Special Edition: Pivotal Road

This publication serves as a precursor to our forthcoming CTAD report, which will be available to all audiences on 7 Dec (CTAD donors will have first access prior to 7 Dec). The precursor focuses on upstream pathways for Alzheimer's Disease.

Introduction: SOTC Analytics spent over 95 hours in Nov 2022, to conduct a deep-dive analysis of Anavex's AAIC gene poster. In combination with the gene poster, previous company slides, recent educational video, third-party Alzheimer's pathway (KEGG & KANPHOS), and a multitude of recent peer-review publications; we assess there to be three critical pathways upregulated (normalized) directly by Blarcamesine. At least two of these three pathways are directly elucidated by in-human data revealed at AAIC 2022. 

We believe this data will be immeasurably important for Blarcamesine's regulatory approval, as it hones in on upstream therapeutics provided by the drug. The level of analytic rigor conducted by Anavex, Ariana, and third-party scientific benefactors currently supersedes that of even the highest tier biopharmaceutical companies. SOTC Analytics assesses this level of data scrutinization will almost certainly propel Anavex to approval, pending a successful readout of Anavex's 2b/3 Alzheimer's trial.

This publication was written by SOTC Analytics and reviewed by the distinguished Dr. Amor Mehta, MD Neurologist, Epilepsy Specialist – President/CEO of Neurology Center for Epilepsy and Seizures, LLC. Five other constituents including investment bankers, healthcare creative directors, and other professional craftsman also contributed to this report.

Image 1: Two Separate Pathways - IP3R/ATP & UPR 

Long-standing Hypothesis Playing Out

Displayed by Image 1, we see that Anavex has been focused on at least two primary pathways, IP3R/ATP, and Unfolded Protein Response (UPR); both of which have been covered to some degree in the Update Compendium on 29 Aug 2022. Along with these two pathways confirmed during the AAIC genomic findings, SOTC Analytics is tracking at least one other newly revealed critical pathway.

The last major pathway was also confirmed in the AAIC genomic findings but has not been presented by the company yet in great detail. We are alluding to the 26S proteasome (proteostasis), which is the primary mechanism for tagging and breaking down misfolded proteins. Whereas we know Blarcamesine clears misfolded proteins, it hasn't been entirely clear by which upstream mechanism the drug was accomplishing this task. We now believe this ability to be vastly better understood post-AAIC, and we will discuss the 26S proteasome later.

Cellular Visualization & Pathway Mapping

In order to fully grasp image 3 (below), image 2 should be examined as to understand the basic shape of the cell. Notice the endoplasmic reticulum and mitochondria share a tethering landscape known as the MAM. It is in the MAM that S1R primarily resides. Here the S1R regulates calcium channels, prompts misfolded protein degradation, reinforces cellular pro-survival genes, and more. Importantly, the MAM is the primary source of ATP (energy) transfer between the mitochondria and the rest of the cell. These core areas of the cell are surrounded by cytoplasm - proteins and other substances in liquid form.

Image 2. Brief Visualization of the Cell; the Mitochondria and it's Tether to the ER

Now that the basic cellular structure is understood, we can make sense of the KEGG database Alzheimer's mapping. The KEGG database was directly referenced by Anavex at the bottom of their AAIC gene poster. All of the individual genes shown in that poster have been displayed in the KEGG database as holding probable involvement in Alzheimer's pathology. SOTC color-coded all of the gene clusters mentioned in the AAIC gene poster which are as follows:

Image 3. KEGG Database Alzheimer's Pathways with Color Coding (high confidence, medium confidence, low confidence, interest)

Visually, it is obvious Blarcamesine is having an effect via a massive upregulation footprint in the mitochondria (top right), the 26S proteasome (center right) and the endoplasmic reticulum - especially the UPR pathway (center/center right). Other pathways influenced include the AGE-RAGE diabetic pathway, autophagic pathway, and insulin signaling pathway - none of which will be covered in great detail here (center bottom).

We will now break out the three major pathways, gene percentages upregulated in each, and their relevance to overall cellular function. 

Image 5. AAIC 2022 Alzheimer's & Parkinson's Disease Dementia Gene Data

CTAD Precursor Summary

On 31 July 2022, Anavex PR'd their AAIC gene poster which included the following quote, "These findings will facilitate contextualization of upcoming readout of ANAVEX®2-73 Phase 2b/3 Alzheimer’s disease clinical trial."

Listening to the Guggenheim Conference on 14 Nov 2022, it is obvious Anavex is still working to completely understand upstream effects of Blarcamesine; however, the company has given investors and researchers fantastic insights into holistic S1R MOA. This is the primary reason for this precursor report. SOTC Analytics wanted to make the most of the genomic data revealed by the company to understand what kind of indicators are being watched behind-the-scenes as well as the magnitude those indicators have on diseases.

After many years, we are finally able to narrow down specific upstream effects with quantitative and qualitative data. Pending a successful 2b/3 data release, we believe this genomic rigor will pay great dividends to the company when approaching regulatory agencies for approval.

While it cannot be 100% certain at time of writing, SOTC Analytics is confident Dr. Missling and the Anavex team is about to present overwhelmingly positive data at CTAD 2022. At last, the company's hard work and investor diligence will pay off. Please stay tuned for part two post-CTAD.

Some Helpful Sources: One, two, three, four, five, six [AAIC-elucidated genes below in one-stop-shop]