Update Compendium 2025

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.