Update Compendium 2025

Bottom-line Up Front (BLUF): On 18 Dec 2024, Cognition Therapeutics released topline data for their proof-of-concept phase 2 Dementia with Lewy Bodies (DLB) SHIMMER trial (COG1201), which featured mild-to-moderate dementia patients. As predicted in our initial coverage of the company, the share price of CGTX tripled to $1.29 before consolidating around the 0.65₵ level. On 31 Jan 2025, the company provided further results which were presented by Doctor Jim Galvin at the International Lewy Body Dementia Conference (ILBDC) 2025 in Amsterdam. A post-presentation video by Dr. Galvin can be viewed here. Excitedly, CT1812 (Zervimesine) showcased a global therapeutic effect for patients. DLB is highly heterogenous, multifactorial, behaviorally sporadic, and the deadliest common dementia. There is currently no approved disease modifying therapy for DLB and Cognition positions itself favorably to be the first.

Recap of CT1812 Mechanism of Action:

Alzheimer’s and Dementia with Lewy Bodies are both heterogeneous diseases associated with aging, mitochondrial deficiency, abhorrent protein accumulation, degeneration of synaptic circuitry, neuronal death, brain atrophy, cognitive loss, and behavioral disorders. DLB especially is associated with psychiatric disorders - especially hallucinations - and dramatically earlier death (5-7 years after diagnosis). 

While Alzheimer’s is classically associated with abundant amyloid and tau protein burden, DLB is primarily associated with a-synuclein aggregates known as Lewy bodies. A large portion of DLB patients share amyloid and/or tau pathology (~80-%). This phenotype has been shown to exacerbate global cognitive loss and represent the most at-risk patient. 

It is almost certain that Alzheimer’s, and possibly DLB pathogenesis begins at least 10 years (and possibly up to 20 years) in advance of pathologically classic protein build-up. This has been especially elucidated for Alzheimer’s disease. In Alzheimer’s, aging-related DNA damage, early mitochondrial dysfunction, and calcium irregularities contribute to lysosomal mutation and leakage - ultimately causing failure to cellular recycling and clearance mechanisms (including autophagy, ubiquitin-proteasome, and CSF/BBB clearance mechanisms).

Lysosomal mutation and clearance failure causes amyloid leakage from the intracellular space to the extracellular space. The proteins then aggregate and attach themselves to synapses which results in synaptic & axonal loss and eventual neuronal death. These mechanisms exacerbate brain atrophy (which started earlier), gene-wide dysfunction, metabolic overdrive, and memory/functional decline. Once the disease course is far enough along (late-mild or moderate stages) it’s likely impossible to reverse patient disease course, though some therapies have shown to have symptomatic benefit or short-term disease modification. 

Between Alzheimer’s and DLB, Alzheimer’s brain atrophy is more prominent in the hippocampus with more pronounced memory deficits (especially in comparative early stages). DLB has higher involvement in the occipital lobe and subcortical regions which contributes to hallucinations, fluctuation in attention, and parkinsonian features (motor impairment). 

CT1812 works by modulating the SIGMAR2 receptor. Amyloid and a-synuclein latch themselves on to synapses & neurons with the help of SIGMAR2 proteins, and in CNS disorders SIGMAR2 expression is elevated. By downregulating SIGMAR2 expression, CT1812 effectively reduced amyloid oligomer binding to synapses & neurons by up to 90% in preclinical trials.

In February 2025, Lancelot published a paper covering the criticality of synaptic loss in dementias titled: Synapse vulnerability and resilience underlying Alzheimer’s disease. Authors state that, “Synapse loss is viewed as a primary pathologic event, preceding neuronal loss and brain atrophy in AD. Synapses may, therefore, represent one of the earliest and clinically most meaningful targets of the neuropathologic processes driving AD dementia.” Presenting a biological description they also state, “synapses are nanomolecular structures that contain up to 6’000 proteins per synapse, are present at around 10’000 synapses per neuron, have a density of 1 trillion synapses per cm3 in the human brain, and show intimate associations with glial cells. In AD and other dementias, synapse pathology is considered one of the earliest events with clinical significance…”

Reading further, it is obvious that synaptic toxicity and subsequent neuronal death is one of the earliest marginally-downstream pathological changes that occur within dementias like Alzheimer’s and DLB. CT1812 stands to preserve synaptic function and neurons through its amyloid & a-synuclein unbinding mechanism, which likely prevents initial binding and unbinds already latched synapses. 

DLB Shimmer Trial Results

Augmenting our initial report on preliminary topline, Cognition provided additional granularity to the DLB trial results at ILBDC. Our key findings for this relatively small and short 26-week trial are below in bulleted format:

• Of the two intervention arms (100mg or 300mg), the higher dose was associated with higher discontinuation due to AE

• On NPI Total Score, CT1812 resulted in an 86% slowing (pooled arms) towards neuropsychiatric deficits with particular improvements towards DLB hallmarks like anxiety, delusions, and hallucinations [not statistically significant]

• On NPI Distress, CT1812 resulted in an 114% slowing (pooled arms) towards caregiver distress (benefit over baseline) with caregivers reporting lower distress due to patient anxiety, hallucination, depression, and sleep behavior in particular [pooled data met statistical significance at 0.025]

• Up to 85% slowing of decline across CDR cognitive domains including episodic memory (85%), working memory (59%), and quality of memory (72%) [none were statistically significant]

• CAF revealed remarkably fewer cognitive fluctuations, which were slowed by 91% (pooled arms) [not statistically significant]

• Activities of daily living degradation was slowed by 52% (pooled arms) [pooled data met statistical significance at 0.05]

• On UPDRS, CT1812 maintained motor function with 62% slowing in decline (pooled arms) [not statistically significant]

• Noisy data was observed for both MoCA (cognitive assessment) and ESS (sleep) with MoCA barely trending in favor of drug and ESS preforming marginally below placebo [neither were statistically significant]

• Biomarkers saw no significant treatment difference, though neurofilament light (NfL, a marker of axonal degeneration) trended positively

Additional Commentary and Conclusion: CT1812 seeks to prevent and displace amyloid & a-synuclein oligomers from synapses/neurons to prevent further downstream disease course. CT1812 has demonstrated its ability to do this extremely efficiently which is met with high magnitude improvements to cognition, function, motor, and psychiatric deficits - especially in patients with lower baseline pathological load. Overall, results from CT1812 in Alzheimer's and DLB likely indicate disease modification, which will be further elucidated in phase 3 trials with better design (more patients for greater statistical power, lower dose arms for better safety, pre-specified baseline p-tau217/pathological load, etc.). 

Something we find particularly interesting is CT1812's mechanism in contrast to monoclonal antibodies (Aduhelm, Leqembi, Kisunla) and Anavex's SIMGAR1/Muscarinic agonist (Blarcamesine):

• CT1812 acts indirectly by modulating SIGMAR2 to dislodge or prevent amyloid & a-synuclein binding to synapses/neurons. 

• Monoclonal antibodies (mAbs) on the other hand act directly on amyloid, binding to them and tagging them for clearance. 

• Blarcamesine upregulates compensatory mechanisms far upstream to prevent disease pathogenesis - reducing or stopping amyloid build-up via upstream mechanisms before overt disease onset. 

• CT1812 and SIGMAR2 modulators have revealed mixed results as far as clearance mechanisms are concerned. Preclinical data indicated the drug may hold potential for this, but SHINE and SHIMMER have both revealed a lack of oligomer clearance post-removal from the synapse. In SHINE, there was no difference to amyloid 42/40 ratio and in SHIMMER there was no treatment difference for either amyloid or a-synuclein. 

• Monoclonal antibodies have shown excellent clearance of amyloid, but aren't designed to target a-synuclein at all.

• Blarcamesine prevents build-up from occurring in the first place, and enhances autophagy & CSF/BBB clearance in patients with pre-existing pathology. Plasma amyloid 42/40 was improved as much as or better than aforementioned mAbs indicating significant clearance. Improvements to autophagic mechanisms almost certainly affect a-synuclein as well. 

With these comparisons in mind, it is likely CT1812 is effective at preventing synaptic damage and subsequent neuronal death; however, appears to stop there without removing displaced oligomers via clearance pathways. It may be too soon to say what the consequence of this is over a longitudinal study, or if there is any consequence at all. Meanwhile, CT1812 clearly benefits patients with high magnitude improvements across global burden. CT1812 is safe & well tolerated (no ARIA) and efficacious, with benefit of being orally administered with cross-CNS implications (Alzheimer's, DLB, Parkinson's, etc.). 

Pairing CT1812 with a mAb or Blarcamesine in clinical practice (upon approval) would likely render additional benefit to patient. Pairing CT1812 with a mAb for Alzheimer's would create an effective dual-mechanism of amyloid displacement with added clearance benefit. In such a scenario, CT1812 and a mAb would be taken simultaneously until amyloid removal reached significant levels (60-70% removal) which would be followed up with CT1812 as a monotherapy to prevent further binding. This pairing would not be beneficial for DLB or any other CNS disorder. 

Meanwhile, pairing CT1812 and Blarcamesine early in disease pathogenesis would likely be an extremely effective prophylactic. Blarcamesine would halt upstream mechanisms involving calcium flux, mitochondrial dysfunction, and lysosomal/autophagy failure; while CT1812 would ensure any low-level pathological binding to synapses was prevented. Blarcamesine’s autophagic enhancement and clearance mechanisms would then remove the little waste that made its way downstream. This approach would likely be highly efficacious and could possibly be used to varying degrees cross-CNS, though an effective dosing regimen would need to be established to reduce the severity of non-lethal AEs. CT1812 would shoulder more responsibility in this adjunctive therapy when prescribed to mild patients vs. prophylactically. We explored this notion previously near the bottom of this report.

All-in-all, Cognition Therapeutics has completed two very insightful phase 2 trials in Alzheimer's and DLB. CT1812 clearly works and makes high magnitude improvements for patients and caregivers. Moving forward it will be interesting to see if lack of pathological clearance has any affect on long-term outcomes. Even if efficacy does drop over a long time horizon due to protein build-up, the drug has demonstrated itself to be a likely disease modifier for at least two CNS disorders. Upon approval the drug could likely be prescribed on its own as a monotherapy or combined with other medications to enhance patient benefit. We are excited to see the next steps for the company which we would theorize includes partnership. As a generality, 40-60% of BP partnerships with biotech occur after positive phase 2 trial data and Cognition Therapeutics now has two under their belt. The need for cash to fund phase 3 trials, expansive indications, lucrative nature of CNS, oral benefit, and looming BP patent cliff (+$400B by 2033) make Cognition an extremely attractive suitor. Meanwhile we await further proteomic (gene data) and sub-population analysis for SHIMMER, end of study meetings with the FDA for Alzheimer's and DLB, and guidance on next steps. Notably, an additional larger (N=540) phase 2 Alzheimer's trial known as START has been actively enrolling and features three arms (100mg, 200mg, placebo). 

Bottom-line Up Front (BLUF): At the 43rd J.P. Morgan Healthcare Conference (JPM25), Dr. Missling gave a company overview and topline data for the ATTENTION-AD open label extension trial (OLE). ATTENTION-AD longitudinally followed cognitive, functional, and safety outcomes for patients previously part of the original 48 week placebo-controlled 2b/3 Alzheimer's trial. In the OLE, patients in North America and Europe completed 96 weeks of additional drug exposure (on top of the original 48 weeks), and patients in Australia completed 144 weeks (on top of the original 48 weeks for a total exposure of 192 weeks in some patients).

• Key Points of the OLE Topline:

  • • Patients were not informed as to whether or not they were on an active arm (drug) during the placebo-controlled trial, thus maintaining a level of blinding by allowing Anavex to calculate efficacy differences between patients that had been on the drug the entire time (144 weeks in North America/Europe and 192 weeks in Australia) and those that were previously on placebo. Those on drug the entire time are called "early start" and those that were previously on placebo are called "late start".

      • • ADAS-COG13 cognitive differentiation between early start and late start at 144 weeks: -2.70 points (P=0.0348)*

        • ADAS-COG13 cognitive differentiation between early start and late start at 192 weeks: -3.83 points (P=0.0165)*

          • • ADAS-COG13 scores that are negative values are better

        • ADCS-ADL functional differentiation between early start and late start at 144 weeks: +2.32 points (P=0.125)

        • ADCS-ADL functional differentiation between early start and late start at 192 weeks: +4.30 points (P=0.0206)*

          • • ADCS-ADL scores that are positive values are better

    • Cognitive and functional comparison indicates that earlier intervention with Blarcamesine is highly likely to significantly slow disease progression, even over a lengthy time horizon (at least up to ~4 years). Additionally, the magnitude of disease slowing is extremely high, with cognitive benefit easily reaching thresholds for clinically meaningful status. Academia is a bit undecided on what constitutes as clinically meaningful functional improvement, but some sources cite +3 to +4 points in MCI and early-stage patients. 192 weeks is the first time point where Anavex has garnered a statistically significant improvement for function (though all other time points trended positively). This is possibly due to the fact that very early patients lack significant deviation in functional decline (as assessed by ADCS-ADL). It is likely that two factors led to significant functional improvement at 192 weeks. The first factor is that with nearly 4 years there had finally been enough disease progression - especially in late start patients - to notice a separation. The second factor is length of drug exposure. Anavex had previously proven in the earlier 2a Alzheimer's trial that longer exposure to drug improves function in patients, and these results appear to corroborate that. 

    • No further safety concerns were found. Instead, titration was much slower (previously 2-3 weeks to now 10 weeks) and dizziness incidence was reduced from 25.2% in the placebo-controlled trial to only 9.6% in the OLE. This underscores the very manageable nature of Blarcamesine-related TEAEs. Blarcamesine is associated with only mitigatable side effects, unlike monoclonal antibodies that are innately associated with ARIA (brain bleeding and swelling). Some patients have now been on Blarcamesine for over 9 years of treatment, indicating high tolerability and safety over an extended period.

Below you will find our highlights on Dr. Missling's JPM25 presentation, and as of Jan 2025 you can find a replay of the presentation here.

• Blarcamesine addresses upstream processes (autophagy) rather than downstream (amyloid targeting). 

• Oral Blarcamesine performs better numerically than SOC (Aricept) and approved monoclonal antibodies (Aduhelm, Leqembi, Kisunla).

• Multiple Blarcamesine formulations improve marketability, patent protection, and disease breadth.

• SIGMAR1 is under-expressed in CNS disorders and needs to be restored (something Blarcamesine has proven to do in preclinical models).

• Blarcamesine and monoclonal antibodies go after totally separate mechanisms which indicates a possible complimentary function.

• EMA application for centralized procedure submitted and accepted; JPAD paper published with Alzheimer's findings.

• Phase 2 Schizophrenia trial with Anavex 3-71 expected to complete and readout in 2025, no safety concerns and the trial has expanded to increase patient size and statistical power.

• Parkinson's disease trial expected, and an update will be available for this (and other indications) by the end of the month.

• Animal models have shown prophylactic (preventative) potential for Blarcamesine and Anavex 3-71 by providing the drug to animals before administering Alzheimer's pathology to the animal.

  • • Looking to move into even earlier stage trials (preclinical) down the road.

• Phase 2 study for Anavex 3-71 and Alzheimer's expected later.

• Parkinson's disease dementia trial will be initiated sometime after classic Parkinson's (motor focus).

• To add on to the 3 trials already ran for Rett Syndrome, Anavex will eventually run another Rett Syndrome trial; some patients remain on drug for over 4 years in compassionate use programs.

• 30mg dose in the placebo-control portion of the 2b/3 Alzheimer's trial was perfectly suitable efficacy-wise and may be the most desirable placement from an efficacy/safety/tolerability standpoint [Note: I would speculate that if a patient could individually tolerate 40mg they would likely see marginal improvement over 30mg).

• Brain atrophy is virtually synonymous with Alzheimer's pathology, a clear and obvious manifestation. 

  • • Entire brain (whole brain), gray matter networks, parietal parietal lobe, temporal lobe, limbic lobe, insular cortex, frontal lobe all saw halt or delay of atrophy.

    • Improves neurodegeneration, a niche for Blarcamesine as no approved drug does this.

• Work has begun on educating clinicians and patients to how Blarcamesine works and what kinds of improvements one could expect from treatment. Pricing potential in Europe is also being explored

• Patent protection is international and valid through at least 2038.

• Cash position is strong enough for 4 years.

• Goal: Provide an equitable and accessible therapy for Alzheimer's; small molecules don't require complex storage or delivery requirements, and Blarcamesine could be more efficacious and less expensive than available therapies.

Conclusion: We know factually that Dr. Missling was busy with multiple undisclosed endeavors in San Francisco last week. Beyond his presentation at JPM25, multiple conversations and meetings concerning potential partnership likely took place. With the EMA acceptance of Anavex's commercial filing, Alzheimer's publication in JPAD, and clear efficacy, safety, and cost benefits over approved therapies, Anavex finds itself in an advantageous positioning to garner a desirable partnership deal with big pharma. OLE topline data was extremely positive and lends credence to Anavex's mechanism of action and upstream neuroprotection. Viewers should contextualize OLE findings by reading the autophagy mechanism of action explanation on the home page. The company niches itself from competitors by being orally available, cognitively more efficacious, and the only registrational drug to significantly reduce brain atrophy (neurodegeneration). We will continue to watch for signs of potential partnership discussions, and look forward to short-term updates to the Parkinson's disease trial suite, further OLE data and gene data (both possibly at AD/PD 2025), and advancement of Anavex 3-71 in Schizophrenia. We anticipate these catalysts will drive near-term value to Anavex's shareholders and further bolster their positioning in partnership discussions.