Straight Dope on Medicine: Annovis Neuroscience

Clean up on aisle 3!

Annovis Bio is performing the pharmaceutical equivalent for Alzheimer’s and Parkinson’s Diseases. They seem to be getting somewhere.

Our lead compound buntanetap (formerly known as Posiphen or ANVS401) attacks neurodegeneration by reducing multiple neurotoxic proteins, therefore improving axonal transport, the information highway of the nerve cell, which has been shown to be the cause of nerve cell degeneration and ultimately death.[i]

They are going upstream to tackle these neurological problems.

If you go “upstream” you get closer to the root or source of the problem.

The AMA lays this out in a piece on health and disease.[ii]

Downstream effects

These upstream factors affect patient behaviors such as smoking, poor nutrition, low physical activity, violence, alcohol and substance use, and sexual behavior.

Further downstream are disease and injury such as communicable disease, chronic disease and intentional and unintentional injury. These lead to mortality, the furthest downstream category, which includes infant mortality and lower life expectancy.

What does buntanetap do?

Specifically, it inhibits the synthesis of amyloid precursor protein (APP), Tau and α-Synuclein. It is distinct from other AD drugs in development, because, unlike many other drugs that attempt to remove one toxic protein, buntanetap inhibits the toxic proteins before they can form, and it inhibits all the major neurotoxic proteins responsible for AD and PD.

The mRNAs encoding HTT, APP and αSYN contain an atypical iron response element (IRE) in their 5′-untranslated regions (5′-UTRs) that bind iron regulatory protein 1 (IRP1), and Posiphen specifically bound this complex.

Posiphen’s safety has been demonstrated in three independent phase I clinical trials.

Why hasn’t anyone done this before?

Good question.

I would venture to say that they were hypnotized by the prevailing dogma and sentiment of the day. They were blinded and trapped by presuppositions. Amyloid and Tau were the crux of the problem, they thought. Even though they aren’t.

In a word, they were captured by their preclusions.

Eventually, with enough spectacular failures, some people start to thing independently and progress begins.

Who got the ball rolling?

The Science

No, this is not Fauci. That is false science and grandiose self-worship. His science card has been revoked.

Normal Axonal Function and the Onset of Neurodegeneration

A normal nerve cell receives signals, processes them in the cell body and transports them through the axon, a long-arm nerve fiber that extends out from the cell body and connects to the synapses.

Neurotoxic Proteins Impair Axonal Transport Causing a Toxic Cascade

When nerve cells become injured or stressed, their response is to increase synthesis of neurotoxic
aggregating proteins, which leads to impairment of axonal transport or slowing of the information flow through the nerve “information highway”.
Once a cell is sick, it gets attacked by the immune system and eventually dies; we call this the toxic cascade that starts with faulty nerve cell function and ends with nerve cell death.

TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE).[iii] 

It has been shown that the aggregation and propagation of TDP-43 may also be regulated by the exosome pathway in vitro as well as in vivo. In addition, previous studies have revealed that prion proteins⁹⁴ and prion-like proteins, such as amyloid-β⁹⁵, α-synuclein⁹⁶, and tau⁹⁷, propagate via exosomes.

Buntanetap inhibits the translation of neurotoxic proteins by increasing the binding of a special mRNA sequence that is preserved among neurotoxic aggregating proteins and its binding protein that keeps it from going to the ribosome and being translated. Details see: Cheng 2021

Solution to Reverse Neurodegeneration

Lowering the levels of neurotoxic proteins restores axonal transport to normal speed. In several studies, we have shown that buntanetap and ANVS405 improve all the functions that are negatively affected by disturbances of axonal transport. Our research consistently shows that by reducing APP, tau and αSYN levels, buntanetap treatment improves axonal transport and impedes the toxic cascade which leads to neurodegeneration, thereby improving or restoring the affected function.

Results

It’s one thing to say that you can do something. It’s another thing altogether to do it.

So far, they are doing it.

According to the Alzheimer’s Association, an estimated 6.7 million Americans 65 and older are living with Alzheimer’s in 2023. Seventy-three percent are age 75 and older.

The Parkinson’s Foundation estimates that there will be 1.2 million Parkinson’s patients in the U.S. by 2030.

In 2020, Annovis began treating a total of 68 AD and PD patients for one month with descending doses of buntanetap. They treated 14 AD (Alzheimer’s) patients randomized to 80mg or placebo once per day (QD) and 54 PD patients who were randomized to 0, 5, 10, 20, 40 and 80mg QD of buntanetap.

80 mg is the highest safe dose in humans.[iv

In both populations, we measured levels of specific biomarkers in plasma and cerebrospinal fluid (CSF) known to contribute to the toxic cascade that leads to nerve cell death, along with clinical functional and cognitive measures.

ata the 14 AD patients show that from baseline to 25 days in the buntanetap-treated group, ADAS-Cog11 improved by 4.4 points in a month (this happens fast), a statistically significant improvement of 30% (p<0.05). Compared to placebo at 25 days the treated group is 3.3 points better than the placebo. The WAIS coding test measures speed in movement and thinking. Treated AD patients show a statistically significant 23% improvement compared to baseline.

In PD, improved cognition was even better, up by 5 points versus the 4.4.

Put another way, that amounts to a 30% improvement.

ap treatment groups combined showed statistically significant improvement in the MDS-UPDRS Part III and WAIS coding test. 10 and 20mg groups are the best performing groups. (* P<0.05; ** P<0.01; *** P<0.001).

Movement and speed of movement improve by about 30%.

Details see: JPAD 2022

The FDA suggested (which means demanded, the FDA doesn’t make suggestions) that the company divide the Parkinson’s patients into an early and late-stage group.

Conclusion.

Will Annovis get the definitive phase 3 data before they run out of money? Time will tell. They are going broke fast.

Their compound does prevent nerve cell death.

All of this data is from “early” patients. It included patients in the early stages of Parkinson’s and the early stages of Alzhiemer’s. To date, there is nothing, absolutely nothing, for late stage Alzheimer’s or Parkinson’s.

This has some possibility, but it will have to be proven.

The other question is whether or not this will be allowed. Everything is corrupt. Having a powerful, transformative agent such as this for AD and PD has political implications as well as health ones. Large pharmaceutical players may make bids to torpedo anything like this getting on the market.

They have inferior products that rake in a lot of money for them. They probably would like to protect them.

Stem cells have been held back for over 20 years. That isn’t by accident.

[i] https://www.annovisbio.com/about-us

[ii] https://www.ama-assn.org/delivering-care/health-equity/3-key-upstream-factors-drive-health-inequities#:~:text=Downstream%20effects-,Downstream%20effects,and%20intentional%20and%20unintentional%20injury.

[iii] Jo, M., Lee, S., Jeon, YM. et al. The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med 52, 1652–1662 (2020). https://doi.org/10.1038/s12276-020-00513-7

[iv] https://www.youtube.com/watch?v=qUvNzBxq3cY

Pharmaceutics, Posiphen Reduces the Levels of Huntingtin Protein through Translation Suppression, Xu-Qiao Chen 1,*, Carlos A. Barrero 2,*, Rodrigo Vasquez-Del Carpio 3,4 , E. Premkumar Reddy 3 , Chiara Fecchio 2 , Salim Merali 2 , Alessia Deglincerti 5 , Cheng Fang 6 , Jack Rogers 7 and Maria L. Maccecchini 6