Cognition Therapeutics 

Bottom-line Up Front (BLUF): Cognition Therapeutics (CGTX) is developing a SIGMAR2 (TMEM97 / S2R) complex allosteric modulator known as CT1812. This drug has proven to displace amyloid oligomers via antagonist-like mechanisms of SIGMAR2, and has successfully completed a myriad of phase-1+2 trials in Alzheimer's disease. These trials were to garner safety, proteomic, atrophy, classic CSF biomarkers, and efficacy data - all of which yielded positive results. Their most recent Alzheimer's trial, SHINE, was conducted in 153 mild-and-moderate stage patient trial evaluating three arms (placebo, 100mg, and 300mg). Over 6 months, the drug demonstrated a 39% slowing in cognitive loss as compared to placebo (though not statistically significant), saw trends in functional improvement, halted amyloid development, reduced NfL substantially (marker of neurodegeneration), revealed that 100mg was likely the better of the two doses from an efficacy/safety perspective, and ultimately paved the way for future trials. The company is currently enrolling a large phase-2 Alzheimer's trial (START) with 540 mild-only patients, and expects to run a phase-3 Alzheimer's trial concurrently (staggered). In the near term, Cognition is set to present additional SHINE data and initial findings from the phase-2 (SHIMMER) Lewy body dementia trial at CTAD 2024. Full SHIMMER data is expected to be released at the 8th International Lewy Body Dementia Conference (ILBDC) held in Amsterdam at the end of Jan 2025. The company has received grants from the National Institute of Aging and the National Institute of Health, and as of 30 June 2024 has a balance sheet of only $28.5M which is expected to bring them into 2H 2025. We fully anticipate CGTX will need to acquire further - likely dilutive funding - in the next 6 months. With this in mind, we find CT1812's mechanism of action to be equally effective as it is interesting, and will be opening a starter position in the next 72 hours (as of 21 Oct 2024). We assess there to be a moderate likelihood that the stock could double or triple from its current share price in the $0.40 range dependent on LBD data, thus making a pre-dilution buy overall favorable. Even without a LBD price bump, the company long-term outlook appears promising and the share price will almost certainly reflect this later. If you consider buying CGTX shares, we recommend you consider these factors carefully, especially as even positive clinical data is often met with sell offs. Finally, we believe there are likely exciting synergies between CT1812 and Anavex's SIGMAR1 drugs - specifically Anavex 3-71. We will explore intricacies of CT1812's data, science, and synergistic potential with Anavex 3-71 in the report below.

Introduction & Science

I was first introduced to Cognition Therapeutics at AAIC 2023 in Amsterdam. I purposefully gravitated over to their poster as I was interested in the mechanism of S2R. My takeaway at the time was that S2R was still relatively undefined; however, molecularly it is situated in the vicinity of S1R, and appeared to influence many distinct pathways as compared to S1R. These distinct pathways drew my interest as I wondered about possible synergies with S1R and S2R modulation. From their poster assessing mouse models, my primary interest was the development negative regulation of WNT/Beta-catenin signaling proteomic pathway which saw large alterations in dosed mice. The WNT/Beta-catenin pathway is crucial for maintaining synaptic integrity, neuronal survival, and enhancing cognitive function. By protecting neurons from stressors like oxidation and inflammation, this pathway aids Alzheimer's patients. The pathway also has roles in amyloid-beta production and aggregation, and tau hyperphosphorylation. From previous research on Anavex, I knew that this pathway is only marginally altered with S1R agonism, which left me thinking of synergism. My interest dropped off after AAIC simply due to life circumstances; however, on 30 Sep 2024 an article titled Stimulating Wnt signaling reveals context-dependent genetic effects on gene regulation in primary human neural progenitors was published in Nature Neuroscience. With most of my personal studies related to brain atrophy, depression, aging and genetic regulation, I was piqued and recalled my experience at AAIC 2023. 

CT1812 is an S2R complex allosteric modulator and weak S1R modulator. The drug works by tackling the most toxic form of amyloid, known as oligomers. Oligomers bind at the oligomer receptor complex which is adjacent to the S2R. When this occurs, synapses and neurons are damaged and correlate to worse outcomes in Alzheimer's patients. CT1812 selectively modulates S2R, which displaces oligomers from the oligomer receptor complex and prevents the oligomers from re-binding. CT1812 can likely provide a similar function against toxic a-synuclein, a protein commonly tied to mixed dementia, Parkinson's disease, Lewy body dementia, and more. Besides this mechanism, S2R has implications in cholesterol metabolism and response to injury or inflammation. The company states that CT1812's mechanism closely mimics a known Icelandic mutation that is extremely protective against Alzheimer's disease. More information on CT1812 is available below and a company-produced video describing the primary mechanism can be found here.

Trial Results

As mentioned in the BLUF, CGTX has completed a number of trials in early-to-moderate stage Alzheimer's patients. Most notably of these are SEQUEL (EEG data), SPARC (brain atrophy data), and SHINE (full trial data). 

SEQUEL was a 16-patient placebo-controlled trial measuring EEG brain wave patterns over a treatment period of 29-days. Dosed patients saw consistent trends of improvement in all measures with statistical significance in relative theta power in the central region as well as statistical significance in amplitude-envelope correlation (AEC-c). Theta waves between 4-8 Hz are involved in working memory, detection of new sensory stimuli, and attention control. A study conducted in 2018 found that theta wave abnormalities may be one of the very first physiological changes in patients with Alzheimer's. Meanwhile, AEC-c measures the strength of synchronization between brain regions, thus indicating how strong the brain regions are interconnected. Alzheimer's patients tend to have weaker AEC values, showing abnormal communication between brain regions. It is well known that different brain regions begin seeing degeneration at different rates and timepoints in the Alzheimer's continuum. 

SPARC was a 23-patient placebo-controlled trial over 6 months which measured a number of facets with a primary outcome of positive brain volume data. Pooled cohorts (100mg and 300mg) significantly halted hippocampal, prefrontal cortex, and pericentral cortex degeneration (see figure 2). Whole brain volume loss saw trends of improvement as compared to placebo. It appears that there was little differentiation between 100mg and 300mg efficacy according to the company slide deck. The hippocampus along with the amygdala are the first two areas to see atrophy in Alzheimer's patients. Compared to healthy aging individuals, Alzheimer’s patients with an atrophied hippocampus have a 220%+ greater likelihood of early death. The prefrontal cortex is in the frontal lobe and is considered the 'executive center' of the brain, whereas the pericentral cortex is also located in the frontal lobe but is responsible for voluntary movement. There are currently no approved Alzheimer's medications that significantly improve brain atrophy. Monoclonal antibodies have so far only proved to increase volume loss over placebo, and Anavex Life Sciences is the closest drug to approval that has shown to directly decrease brain atrophy.

SHINE was conducted in 153 mild-and-moderate stage patient trial evaluating three arms (placebo, 100mg, and 300mg) over 6 months. This was the company's first major trial attempting to showcase cognitive and functional efficacy, along with positive safety and biomarker data. In the pooled (100mg + 300mg) dosed cohort, the drug allowed for a 1.04-point improvement over placebo in ADAS-COG11 (though this was not statistically significant), which the company says was a 39% slowing in cognitive loss. A similar 39% slowing was found in ADAS-COG13. Because this was a smaller sized trial that included moderate-stage patients, it is highly likely a larger, longer, and mild-stage only trial like the currently enrolling START would see better result. The company's own data suggests that earlier-stage patients faired substantially better (though moderate patients benefitted to a lesser degree). APOE4 negative patients also performed marginally better than APOE4 positive patients, and men tended to fair better as well. Men performing better than women in the SHINE trial is unsurprising as this seems to be a common trend in Alzheimer's trials which likely has to do with sex hormone imbalances experienced by women - specifically how estrogen plays neuroprotective roles and is dramatically reduced in women at menopause or who meet specific conditions (large number of children, early-menopause, cardiovascular disorder). Functional outcomes trended positively but only marginally improved over placebo and wasn't statistically significant, and the amyloid-beta and NfL biomarkers showed very nice improvement in dosed patients. A conclusion of Cognition was that of the two doses, the 100mg was likely the better choice going forward. We agree entirely based on all publicly available information. In this trial as well as the SPARC atrophy trial, there were marginal differences in efficacy outcomes between the 100mg and 300mg cohorts; however, there were safety differences. For example, in SHINE there were 4 patient discontinuations in the 100mg arm (0 due to adverse effects) and 16 patient discontinuations in the 300mg arm (11 due to adverse effects). Placebo saw 5 discontinuations, 3 of which were due to adverse effects. Cognitive benefits between the 100mg and 300mg arms were extremely similar making the 100mg dose standout as it included less adverse effects. In these patients, proteomic analysis was also conducted to reveal genetic improvements. It was found that protein folding, immune response, and oxidative stress pathways were all improved in dosed patients. The company also identified 3 genes significantly altered in Alzheimer's patients that were improved or reversed with treatment. These 3 genes are SERPINA3, CLU, and DDAH1 (see figure 5). The SERPINA3 gene is involved in regulating inflammation and is heightened in Alzheimer's disease, particularly in areas with abundant amyloid. The CLU gene plays a role in lipid metabolism, apoptosis (cell death) and immune response. Finally, DDAH1 regulates nitric oxide production and has impacts on vascular health and inflammation. The core findings of the CSF analysis was that "brain network mapping and pathway analysis of differentially abundant proteins supports role of CT1812 in synaptic biology, immune response, oxidative stress and  vesicle trafficking".

Ultimately, we believe the criticism published by Fierce Biotech in July 2024 was exceedingly harsh for what Cognition has accomplished, and we feel that the SHINE trial paved the path for more pointed future trials more likely to reach statistical significant improvements. 

SIGMAR1 Compared to SIGMAR2

This section will compare functions and locations of S1R and S2R. This section should not be seen as exhaustive due to the sheer breadth of influence these receptors have in the CNS. More information on these two receptors can be found in this article and this article.

SIGMAR1 Overview and Expression

S1R is primarily a chaperone protein residing at the endoplasmic reticulum in the MAM. The receptor aids an extremely high number of downstream mechanisms, many involved around DNA damage, chromatin remodeling and gene expression, lipid (cholesterol) regulation, cellular death rescue, oxidation, calcium signaling, autophagy, protein misfolding, and neuroprotection - though this is list is not exhaustive. S1R can be found throughout most of the body beyond the CNS. In Alzheimer's disease, early-stage patients see an increase in S1R expression suggesting a compensatory response to Alzheimer's pathology. However, postmortem imaging has revealed that by moderate-to-late stages of disease course, S1R expression is reduced by approximately 50% in areas like the hippocampus and frontal cortex which may indicate that rapid decline in those stages corrupt S1R ability to continue providing relief.

In the CNS, S1R is primarily expressed in neurons in the hippocampus, frontal cortex, and cerebellum where it modulates calcium homeostasis, neuronal excitability, synaptic plasticity, and creates lipid rafts. It also has moderate levels of expression in astrocytes and oligodendrocytes, where it regulates inflammation and supports metabolic processes, as well as myelination and axonal support respectively. Finally of note, S1R is expressed at lower levels in microglia, where it supports immune response.

SIGMAR2 Overview and Expression

S2R acts as a regulatory receptor rather than a chaperone protein and resides at the endoplasmic reticulum and plasma membrane of cells. The function has traditionally been less understood than S1R but has made solid scientific gains in recent years. S2R interacts frequently with co-localized progesterone receptor membrane component 1 (PGRMC1), and also aids a vast array of downstream mechanisms such as autophagy, lipid (cholesterol) regulation, amyloid toxicity, calcium signaling, and synaptic protection. Again, this list is not exhaustive and S2R is also found throughout most of the body beyond CNS. Unlike S1R, S2R is upregulated in Alzheimer's patients over 1.5 fold more than standard aging brains, with higher concentration of S2R at the synapse. As mentioned previously, CT1812 has been shown to modulate S2R at the synapse and reduce oligomer binding which prevents synaptotoxicity. This function should ablate inflammation and allow the synapses time to recoup from pathological conditions. 

In the CNS, S2R is primarily expressed in microglia, bolstering immune response, clearance, and responding to injury. Earlier we mentioned that NfL levels were drastically improved in dosed patients. NfL is a marker of degeneration and injury, so this S2Rs high expression in microglia supports this result nicely. S2R is also moderately expressed in the neuron where is plays a role in cholesterol metabolism and oligomer displacement. And finally of note, S2R is expressed at lower levels in the astrocyte where it is likely involved in metabolic regulation and cholesterol handling.

STRING Database Protein Interactions

We utilized the STRING database to derive protein-to-protein interactions. We assayed each protein individually (figures 6 and 7) and then combined (figure 8). We then compiled top pathways in a chart (figure 9) and identified most shared items in red. STRING is only as good as scientific data is available. We used the following criteria for our computations:

• In the S1R individual computation we included only high-confidence interactions and limited the result to 50 proteins

• In the S2R individual computation we included only moderate-confidence or higher interactions and limited the result to 50 proteins

  • • We allowed for moderate-confidence in S2R to partially account for less protein elucidation as high-confidence only interactions yielded only 6 results, one of which was S1R

• For the combined computation we included only high-confidence interactions and limited to 100 proteins

• Note: Denser connections indicate strong interactive confidence

SIGMAR1 & SIGMAR2 Comparison Conclusions

S1R and S2R have striking similarities in steroid and cholesterol regulation. In addition, both S1R and S2R act as compensatory mechanisms in the face of Alzheimer's pathology (and a myriad of other CNS disorders like LBD, Parkinson's, FTD, and more). There are numerous complimentary functions between the two, addressing similar disease pathways but in different ways with different strengths and weaknesses. The two have overlap in cell type abundance but have unique distinctions. As a generality, S1R likely has an exceptionally high number of downstream effects due to chromatin remodeling and DNA damage properties as compared to S2R; but S2R addresses unique pathways and some shared pathways with greater strength than S1R. 

We propose that Anavex 3-71 and CT1812 would likely make an extremely potent Alzheimer's treatment. As mentioned earlier, S1R is significantly downregulated in Alzheimer's patients while S2R is significantly upregulated. CT1812 would provide S2R modulation and unique oligomer displacement. Meanwhile, Anavex 3-71 would provide unique calcium signaling and massive downstream gene regulation with S1R and neuroprotective benefits with M1 agonism. When combined, both mechanisms (S1R/M1 + S2R) would provide benefit to calcium signaling, cholesterol regulation, amyloid displacement and clearance, degeneration & brain atrophy improvement, axon & myelination improvements, synaptic plasticity, endothelial improvements, autophagy, inflammation reduction, gene regulation and DNA damage, and more. Many of these pathways are shared between the two mechanisms but approach them in different ways which adds robust redundancy. Blarcamesine (Anavex 2-73) may also be useful as an adjunctive therapy with CT1812, but it seems likely that its quad muscarinic agonism with S1R on top of S2R may create an unfavorable safety/efficacy benefit - though this remains to be seen. 

Spirit of the Coast Analytics makes two recommendations to Anavex Life Science Corporation (AVXL) and Cognition Therapeutics (CGTX):

• Initiate preclinical or 1a/b trials using CT1812 + Anavex 3-71 (or Blarcamesine) in Alzheimer's, Parkinson's disease (dementia), and/or frontotemporal dementia (FTD)

• CGTX should initiate a trial in FTD based on SPARC's atrophy data, microglia abundance, and mechanism 

Conclusions of our analysis can be found below in figure 10.

Overall Conclusion

It is highly likely that S1R and S2R modulation is complimentary to each other based on cell-type abundance, expression levels in Alzheimer's disease, and unique strengths - as well as shared strengths targeted via separate avenues of approach. 

I spoke with the CEO (Lisa Ricciardi) and CMO (Anthony Caggiano) on 11 Oct 2024. During the call we discussed CT1812's mechanism of action, company 'next steps', monoclonal antibodies, and brain atrophy. Based on the conversations the next steps for the company are to finish the post-SHINE meeting with the FDA, complete enrollment of the large START Alzheimer's trial, and eventually initiate a concurrent phase-3 Alzheimer's trial. SOTC is interested in the fact that Cognition's phase-3 trial would be one of the first large trials allowing Leqembi and Kisluna patients. The company will likely initiate an approval request if the START trial sees statistically significant benefit improvements over placebo - especially if the improvement matches or exceeds available monoclonal antibodies. Additionally, Ricciardi acknowledged the need for additional financing. Despite this, we feel Cognition Therapeutics has positioned itself very nicely for possible longer term approval prospects with excellent atrophy, classic biomarker, EEG, and efficacy trends - though this is likely still years away. We're almost certainly going to initiate a starter position in the next 72 hours (as of 21 Oct 2024) and increase this position post-financing (further detail in the BLUF). 

It is our opinion that small biotech companies like AVXL and CGTX are primed to take advantage of poorly received monoclonal antibody roll-out (Aduhelm, Leqembi and Kisluna). Approval by global regulators has been extremely mixed with an exceptional opening in the European market. Both AVXL and CGTX boast favorable safety profiles with oral availability and potentially low cost. Both companies use novel mechanisms to address unmet downstream needs of Alzheimer's disease, perhaps most notably in neurodegeneration with favorable brain atrophy data. We look forward to seeing Cognition's Alzheimer's presentation and initial LBD findings at CTAD 2024. Upon full LBD data release at ILBDC (Jan 2025), our hope is that the cognitive improvement (or slowing) bolsters confidence in SHINE cognitive data. Finally, we look forward to Anavex's CTAD 2024 presentation, forthcoming Alzheimer's OLE data, peer review paper, and EMA submission. 

Note: As a reminder SOTC is in no way propositioned by or compensated by the companies it writes about. We assess and value compounds with long term potential and are not concerned with short term volatility during development.