Special Edition: Parkinson's Disease Modification

Introduction: SOTC Analytics spent over 80 hours in Feb & Mar 2023, to conduct a deep-dive analysis of Anavex's AAIC gene poster as it relates to Parkinson's Disease. In combination with the gene poster, previous company slides, recent educational video, third-party Parkinson's pathway (KEGG & KANPHOS), and a multitude of peer-review publications over the last decade; we assess many of the pathways targeted by Blarcamesine in Alzheimer's Disease to remain relevant in Parkinson's Disease, indicating CNS-wide potential. Beyond these shared pathways (mentioned later), we identified at least four Parkinson's-specific targets, some of which are largely regulated by Blarcamesine's non-S1R binding affinities.

We assess Anavex will use the Parkinson's Disease P2 and OLE data towards Alzheimer's Disease approval considering the strong correlation between the two disorders. 

Parkinson's Disease: Genetics & Environment

Parkinson's Disease is characterized by significantly reduced dopamine in the substantia nigra, misfolded protein accumulation, oxidative stress, abundant a-synuclein, Lewy bodies, and cell death. Primary symptoms include motor impairment, tremors, anxiety, depression, constipation, REM sleep disturbance - and as we know, 80% of Parkinson's Disease patients develop dementia in later stages. Ultimately, the cause of dopaminergic death in the substantia nigra is still under investigation, but the disorder appears to be hereditary in approximately 10-15% of patients, with environmental toxins making a substantial impact according to numerous large studies. Perhaps one of the best known environmental factors influencing Parkinson's Disease is the use of pesticides which has recently been proven to increase chances of gaining the disorder by 150-500% depending on the specific pesticide and for how many years the individual was exposed to the chemical. Another well-investigated environmental factor is heavy metal toxicity. Effects from both of these toxins are alleviated to some extent with Blarcamesine.

Figure 1. From Electron Transport Chain Complex 1 to Protein Clearing & Calcium Homeostasis, Blarcamesine Addresses all Known Pathways in Parkinson's Disease - Including Some Parkinson's Specific Genes (explained later)

Alzheimer's & Parkinson's Disease Major Pathways

Visualization & Overlay of the KEGG Parkinson's Disease Map

Now that we have had a brief overview of the specific functions impacted by Blarcamesine, we can take a look at the KEGG database. The KEGG database was directly referenced by Anavex at the bottom of their AAIC 2022 gene poster. All of the individual genes shown in that poster have been displayed in the KEGG database as holding probable involvement in Parkinson's pathology. SOTC color-coded all and assigned confidence levels to all of the gene clusters mentioned in the AAIC gene poster which are as follows:

Figure 2. KEGG Database Alzheimer's Pathways with Color Coding (high confidence, medium confidence, low confidence, interest) 

Perhaps even more so than in the Alzheimer's gene mapping, overlaying regulated genes unto known Parkinson's Disease pathways reveals robust upstream therapy with enticing breadth of effect. Every Parkinson's Disease pathway catalogued in the KEGG database is addressed to some extend by Blarcamesine. Let's dive a little deeper.

As mentioned in previous SOTC articles, UPR exists to save the cell, but triggers apoptosis (cell death) if these cell survival mechanisms fail. Apoptosis isn't inherently bad; however, in CNS disorders, rampant cell death generate compounding pathological effects. CHOP is downstream of the UPR, and is a singular gene responsible for pro-survival amplification. In Parkinson's Disease, UPR is elevated and CHOP is modulated. Evidence of increased apoptosis, increased endoplasmic reticulum folding gene levels, load reduction genes, and increased proteostasis (Proteasome 26S) genes have been found in the substantia nigra of Parkinson's Disease patients. 

Parkinson's Disease-centric Gene Regulation & Effects

Figure 3. Significant Overlap Between Alzheimer's and Parkinson's - But Some Key Differentiation

Figure 4. PARK7 (DJ-1) Has a Robust Impact on a Wide Swath of Parkinson's-related Function

Figure 5. Meta Analysis of Pesticide Impact on Parkinson's Disease Odds

Parkinson's Disease Genomic Study Summary

Whether due to heavy metal toxicity, pesticide/chemical exposure, S1R deficiencies, genomic mutations - or more likely, a combination of these facets and more, dopaminergic function dramatically reduces in the brains of Parkinson's Disease patients. These dopaminergic changes manifest classic motor loss with a string of potent downstream effect to include a-synuclein aggregation & lewy body abundance. 

Blarcamesine's primary effect on Parkinson's Disease (and the dementia aspects of Parkinson's Disease which are later stage and likely distinct in cause) takes root upstream by enhancing S1R expression, and prompting improvements to dopaminergic receptor function whilst balancing muscarinic receptors simultaneously. Furthermore, Blarcamesine protects against DNA damage, RNA transcription, and resuscitates aspects of the ubiquitin-proteasome process. By improving the bodies ability to identify and tag misfolded or metal-inundated proteins, the 26S proteasome (also enhanced) can clear some 80% of our brain's dysfunctional proteins - including a-synuclein & lewy bodies. 

On a more focused level, Blarcamesine is able to upregulate PARK7, TXN, and TXN2, unlocking a treasure trove of therapeutic effect by improving dopamine synthesis, reducing ROS - especially that caused by pesticides, promotes healthy autophagic function to rescue a-synuclein aggregation (in combination with S1R autophagic function), provides potent antioxidant effect, and reduces chances for apoptosis. A-synuclein nitration - which is enhanced during oxidative stress - are found within lewy bodies. 

PARK7 also communicates directly with electron transport chain complex 1, which includes enhancing the membrane wall of the mitochondria to decrease ROS creation/leakage. It is our assessment that the electron transport chain improvements noted in the Alzheimer's gene pathway report along with calcium funneling regulation (including normalizing calcium output levels) is more related to the dementia aspects of the Disease - although not exclusively. As shown in figure 3, there is immense overlap between Parkinson's and Alzheimer's Disease, but two of the most corollary facets are protein aggregation/misfolding, and oxidative stress resulting in superoxide or ROS. For the latter, the electron transport chain is at the pinnacle of importance when addressing ROS. Holes in the mitochondrial membrane, dysfunction in nutrient in-flow, and complex 1, 3, and 4 downregulation are the most prominent causes of increased ROS. Ultimately, these effects reduce ATP (energy) for the rest of the cell, nulling axonal & synaptic activity - all the while causing enhanced endoplasmic reticulum stress and ending in apoptosis (cell death).

Bottomline & Assessment: As investors prepare for Anavex's long-awaited Parkinson's Disease dementia OLE trial data, we believe it is prudent and useful to elucidate Blarcamesine's full mechanism of action, especially as we think it likely Anavex is combining the Parkinson's Disease dementia and OLE data with the Alzheimer's 2b/3 for a robust regulatory data package. With the Parkinson's Disease dementia & OLE in-hand, the company would have ~1.2 years worth of Parkinson's Disease dementia data and 9 months worth of Alzheimer's Disease data. It is feasible that Anavex will wait to submit their regulatory package until their first Alzheimer's OLE data read (hypothesized at the first 48 week mark) in order to have 3 years worth of total data between the two indications - but we see this as less likely. If that scenario holds true however, the first 48 weeks worth of Alzheimer's OLE data is expected to close out in the last week of May or the first week of June 2023. In any case, we hope to see continued improvement in both cognitive & motor domains for those with high concentrations of the drug. We also hope to see a longer time horizon result in statistically significant REM sleep improvement. We grow anxious in anticipation of the full data read for Parkinson's Disease dementia OLE and the full Alzheimer's 2b/3 topline, and are looking forward to analyzing additional genomic and biomarker data once it is available.