Update Compendium 2025

Bottom-line Up Front (BLUF): On 6 Apr 2025, Spirit of the Coast Analytics provided modeled placebo decline compared to Anavex's OLE trial results. The outcomes of the previous analysis was based on Eli Lilly's TRAILBLAZER-ALZ 2 trial which featured extremely similar patient populations. In order to expand on that analysis, we set out to model holistic, or "full spectrum" patients in more realistic real world conditions. Using the paper: Disease progression model using the integrated Alzheimer's Disease Rating Scale we were able to calculate surrogate placebo decline for moderate-stage Alzheimer's patients. 

The paper features a meta-study of 2,208 early-stage Alzheimer's placebo patients (MMSE between 21 - 26) and 677 moderate-stage Alzheimer's placebo patients (MMSE 20 or less) across 6 trials, which included TRAILBLAZER-ALZ 2. Researchers overlaid ADAS-COG13 scores to compare decline rate between early and moderate Alzheimer's patients to 104-weeks. 

There were 4 timestamps that we used in our analysis, as they featured the least "noise". The timestamps were at 52, 64, 78, and 104-weeks. 

At these time points the difference between early and moderate was:

• 52-weeks: moderate declined approximately 92% faster than early-stage

• 64-weeks: moderate declined approximately 130% faster than early-stage

• 78-weeks: moderate declined approximately 75% faster than early-stage

  • • Between 64 and 78-weeks it's probable some early-stage Alzheimer's patients began transitioning to moderate-stage Alzheimer's which resulted in less perceived decline between the early and moderate groups. This effect persisted for 104-weeks as well.

• 104-weeks: moderate declined approximately 50% faster than early-stage

  • • It's probable even more early-stage Alzheimer's patients were now moderate, decreasing the perceived decline delta even further.

We then took the smallest acceleration figure (50%) which is modeled with the light blue line, and began accelerating the placebo patients after 64-weeks, when the average early-stage Alzheimer's placebo patient had progressed to moderate-stage.  

To finish we calculated the average acceleration taken across all four of those timepoints and modeled in purple (87% average acceleration).

The analysis within this report is modeling and thus should be viewed with speculation or as entertainment. Nonetheless, we believe these charts and their outcomes are well within the realm of possibility of fact when assessing the entire patient spectrum. 

DB/OLE ITT Population Vs. Placebo Trajectories

For this group, there was a substantial -14.875 ADAS-COG13 delta between early-start patients and the 50% accelerated moderate-stage Alzheimer’s placebo group, and an even greater -21.211 delta compared to the 87% accelerated placebo group. If early-start patients continued to decline at their current rate while the 87% accelerated placebo group experienced no further decline, it would take approximately 254.5 weeks—or about 4 years and 10.5 months—for early-start to catch up in cognitive decline.

No/Short Interruption Vs. Placebo Trajectories

In this group, the delta widened: a significant -15.895 ADAS-Cog13 difference versus the 50% accelerated placebo group, and an extraordinary -22.211 difference versus the 87% accelerated group. At current trajectories, early-start patients would take approximately 284.4 weeks, or roughly 5 years and 5.4 months, to reach the same level of decline—assuming the placebo group halted decline entirely to allow for early-start to catch up.

Conclusion

Patients in Anavex’s Phase 2b/3 study began treatment at an approximate age of 74. According to a Johns Hopkins report from last year, average U.S. life expectancy is 75.9 years for men and 81.3 for women, with European averages slightly higher. Based on this data, if real-world outcomes mirror our projections, it is highly likely that patients who begin Blarcamesine treatment in very early-stage Alzheimer’s or MCI may never progress to late-stage Alzheimer’s. Instead, they could spend the remainder of their lives in early-stage Alzheimer's or an uncharacteristically slowly progressing moderate-stage. Given Blarcamesine’s mechanism of action in targeting very early pathology, we believe that combining the drug with lifestyle interventions during preclinical stages could halt cognitive decline entirely.

To finalize, our previous analysis was a good peer-to-peer comparison, but this analysis opens the window to what Blarcamesine therapy could look like in the real world with full spectrum, real world conditions. Our placebo arm at week-192 is in line with academic generalizations of 8-12 point annual ADAS-COG13 declines.

Bottom-line Up Front (BLUF): On 5 Apr 2025, Anavex Life Sciences presented compelling longitudinal Alzheimer's data from their 144-week OLE. Combining the original 48-week 2b/3 trial in early-Alzheimer's, some patients had uninterrupted efficacy scores to 192-weeks (nearly 4 years). Spirit of the Coast used placebo scores from Eli Lilly's Trailblazer-2 trial (Kisunla / Donanemab) as a surrogate arm to showcase what long-term Blarcamesine treatment looks like compared to placebo (patients on Memantine and acetylcholinesterase inhibitors). As a reminder, Anavex presents at the 24th Annual Needham Virtual Healthcare Conference tomorrow, 7 Apr at 3:45 PM (ET). It is highly likely that additional granularity will be shared on these base findings.

Key Points:

• Over 192-weeks Blarcamesine proved to be safe with no treatment related deaths or ARIA (brain bleeding/swelling). Slower titration for patients in the OLE (10 weeks vs. 3 weeks in the original trial) favorably cut down on treatment emergent adverse events including dizziness from 25.2% to 9.6%. The ability to dramatically reduce adverse events with slow titration lend credence to the manageability of side effects without need of therapy withdrawal. 

• COVID restrictions during Anavex's global 2b/3 and subsequent OLE resulted in some patients being enrolled with a delay. This allowed Anavex to lump patients into four boxes for pre-specified analysis:

  • • Box 1: Dosed patients from 48-week trial that were able to enroll into the OLE quickly (<19 days without therapy, 2.5 days avg) = No/Short Interruption EARLY-START

    • Box 2: Dosed patients from 48-week trial that enrolled into the OLE slowly (>19 days without therapy, 75 days avg) = DB/OLE ITT Population EARLY-START

    • Box 3: Placebo patients from 48-week trial that were able to enroll unto the OLE quickly (<19 days without placebo, 2.5 days avg) = No/Short Interruption DELAYED-START

    • Box 4: Placebo patients from 48-week trial that enrolled into the OLE slowly (>19 days without placebo, 75 days avg) = DB/OLE ITT Population DELAYED-START

    • Note: Genetic variants including SIGMAR1 status (wild type or mutation) was another pre-specified analysis that has yet to be revealed. With this in mind, all efficacy data from the OLE features mixed SIGMAR1 status patients. SIGMAR1 WT-only patients in a similar analysis would yield vastly superior result. 

• Provided cognitive outcomes (ADAS-COG13) and functional outcomes (ADCS-ADL):

  • • ADAS-COG13 cognitive differentiation between ITT dosed and placebo at 48-weeks: -2.027 points (P=0.015)*

    • ADAS-COG13 cognitive differentiation between SIGMAR1 WT and placebo at 48-weeks: -2.317 points (P=0.008)**

    • 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)* [DB/OLE ITT]

    • ADAS-COG13 cognitive differentiation between early start and late start at 192-weeks: -4.20 points (P=0.0083)** [No/Short Interruption]

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

    • ADCS-ADL functional differentiation between ITT dosed and placebo at 48-weeks: +0.775 points (P=0.357)

    • ADCS-ADL functional differentiation between SIGMAR1 WT and placebo at 48-weeks: +0.727 points (P=0.466)

    • 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)* [DB/OLE ITT]

    • ADCS-ADL functional differentiation between early start and late start at 192-weeks: +5.75 points (P=0.0015)** [No/Short Interruption]

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

• Longer lapses in therapy yielded worse results. Additionally, starting therapy later (delayed start patients) yielded worst results. Together these outcomes strongly suggest earlier and maintained treatment with Blarcamesine provide strongest benefit to patient. 

• Observing company provided OLE charts below, it is important to frame in context that the arms are both dosed cohorts.

ADAS-COG13 Observations:

You'll notice immediately the convergence of scores at 96-weeks. In Anavex's published 2b/3 paper it was suggested that the 3-week titration schema was too aggressive for tolerability and caused temporary functional weakening (discussed later) and weak efficacy scores at the original 12-week collection point. Titration was slowed to 10-weeks in the OLE which dramatically reduced adverse events. We hypothesize that while this slower titration was significant for adverse event reduction, it may have a dual effect of creating noise/weaker initial scores. If 3-weeks caused weakness at the 12-week collection point, perhaps 10-weeks caused weakness at the 36-to-48 week zone. In any case, we hope Dr. Missling will address this at Needham tomorrow.

Beyond that, cognition began to improve as expected, especially in previously dosed patients (early-start) in the no/short interruption group. By 192-weeks we can clearly see the early-start patients reduce the slope of decline significantly - potentially even beginning to level out entirely (cease further decline). ADAS-COG13 clinically meaningful thresholds for MCI and early-Alzheimer's have been established as a change of -1.5 to -2 points at 1 year of therapy. Anavex is the first disease modifying therapy to achieve this for ITT (and pre-specified SIGMAR1 WT) in a pivotal trial. Clinically meaningful thresholds beyond 1 year have yet to be established and it is better over long periods of time to determine clinically meaningful thresholds on a case-by-case (individual patient) level.

ADCS-ADL Observations:

As mentioned in the ADAS-COG13 section, the authors of the 2b/3 paper suggested an overly ambitious titration schema caused temporary functional weakening in patients which yielded poor results in the original 48-week trial. Additionally, authors proposed that ADCS-ADL's low sensitivity to MCI and early-stage Alzheimer's patients played a hand in lack of response. As patients progressed in disease (post 48-week) and titration was slowed to 10-weeks we can see these theories confirmed. Very nice consistent slopes are observed across the board with statistically significant deltas between arms starting at 96-weeks for the no/short interruption group. Academia is a bit undecided on what constitutes as clinically meaningful functional improvement in ADCS-ADL, but some sources cite +3 to +4 points in MCI and early-stage patients. Concrete thresholds for ADCS-ADL have yet to be fully fleshed out, partially due to wild subject-ability on case-by-case basis. What a patient considers to be important from a function standpoint differs significantly patient-to-patient. 

Using Eli Lilly's Trailblazer-2 Placebo As a Surrogate Comparison:

Eli Lilly’s Kisunla trial placebo group served as an excellent surrogate comparator due to several key factors: the trial had a nearly identical cognitive baseline (MMSE), a robust sample size, and utilized ADAS-COG13 with published scores extending to 76-weeks. When analyzing the placebo group’s rate of decline on ADAS-COG13, we found it aligned closely with third-party studies documenting longitudinal decline rates in both early- and moderate-stage Alzheimer’s patients. Ultimately, we determined that Trailblazer-2 provided a more relevant benchmark than ADNI. Our findings are presented below.

DB/OLE ITT Population Vs. Placebo Trajectories

To create our placebo arms (light blue and purple lines) we used Anavex's original 48-week placebo data and then calculated the rate of change for Trailblazer-2 from 48-weeks to 76-weeks. As expected, rate of decline was relatively consistent from 48-weeks to ~64-weeks before accelerating. It is likely around this time patients as a whole were progressing to moderate-stage Alzheimer's which is associated with an ~25.12% faster decline on ADAS-COG13. At 76-weeks we established two branches. The first branch is light blue, and is more true to known Trailblazer-2 placebo decline. That is to say, we extrapolated out the 64-week acceleration seen in Traiblazer-2 all the way until the end of trial at 192-weeks. This resulted in a delta of -2.58 between late-start and the Trailblazer-2 placebo. It also resulted in a delta of -6.41 between early-start and the Trailblazer-2 placebo. The latter is a very large delta, and we have moderate confidence this is a conservative decline as its more likely that the longer moderate-patients go untreated the more rapid their decline becomes. To account for this, we devised the purple placebo cohort. This cohort used Trailblazer-2 data through 76-weeks and then applied a stacking 25.12% increase at each subsequent data read. This showcases a more 'worst case', but realistic scenario, and resulted in a -10.05 point difference between early-start patients and the Trailblazer-2 accelerated placebo (moderate-stage decline trajectory). This is a massive delta, and it's most likely that a true placebo group falls somewhere between the purple and light blue lines. Some of the difficulty in this analysis is lack of insight into individual MMSE scores at end of trial, the fact that 15% of Anavex's patients had progressed to moderate-stage Alzheimer's by their first dose, and obvious sensitivity hinderances due to longitudinal modeling. Nonetheless, we find this analysis extraordinarily encouraging. 

No/Short Interruption Vs. Placebo Trajectories

Concluding our analysis in the no/short interruption comparison, we once again compared our original Trailblazer-2 placebo and Trailblazer-2 accelerated placebo (moderate-stage decline trajectory) to early-start. This yielded a -7.43 point delta and -11.05 point delta respectively. Enormous differences between early start patients and modeled placebo patients. Once again, it is likely a true placebo comparison is somewhere between the purple and light blue lines. 

Conclusion:

Despite significant OLE enrollment delays caused by global COVID regulations, Anavex was able to defy all odds with a highly successful Alzheimer's trial. Slower titration ameliorated most mild, transitory safety concerns seen in the primary 48-week trial. No treatment-related death or ARIA was noted in the OLE. 

After placebo surrogacy modeling, Spirit of the Coast proposes the following efficacy scores:

• DB/OLE population early-starters vs. Trailblazer-2 surrogate placebo: -6.41 ADAS-COG13 point saving (~22.83%)

• DB/OLE population early-starters vs. Trailblazer-2 accelerated placebo (moderate-stage decline): -10.05 ADAS-COG13 point saving (~38.6%)

  • • While we have less confidence in the accelerated placebo, it is more likely closer to truth 

• No/Short interruption early-starters vs. Trailblazer-2 surrogate placebo: -7.43 ADAS-COG13 point saving (~32.27%)

• No/Short interruption early-starters vs. Trailblazer-2 accelerated placebo (moderate-stage decline): -11.05 ADAS-COG13 point savings (~42.42%)

  • • While we have less confidence in the accelerated placebo, it is more likely closer to truth based on what we know about decline acceleration in moderate-stages

    • Note: As mentioned earlier, this does not take into account SIGMAR1 typing in any way

During the original 48-week trial, ADAS-COG13 showed a 36.3% slowing of decline in the ITT population and a 49.8% slowing in SIGMAR1 wild-type (WT) patients, who represent approximately 70–80% of the population. Our results are consistent with these findings and reinforce the company’s view that earlier, uninterrupted treatment leads to better efficacy. 

Based on our modeling and the original 48-week outcomes in prespecified SIGMAR1 patients, it is highly likely that similar early-start patients without a break in therapy experienced over 50% slowing in ADAS-Cog13 decline—potentially as high as 60% or more. As suggested by the slopes in the data, it's exciting to consider that patients who start therapy early or maintain treatment long enough may potentially halt cognitive decline—though this is yet to be proven. 

We look forward to tomorrow’s presentation at Needham, as well as additional insights into SIGMAR1 status in the open-label extension, time-saved modeling, gene data, EMA progress, and the upcoming FDA submission.

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.

• Additionally, we examine multi-year trends within the Alzheimer’s research community, particularly the shifting standards for monoclonal antibodies and the premature, irresponsible enthusiasm for their prophylactic use.

• While Leqembi and Kisunla are currently the most effective approved Alzheimer’s therapies, longer-term safety data is needed before considering preventative studies, especially given the potential increased risk of mortality from ARIA and atrophy in younger patients.

• Finally, with amyloid now recognized as a downstream pathology rather than the root cause of Alzheimer’s, the field must prioritize earlier, more effective therapies rather than continuing to disproportionately focus on amyloid-targeting approaches.

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.

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.