Update Compendium 2025

Update 3: 24 March 2025

Atrophy, Mortality, and Moving the Goal Posts

Bottom-line Up Front (BLUF): This report is primarily graphical and aims to highlight mortality risks associated with microbleeds (ARIA) and brain atrophy. It compares atrophy, cognition, and global outcomes between Anavex and monoclonal antibodies, including Gantenerumab, Aduhelm, Leqembi, and Kisunla.

Mortality Risk Amplifiers in All-Cause Dementia:

Anti-amyloid treatments are associated with significantly higher levels of ARIA-E (ARIA-H + ARIA-A) and brain volume atrophy over placebo. ARIA-H includes microbleeding and superficial siderosis. In 2009, an MRI study was conducted across the memory clinical population (subjective memory complaints, MCI, AD, vascular impairment, other dementia, and other diagnosis) to find MRI associations to mortality. With a large population (N=1,138), the study found that over 2.6 years, there was a 2% increased risk of mortality per microbleed (~50% increased culminate risk when adding the number of microbleeds), and a 70% increased risk of mortality in younger patients experiencing heightened cortical atrophy. As expected, mortality was especially high in patients with combined microbleeds and greater cortical atrophy (480% increased risk). 

Brain Atrophy Comparisons 

Anavex Life Science’s successful 48-week, placebo-controlled Phase 2b/3 trial in Early Alzheimer’s disease (AD) patients significantly reduced whole brain atrophy (37.6%), gray matter atrophy (63.5%), and lateral ventricle atrophy (25.1%), and was not associated with an increase in ARIA-H. Notably, the frontal and parietal lobes even restored volume over baseline at the end of the study. This result indicates a rejuvenate effect, and likely forbodes a significant altering to the well-studied frontoparietal network – involved in cognitive control, executive function, attention, regulation, and working memory. [Note: Cognition Therapeutics (CGTX) has also shown early evidence as a neuroprotective with their SIGMAR2 (TMEM97) amyloid oligomer inhibitor].

Cognition (ADAS-COG) and Global/Functional (CDR-SB) Comparisons

A 2006 publication in the Journal of Alzheimer’s Disease showed brain regions with significant correlation of gray matter concentration and their congruency to ADAS-COG scores. In that study, it was found that left middle frontal lobe, left interior frontal lobe were the most significant followed by the right orbitofrontal region and the left posterior temporal lobe & fusiform gyrus. 

Numerous publications have now demonstrated that the frontal and temporal lobe correlate significantly to performance on ADAS-COG and are some of the first regions to show neurodegeneration along with the parietal region and cortical gray matter. 

These findings align closely with the ADAS-COG13 and CDR-SB results from the trial, which were a 49.8% and 33.7% slower decline, respectively, in SIGMAR1 WT patients (~70-80% of the population)—an unprecedented outcome for a registrational trial (36.3% and 27.6% in ITT).

Furthering this significance, a 2023 study found that synchronization of gray matter atrophy between the hippocampus and other brain regions was an accurate predictor of whether an MCI patient would #progress to early AD or revert to normal cognition (up to 77-81% accuracy).

Prophylactic Use, Safety, and Move the Goal Posts

On 19 Mar 2025, The Lancet published a small longitudinal OLE study featuring Gantenerumab (failed anti-amyloid treatment). The report focused on patients with mutation genes known to cause dominantly inherited Alzheimer’s disease (DIAD). Of the 73 enrolled patients, 47 were discontinued due to early termination by sponsor, 13 dropped out due to other reasons, and only 13 completed 3 years of treatment. At the interim measurement, 79% of patients did not see cognitive decline (N=53), and at the final measurement, 53% of patients did not see cognitive decline. Meanwhile, 53% of participants experienced some level of ARIA. The Alzheimer’s Drug Discovery Foundation (ADDF) sensationalized the findings, indicating that patients that start anti-amyloid treatment in their 30’s, 40’s or 50’s may prevent Alzheimer’s. The article itself more appropriately laid out disclaimers, and we recommend extreme caution while interpreting these results.

Beyond these temporary bouts of undue exuberance, the broader Alzheimer’s research community has consistently moved the goalposts for anti-amyloid therapies—a pattern that ranges from questionable to irresponsible, and even dangerous.

This is evident in continued funding for anti-amyloid research, systematic efforts to redefine efficacy to align with antibody outcomes, and even potential misconduct by the FDA, as suggested by findings from the 2022 congressional investigation.

Conclusion:

Institutional bias has prevented Alzheimer's research from meaningfully advancing for far too long. The Alzheimer's community and relevant regulators have a responsibility to propel unique and efficacious therapies into the hands of the afflicted. The number of U.S. adults who are projected to develop dementia each year is set to increase from approximately 514,000 in 2020 to approximately 1 million in 2060. Blarcamesine has demonstrated superior safety and efficacy compared to currently approved disease-modifying Alzheimer’s therapies. Its mechanism suggests strong potential as a prophylactic treatment across multiple CNS disorders, including Alzheimer’s, Parkinson’s, Frontotemporal Dementia, Schizophrenia, DLB, ALS, and more.

Note: If you would like a copy of these slides in PDF format you can contact the author using the contact page.

Update 2: 10 February 2025

Cognition Therapeutics at ILBDC 2025; Phase 2 Study of CT1812 in Mild-to-Moderate Dementia with Lewy Bodies: Topline Results

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:

Figure 1: Forest plot showcasing overall favorable treatment of CT1812 against global disease burden

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):

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). 

Update 1: 20 January 2025

Commentary on Anavex's 2b/3 Alzheimer's Open Label Extension Topline Data and JPM25 Presentation

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).

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.

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.