Annovis Bio updates on Alzheimer's candidate

 Annovis Bio, Inc. (NYSE: ANVS) ("Annovis" or the "Company"), a late-stage clinical drug platform company addressing neurodegenerative diseases, today released the following letter to stockholders from its Chief Executive Officer Dr. Maria Maccecchini.

Figure 1: Neurotoxic proteins inhibited by buntanetap. Aggregation of these proteins results in the loss of affected function in various neurodegenerative conditions.

Dear Fellow Stockholder,

Over the years we have been talking about the potential of buntanetap to treat more than Alzheimer's disease. In cell models, animal models and human clinical studies, we have seen that buntanetap works in numerous acute and chronic neurodegenerative conditions. I would like to take this opportunity to explain how one drug can be so broadly applicable.

Buntenatap works by inhibiting specific neurotoxic proteins such as amyloid precursor protein (APP), Tau, alpha-synuclein (αSYN), TAR DNA binding protein 43 (TDP-43), huntingtin (HTT) and prion protein. These proteins have normal functions but in their neurotoxic aggregating form, they impair axonal transport, slow synaptic transmission, cause inflammation, and ultimately, kill nerve cells, resulting in the loss of affected function in various neurodegenerative conditions.

The overexpression and aggregation of these proteins is caused by elevated levels of iron in the nerve cell. The mRNAs of neurotoxic aggregating proteins contain an iron response element (IRE) which binds to an iron regulatory protein called IRP1. At normal iron levels, translation occurs at appropriate physiological levels. When iron flows into the cell, the mRNAs are released and translated at higher rates by the ribosome. When massive iron flows in, the mRNAs remain unbound for as long as the iron is high and the proteins for these neurotoxic aggregating proteins are overexpressed. In this high iron situation, buntanetap binds to the atypical IRE-IRP1 complex and prevents the mRNA from being released and, therefore, from being translated and overexpressed.

Buntanetap is able to inhibit the translation of multiple neurotoxic proteins through this mechanism of action, and as a result has the potential to treat numerous acute and chronic neurodegenerative conditions that share this pathway. In mouse or rat models of Alzheimer's, Parkinson's, stroke, frontotemporal dementia, traumatic brain injury, glaucoma, and Down Syndrome, buntanetap has been shown to normalize the levels of these neurotoxic proteins and to restore function.

Most importantly, this has been demonstrated in human clinical trials. In our recent Phase 2 clinical trial in Alzheimer's disease and Parkinson's disease, treatment with buntanetap resulted in reduction of aggregating proteins and statistically significant improvement in motor function in Parkinson's disease patients and cognition in Alzheimer's disease patients.

FUNCTION	TEST	SUBJECT
ANIMALS
Memory, learning	Mazes	AD mice, DS mice, stroke mice, TBI rats
Movement	Colonic motility, grip strength	PD mice, tau mice
Vision	Sight	Glaucoma rats
Infections	Cell death	P. Gingivalis mice, Covid mice
HUMANS
Cognition, memory, learning	ADAScog11	Early AD patients
Attention, thinking speed	WAIS coding	Early AD patients
Movement, coordination	MDS-UPDRS	Early PD patients
Movement speed	WAIS coding	Early PD patients
Table 1: Summary of all animal and human study data.

We look forward to unlocking the full potential of buntanetap and addressing unmet needs across a range of acute and chronic neurological conditions.

Maria L. Maccecchini, Ph.D.,
Founder, President, CEO and Executive Board Member

About Buntanetap

Buntanetap (previously known as ANVS401 or Posiphen) is an oral translational inhibitor of neurotoxic aggregating proteins (TINAPs), which mode of action leads to lower levels of neurotoxic proteins and consequently less toxicity in the brain. In a Phase 2a clinical trial in AD and PD patients, treatment with buntanetap resulted in statistically significant improvement in motor function in PD patients and cognition in AD patients. Additionally, the drug was well-tolerated and safe, and its pharmacokinetics were found to be in line with levels measured earlier in humans, meeting both the primary and secondary endpoints.

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