bio.
Conclusion
At this point in time, the market cap of Annovis has fallen dramatically, yet it is still about twice its cash value. My gut feeling, after a lot of research that I feel should have been shared by Annovis in the first place, tells me ‘stay away’. And that is what I will do. That does not mean I am certain Annovis does not have a drug candidate that may one day be beneficial to patients. Whether buntanetap will ever be more than just another acetylcholinesterase inhibitor with dramatic effect over a four-week timeframe is still to be found out.
I feel that that can only become clear after Annovis shares long term biomarker and possibly efficacy data on a whole array of biomarkers, and not just some that are possibly selectively chosen, for a period of time of preferably a year and at least six months.
In any case, any long-term benefit would not come from its cholinergic actions (edited), but would need to come from something else that would be able to reduce neuroinflammation and neurodegeneration drastically, in my opinion.