Update Compendium 2023

While not a perfect analysis, this chart reveals the following:

• AGK, SLC20A2, ANK3, PSMC1, NDUFA5, and COX7B have the strongest and most consistent response across dosed patients

• NDUFA9, TIMM17A, AUH had the weakest and least consistent response across dosed patients

• When combining neutral/good and super-response together, there were no genes that had more 'non response' than response

Assessment: While this report serves only as a quick-look, we look forward to analyzing this data further in the coming days/weeks. We are specially interested in the COX7B, PSMC1, ANK3, AGK, NDUFA5, and ACAT1 genes in that order. Ultimately, this data bodes well for the RS-003 trial data and Anavex's chances of approval for Rett Syndrome.

Bottom-line Up Front (BLUF): On 20 Nov 2023, Anavex re-ignited investor interest by disclosing that the company has been in discussions with the European Medicines Agency (EMA), and that the company has made initial filing for Centralized Procedure. 

Assessment: It has been Spirit of the Coast's position for nearly a year that Anavex's first - or at least most emphasized - regulatory effort would be with the EMA. In fact, on the SOTC homepage we write: we assess it is likely Anavex will pursue European approval first and foremost, as they designed the 2b/3 trial to accommodate EMA Alzheimer's guidance, and the European population has the absolute most favorable genomic qualities for effective therapy.

According to a large genome database, the European population has approximately 7.5% greater S1R WT prevalence than the American population, 2.5% greater than the African population, and 18% greater than the Asian population. This statistic is bolstered by the fact that Americans with European ancestry have the highest S1R WT prevalence of American population groups.

Beyond having the most favorable genomic qualities for efficacious therapy, the Alzheimer's 2b/3 trial design and outcomes are both in alignment with EMA guidance and approval values. Earlier in the year, we had this to say:

Anavex approached their trial design deliberately with EMA (European) approval as a primary consideration. Unlike the Aducanumab and Lecanemab trials (ENGAGE, EMERGE & CLARITY), the Anavex Alzheimer's 2b/3 utilized guidance directly from the EMA's 2018 Alzheimer's instruction. This is important because so far, MaB treatments like Aducanumab and Lecanemab have failed to garner approval in Europe and Australia. Reason being, the EMA noted that although Aducanumab reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established. In addition, the studies did not show that the medicine was sufficiently safe. Therefore, the EMA's opinion was that the benefits did not outweigh the risks.

Anavex has excellent opportunity for approval in Europe due to their deliberate accommodating design. These are some of the items implemented towards this end.

• Favors co-primary endpoints with a cognitive outcome (ADAS-COG) and a functional outcome (ADCS-ADL).

• Secondary endpoint with global measure (CDR-SB).

• Company  clearly identified the 'responder' criteria. 

Beyond those design considerations, differences between FDA & EMA Alzheimer's guidance is favorable towards Blarcamesine as shown below:

• EMA favors disease modification whereas FDA favors a 'persistent effect on disease course.

  • • This is interesting because when Lecanemab patients stopped dosing, the little improvement they had began to once again degenerate.

    • Blarcamesine is easily identifiable as the only true disease modifying compound to complete pivotal trials. [Edit: with Donanemab data now available, I do believe it is sound to consider the drug disease modifying]

• EMA favors trial designs showing dose dependency (30mg + 50mg).

• EMA approves less drugs than the FDA, but the EMA places higher value on high therapeutic value.

  • • From a semi-recent analysis: 

      • • Expedited drug approvals requiring high therapeutic value: 45% (FDA), 67% (EMA)

        • Standard drug approvals requiring high therapeutic value: 13% (FDA), 27% (EMA)

• "In mild to moderate AD to accept an effect on cognition it should be clinically meaningful. The clinical relevance should be confirmed by an effect on function or clinical global assessment in a co-primary endpoint approach."

More information can be found here, but as a brief summation, Anavex has postured themselves in clinical design to approach the EMA for approval. Additionally, their 2b/3 outcomes meet approval preferences by the EMA, being an efficacious, inexpensive, and safe drug. In our opinion, Lecanemab still fails to meet many of the criteria set out by the European regulatory agency, and Lecanemab is unlikely to garner approval there; we give an ~20% chance.

With these facets explained, it is of no surprise that the first regulatory meetings publicly disclosed by the company were with the EMA. For those that may not know, the EMA is a medical conglomerate which oversees the approval for drugs in the EU. However, it is not always the case the drugs approved by the EMA are available in every country within the EU. Some drugs are available through all member states - which requires a Centralized Procedure, and some drugs are approved for specific countries. It is obviously quite desirable for Anavex to have pursued an all-encompassing approval. Separately, it is not clear at this time which type of approval the company is pursuing - although it is likely these discussions with the EMA are to probe whether or not they could acquire Accelerated Assessment (accelerated approval pathway). As can be found here, the EMA has seen an increase in Accelerated Assessment applications forms over the last few years, paired with an increase in accepted applications. The primary reasons for rejection of Accelerated Assessment are as follows:

• Unmet medical need not adequately justified or not substantiated by the patient population included in the clinical programme 

• Data not sufficient to justify a major public health interest 

• No major advantages compared to available treatments 

• Dossier not mature enough

Considering there have been no new Alzheimer's drugs approved in Europe in decades, there is certainly an unmet need. Anavex's background work on in-depth genomics and complimentary pipeline suite certainly contain robust data. And Blarcamesine's drug is safe, oral, likely inexpensive, and the most efficacious phase 2b/3 data to date - able to be prescribed to MaB excluded co-morbidity groups like cardiovascular and epileptic Alzheimer's patients. None of these are problems for Anavex. The company hits this home in the 20 Nov PR by emphasizing that the administration of Blarcamesine does not require complex logistical resources, added personnel, or monitoring via expensive (and exceedingly rare in the EU) MRI technologies. There are multiple peer-reviewed reports backing up the significant burden hypothesized MaB approval would cause the EU healthcare system, both financially and logistically.

Overall, we remain extremely bullish on Anavex's pipeline, clinical outcomes, patient-focused care, cutting-edge genomic approach, and their ever-approaching utility in the homes of Alzheimer's, Rett Syndrome, and Parkinson's Disease patients. We believe Anavex's social connection with front-running Europe-based scholars and clinicians like Timo Grimmer, Dag Aarsland and Tangui Maurice, along with Dr. Missling's circle, position Anavex ideally for European markets.

Bottom-line Up Front (BLUF): On 25 Oct, the results of a preventative rat study were fully reported. Results are exciting and do foreshadow multiple points investors and industry are likely to see in the forthcoming full Alzheimer's 2b/3 study paper. As expected, Anavex 3-71 was able to effectively prevent cognitive decline and preserve certain social behaviors of advanced disease-stage rats - even after a lengthy (for rats) month-long washout period. In addition, a slew of biomarkers to include amyloid, inflammation, and cholinergic receptors were assayed to confirm results. Certain percentage estimates will be provided - those colored in red are based on my visual interpretation of a chart and should be seen as an approximate value, not fact.

Study Design:

7-month-old McGill-APP rats were pooled to 7-month-old wild-type (WT, normal) rats and assigned to 4x separate cohorts: 

• Placebo-WT

• Dosed-WT

• Placebo-mutation

• Dosed-mutation

The rats began dosing regimen at 7-months and continued dosing at 10 μg/kg for a 7-month period. At the end of the 7 months, and now at 14-months of age, the rats underwent clinical testing for 2 weeks before having their brains collected (RIP). 

Clinical Tests:

• Open Field: Used to test general activity and total locomotor skills.

• New Object Location & Novel Object Recognition: One of the subtests evaluates spatial learning, which relies heavily on hippocampal activity. The other evaluates non-spatial learning of object identity, which relies on multiple brain regions.

• Social Preference: Tests social engagement behaviors.

• Morris Water Maze: Tests spatial learning and memory by use of hidden platforms in a maze.

Summary of Clinical Test Results:

• Open Field: No differences between any groups were noted, indicating motor skills were unaffected in all groups.

• New Object Location & Novel Object Recognition: Placebo-mutation rats saw a substantial worsening (37.5%) over placebo-WT. In contrast, dosed-mutation rats saw no worsening, and in fact, performed slightly better than placebo-WT, especially in male rats.

• Social Preference: Placebo-mutation rats once again saw a substantial worsening (16.6%) over placebo-WT. In contrast, dosed-mutation rats saw a significant improvement over baseline (placebo-WT) of 18.8%. 

• Morris Water Maze: This test was over a period of 5 days. At day 3, placebo-mutation rats saw an impressive 38% worsening over placebo-WT. Meanwhile, dosed-mutation rats saw a comparable performance to baseline (placebo-WT). At day 5, there was an extremely noticeable improvement in dosed-WT rats. To put this miraculous improvement into perspective, the dosed-WT rats appeared to complete the maze 45% faster than the placebo-WT & mutation-dosed groups, and approximately 56% faster than the placebo-mutation group.

Assessment of Clinical Test Results: Even after a 1 month washout period, Anavex 3-71 was able to prevent cognitive decline in McGill-APP mutation rats. Efficacious and significant results were garnered in working memory, spatial navigation, and reference memory tests. In addition, the drug had profound affect on the decline in social interaction. Social engagement has a protective effect against age-related cognitive decline, and social withdrawal is one of the earliest signs in Alzheimer's progression. Importantly, these combined cognitive tests show that Anavex 3-71 has marked improvement on multiple brain regions and region interaction. Finally, it is my opinion that some of the results seen lend to the possibility that completely healthy people could see improvement over baseline for both spatial learning and working memory, as well as possible minor social/behavioral benefits.

Biomarker Assays:

• Amyloid-beta 42, 40, & 38: Classic amyloid biomarkers. The 42/40 ratio in particular is of great importance and has been decreased (improved) significantly in the Blarcamesine Alzheimer's 2b/3 study.

• Astrocytes & Microglia: Immune cell response. Typically overabundant in Alzheimer's patients (as well as various other disease and disorders including depression and schizophrenia). Produce cytokines which provide varied inflammatory response.

• Cytokine IL-1β : Pro-inflammatory marker. Studied to a good degree and known to be associated with Alzheimer's disease.

• Cytokine IL-6: Pro-inflammatory marker. Studied to a good degree and known to be associated with Alzheimer's disease. 

• Cytokine IL-5: Unclear role, associated with either promoting neurotrophic activities in the brain or a mitogenic factor supporting microglia growth.

• Cytokine IL-10: Anti-inflammatory marker.

• Cytokine IL-4: Anti-inflammatory marker.

• Cytokine IL-13: Anti-inflammatory marker. 

• TNFα: Dual-role; pro-inflammatory but plays a role in amyloid clearance.

• IFN-γ: Dual-role; pro-inflammatory but decreases Aβ deposits and infiltration of peripheral monocytes.

• proBDNF & mBDNF: BDNF begins as proBDNF and then turns into the useful mBDNF. Conversion of proBDNF is stifled in Alzheimer's disease patients and McGill-APP mutation rats.

• Cholinergic & Glutamatergic Terminals: Neurotransmitter specific terminals to carry muscarinic & glutamatergic transmissions in the neuron. Necessary for normal brain function.

A good source to find more information on some of these cytokines can be found here.

Summary of Biomarker Assay Results:

• Amyloid-beta 42, 40, & 38: In placebo-mutation rats, 90% had abundant amyloid plaque in the hippocampus and 50% had abundant amyloid plaque in the cortex. In comparison, in dosed-mutation rats, only 33% had abundant amyloid plaque in the hippocampus, and 8% had amyloid plaque in the cortex. Again, this was after a 1 month washout period. Treated rats also saw less 'mature' amyloid plaques over placebo rats. And lastly, dosed rats saw significantly decreased amyloid beta 42 and 40, as well as a significantly lower 42/40 ratio than placebo rats. Overall density of plaques between placebo and dosed mutation rats was staggeringly different; in the hippocampus, dosed rats saw amyloid density reduced by 76% compared to placebo and 73% similarly in the cortex. 

• Astrocytes & Microglia: Dosed rats saw reduced recruitment of microglia and astrocytes toward amyloid-affected neurons in the hippocampus. The overall shape of their structure was also significantly altered, with changes to area (volume), appendage quantity, and appendage length.

• Cytokine IL-1β : Pro-inflammatory marker was significantly decreased in dosed rats. Dosed-mutation rats were completely rescued to normal levels. In fact, dosed-WT rats also saw lower levels over baseline.

• Cytokine IL-6: Pro-inflammatory marker was significantly decreased in dosed rats. Dosed-mutation rats were completely rescued to normal levels. In fact, once again, dosed-WT rats also saw lower levels over baseline.

• Cytokine IL-5: IL-5 was significantly increased in dosed-mutation rats. This was probably the largest response of all of the cytokines and probably warrants further investigation. IL-5 was increased by approximately 100% over baseline.

• Cytokine IL-10: Anti-inflammatory marker was significantly increased in dosed rats. Both dosed-mutation and dosed-WT rats appeared to benefit.

• Cytokine IL-4: Anti-inflammatory marker was significantly increased in dosed rats. Both dosed-mutation and dosed-WT rats appeared to benefit; dosed-mutation rats by approximately 90% over baseline. 

• Cytokine IL-13: No changes observed.

• TNFα: Dosed-mutation rats saw a significant increase over baseline. 

• IFN-γ: Dosed-mutation rats saw a significant increase over baseline.

• proBDNF & mBDNF: Comparing placebo-WT and placebo-mutation, the latter saw far less proBDNF converted to mBDNF. This failure of conversion was completely rescued in dosed-mutation rats.

• Cholinergic & Glutamatergic Terminals: Cholinergic terminals were reduced in quantity for placebo-mutation rats compared to placebo-WT, whereas dosed-mutation quantity was unchanged. Glutamatergic terminals was unchanged across the board. 

Journal Author's Key Points: There are a number of key takeaways outlined by the authors within this paper:

1. 3-71 prevents cognitive decline in McGill-APP rats

2. 3-71 prevents extracellular Aβ deposition in McGill-APP rats

3. 3-71 reduces the recruitment of microglia and astrocytes toward neurons in the hippocampus

4. 3-71 rescues microglia morphological changes and the profile of inflammatory mediators

5. 3-71 prevented the increase in the ratio proBDNF/mBDNF

6. Selective M1 with no binding bleedover to M2-M5 combined with ultra low dosing likely reduces most peripheral side effects that are sometimes associated with cholinergic drugs

7. 3-71 prevents cognitive decline, reduces amyloid pathology and neuroinflammation, and increases BDNF availability

8. 3-71 can prevent neuroinflammation, not only by reducing the recruitment of microglia but also of astrocytes. This effect could be directly mediated by M1, as astrocytes have M1 muscarinic receptors. In addition, this anti-inflammatory effect may be explained by the activation of Sig-1Rs

9. Results were dramatic, even in rats that should feature later stage progression

Additional Key Points & Assumptions by SOTC:

1. The author spends substantial time on M1 activation. This is often publicly overlooked by Anavex, although I am certain they are aware that muscarinic and secondary bindings play a leading role in their S1R pipeline's efficacy.

2. 3-71 did not prevent cognitive impairment by action of increasing cholinergic synapses, as the number of synapses between treated rat and non-treated rat remained the same. Significantly it has been found that S1R antiamnesic properties likely take place even in animals with complete cholinergic depletion. So, human patients who have degraded/eroded away all/most of their cholinergic sites are unlikely to see any major benefit from the M1 (or M2-M4) part of the drug. However, they do still get muted benefit via S1R. This confirms my thoughts in 2021 that the rest of the drugs binding affinities are equally as important as S1R - even though the company mostly only ever talk about S1R. This also means there is another variable that must be assessed in patients in order to see if they will be super-responders (patients still have abundant cholinergic synapses), responders (patients have some cholinergic synapses), or poor response (patients with nearly depleted cholinergic synapse). While S1R can act independent of muscarinic action, the combined effect is necessary for full response - this was alluded to a couple of times by Dr. Missling and the CSO over the last year but never described in any sort of detail.

3. Fascinating to me, it appears as though completely healthy rats saw benefit over baseline in a slew of performance and biomarker tests. 

Final Thoughts: This paper continues to provide verification for both Blarcamesine and 3-71 as probable disease-modifying compounds by virtue of dual muscarinic-S1R modulators and their potential as prophylactic preventative medicines. Additionally, the paper serves to confirm my thoughts on secondary binding affinities of both Blarcamesine and 3-71 having direct and meaningful impact on the drug's efficacy in mostly overlapping, yet distinct indications. 3-71 benefits over Blarcamesine with extremely low dosing with a somewhat greater safety profile (not that Blarcamesine's is poor), and hyper-focus on mood/behavior disorder pathways like depression and schizophrenia. Blarcamesine on the other hand has good cognitive benefit, decent tolerability, and has notable effect on movement disorders and seizures. Blarcamesine may also see greater effect on the cardiovascular system although this remains to be seen. Moving forward, it is likely the full Blarcamesine Alzheimer's 2b/3 readout (which may include 48 week OLE data) is likely going to mirror portions of this rat study. As we know already, Blarcamesine significantly decreased brain atrophy, significantly improved amyloid 42/40 levels, and provided marked improvement over baseline in both cognitive and activities of daily living scores in a likely-sizable sub-group of patients. Upon final release, I expect the overall trial results to look something similar to the phase 2 PDD patients on page 15 of this presentation. I remain excited for Anavex's full Alzheimer's 2b/3 data readout and continue to impress upon the significance of what progress Anavex is making in the CNS precision medicine space. As described, the 2b/3 landmark study is likely to garner data identifying a clear new SOC in most patients.

Bottom-line Up Front (BLUF): On 12 Sep 2023 it was announced that Dr. Marwan Sabbagh, a behavioral neurologist in the Alzheimer's and Memory Disorders Program at Barrow Neurological Institute joined the Anavex team as Chairman of the Scientific Advisory Board. He is the Vice Chair of Research in the Institutes Department of Neurology. A look at Dr. Sabbagh's recent peer-reviewed journal work points to an exceptional repertoire of skills useful to Anavex and their precision medicine approach, with keen focus on differentiating various types of CNS disorders via clinical assay and biomarkers, and how co-morbidities play into severity, progression, and treatment. Here are some of his latest works and commentary:

• ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium

• Type 2 Diabetes Comorbidity and Cognitive Decline in Patients with Alzheimer's Disease

• Listening session with the US Food and Drug Administration, Lewy Body Dementia Association, and an expert panel

• Integration of canonical biomarkers in the diagnosis of preclinical Alzheimer disease

• Effect of ApoE isoforms on mitochondria in Alzheimer disease

• APOE ε4/ε4 homozygotes with early Alzheimer's disease show accelerated hippocampal atrophy and cortical thinning that correlates with cognitive decline

Independent Interview with Deborah Kan and Dr. Sabbagh on CNS Disorders, FTD, Biomarkers, and Mis-diagnosis [Link]

As mentioned, Dr. Sabbagh recently joined Anavex as inaugural Head of the Scientific Advisory Board. After watching three hours of his lectures and reading through about 15 articles co-written by Dr. Sabbagh, it is clear that Anavex found an absolute honcho in the biomarker and diagnostic space. Listening to him speak, it is certain that he has garnered expertise rarely seen in the field, and has access to vast clinical resources including databases, most clinical assays, (blood, MRI, CSF, PET) and laboratories that are not normally at the immediate disposal to most doctors/researchers. Beyond this, Dr. Sabbagh carries himself with utmost professionalism, pride, and ambitious gusto. His intelligence and awareness in ongoing CNS research is obvious and definitely has my attention.

During the interview linked above, he points out that only 1/3 of CNS patients have a pure disease. Only 1/3 of Alzheimer’s patients have plaques and tangles and nothing else. The other 2/3 of patients have a-synuclein or vascular disease, immune disorder and otherwise. Most CNS disorders converge in some manner with variation in disease progression and severity dependent on the combination and genetic makeup. This is an important metric and underlies significant inabilities for primary care providers to accurately and consistently diagnosis dementias. Further evidence of this can be found in this article on Lewy Bodies, which was extremally insightful. Within, it is stated that up to 11.1% of patients showing amyloid and tau pathologies also have Lewy Bodies. Conversely, 22.4% of patients had no amyloid, tau, or Lewy Bodies at all (Fig 1 in article). This is important because patients with Alzheimer's disease and Lewy Bodies consistently scored lower on clinical performance tests compared to dementia patients without Lewy Bodies, and patients without both Alzheimer's pathologies and Lewy Bodies scored higher on average (Fig 2 in article). Additionally, the rate of cognitive decline was significantly altered in Alzheimer's patients with Lewy Bodies (Fig 3 in article), and it's a big difference. Combination of co-morbidities and disease pathologies matter to a clinical trial outcome and therapeutic effect of a drug candidate. 

Anavex is looking to be the leader in CNS precision medicine, we know this.

16 Mar 2021 PR: ‘“This paper highlights the relevance of the analyses of gene expression data in precision medicine to drug development that may predict increased chances of success of Alzheimer’s disease treatments, which is especially relevant in late-stage clinical studies like the ongoing ANAVEX®2-73 Phase 2b/3 clinical Alzheimer's disease study,’ said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.” 

Furthermore, as stated in the AAIC 22 PR from 31 Jul 2022, Anavex was one of the first to run a genomic analysis of a now-definitively disease-modifying compound in Alzheimer’s disease and Parkinson’s disease dementia. Dr. Missling, Ariana Pharma, and staff found a myriad of genes that were improved upon taking the drug. These genes were primarily related to protein clearing, mitochondrial health, and apoptosis (cell death); although, there were many other genes identified with implications in vascular health, neuronal networking, mRNA stability, amyloid processing, and many more. “These findings will facilitate contextualization of upcoming readout of ANAVEX®2-73 Phase 2b/3 Alzheimer’s disease clinical trial.”

So how does this tie into Dr. Sabbagh? After reviewing his work, it is easy to conclude that Anavex chose an expert in the diagnostics and biomarker field to come in and help contextualize disease combination, co-morbidities, and genomic sequencing for their Alzheimer's trial. Being able to fully distinguish responders to non-responders is next generation precision medicine that has not been fully possible up until the last few years. As blood diagnostics, emerging genomic research, and understanding of disease effect become more available, other companies will be able to follow the path Anavex currently trailblazes in CNS precision medicine. 

Assessment: Post-trial, Anavex needed an in-house statistician, and fast. A few months later, it was announced that the company hired the FDA's former Lead Neurology Statistician as Vice President, Head of Biostatistics. Dr. Kun Jin was an impressive hire to be sure. Waiting until after the trial ended before hiring a statistician was certainly an oversight; but what the company lacks in timeliness, they absolutely make up in quality. The hiring of Dr. Sabbagh is a very similar situation. Anavex once again brought in an extremely qualified specialist to fit a need the company has to excel their lead compound through approval and into patient hands. In this case, it is almost certain that Dr. Sabbagh was brought in specifically to help contextualize patient pathologies and genomics to therapeutic effect. Having met and spoke with Dr. Sabbagh in-person at AAIC 23, I can say with utmost confidence that his expert guidance in this endeavor will be some of the best in the industry. It is likely that Anavex's full scientific release will include detailed precision medicine unseen before in the CNS-space. If you'd like to listen to more of Dr. Sabbagh, here is another interview that I believe shows off the kind of confidence and expertise he brings to Anavex.

Assessment: To be straightforward, it is highly unlikely that ADCS-ADL failed. Even if the endpoint did fail to reach statistical significance in the whole dosed population, it almost certainly succeeded in the higher dose cohort. Anavex has substantial work to do (possibly well underway) with contextualizing their data considering major factors likely APOE status, S1R status, disease severity, sex [not covered but likely important], dosing, genomics, and comorbidities. While I empathize with the investment community demanding further data with expedited timelines, it is important to remember that the company is small with a large dataset and even larger vision for precision medicine approaches (shoutout to Kun Jin - Biostatistics Head). SOTC has full faith that the final data release will reveal efficacy unprecedented in the late-stage Alzheimer's space, as evidenced by a met high-bar threshold for responder criteria, decreased brain shrinkage/atrophy, and classical Alzheimer's biomarker improvement. Finally, it is our belief based on evidence procured earlier in the year that the company is under late-stage negotiations with a late-stage partner. We believe the following are the most likely in no particular order: Sanofi, Roche, Pfizer. 

As a final note, I will be introducing another sub-page to the SOTC website that will be periodically updated with key scientific discoveries related to Alzheimer's, Parkinson's, Rett Syndrome, Angelman Syndrome, Fragile-X, muscarinic receptors, Sigma-1 receptors, and general health. These will be links to emerging science with very short synopsis. I may also be open to 1-on-1 video conferences with individual investors in the near future as time allows and demand persists. 

Bottom-line Up Front (BLUF): Short, sweet, and to the point. Anavex is continuing towards approval in Alzheimer's and Rett syndrome - both indications in very-late stage development. While I hope for a long and prosperous road with Anavex, I can't get this feeling out of my mind that the company will be acquired. One day. Perhaps not even that far off. Since the pandemic, 2023 is quickly blowing past M&A spending from 2020, 2021, and 2022. The Federal Trade Commission (FTC) has been hard on larger acquisitions of late, but have turned a blind eye to acquisitions of small, promising companies. In this manner, smaller companies like Anavex, companies on the cusp of explosive revenues, fare far better than companies with pre-existing/established blockbusters. Cantor Fitzgerald themselves recently weighed in on this, stating that they are curious to see if this fact will factor into shopping considerations of big pharma towards later-stage clinical or early-commercialization companies to reduce FTC risk. Acquisition or not, Anavex is certainly on the cusp of revenue. I have, as of today, created various strategic buy orders to account for this.

• Good to hear key opinion leaders (KOL) believe Anavex’s 2b/3 Alzheimer’s extension could be the ‘potential accelerated approval confirmatory trial’. I have thought this myself and believe I prepped audiences well with this thought in the AAIC wrap up (mentioning 48 week completion). I have to think these KOL probably include George Perry, and Jeffrey Cummings. I still wonder if Dr. Cummings was referring to Anavex at AAIC when he mentioned a company that had a large amount of impressive data that still needs refining (see in AAIC notes). No further information on that ATT, but the space isn’t exactly large when it comes to completed phase 3 (2b/3) trials so…

• I figured there was more to Partex AI which is why I've recently initiated contact with IR on the subject. I think Partex is going to make it very, VERY easy for patients to determine which medication someone should take (based on genes, or co-morbidity precluding them from taking MABs, such as cardiovascular/seizures). Rett will be an excellent testbed here due to lack of competition and clear benefit to Blarcamesine over Trofinetide (DAYBUE).

• I do empathize with irritation over lack of Parkinson's trial initiation and the rest of the pipeline. I have to think it’s been purposefully slowed to include in partnership discussions. By partnering before initiation, Anavex could make a much larger, greater legitimacy trial which is what investors and regulators want. A robust phase 2 trial with amazing results really could propel straight to approval. I tend to think Parkinson's Disease is our strongest indication. 

• Nice to hear about unsolicited interest in Rett. Don’t think it’ll matter in western nations as we are more likely to go alone. Licensing and partnership in Rett Syndrome seems much more plausible in Asia.

Bottom-line Up Front (BLUF): As we wait for full Alzheimer's 2b/3 data, this presentation was an excellent reminder to where the company is at now, and near-term commercialization prospects. Considering probability of Rett approval and subsequent revenue-generation, we assess chances of significant stock value increases in the next 8-12 months to be effectively certain, even absent of Alzheimer's results.

Presentation Key-Items:

• 3:10 min: S1R as a Target

  • • S1R is a relatively new therapeutic intervention target. There are other drugs approved which stimulate S1R activity, but they aren’t pure/effective S1R agonists. Other S1R activators may not be able to show an in-vivo [in animal] engagement needed for true therapy. However, safety profiles of drugs that partially modulate S1R lends further credence to the fact that S1R is a safe target. [Comment: this goes back to molecular docking as SOTC has mentioned on several occasions now]

• 5:15 min: Regulators

  • • Drugs approved for Alzheimer’s have all recently used the accelerated approval pathway. Key criteria for approval are based on a biomarker response to pathology. With this in mind, we are poised similarly (as discussed in the latest financial call). If we can convince regulators with our biomarker data, we are in good shape for approval.

• 6:30 min: Patients

  • • Inclusion criteria & enrollment was stringent in the Lecanemab CLARITY trial. 80% of patients were excluded during screening. Anavex did not have even close to such a stringent requirement (maybe 10% excluded). Exclusion was very, very low. Anavex data is representative of the true Alzheimer’s population without limitations like in the Lecanemab case.

• 8:30 min: Safety

  • • mAb require lengthy administration (hours) and PET assessment every three weeks. PET assessments do often include minor irritations to the skin, are extremely expensive, and there are a lack of PET centers anywhere not in a major city. Additionally, Anavex has no ARIA issues (brain bleeding or swelling) like mAb. Blarcamesine features simple pill administration – at bedtime for example. No need to leave your house. [Comment: it was interesting to hear Dr. Missling once again mention nighttime dosing. As we know, this was Anavex’s stated remedy for a subset of patients experiencing dizziness & confusion in the Alzheimer’s 2b/3 trial]

• 10:10 min: Adjunctive (Combination) Therapy

  • • No competition with antibodies from a molecular docking perspective. The drugs could be combined and work synergistically, hypothetically.

• 11:15 min: Alzheimer’s vs. Parkinson’s

  • • S1R does not discriminate based on pathology (initial cause of the disease). In Parkinson’s genes, we found active arm (dosed patient) genes were up-regulated again. Functionality was improved on a molecular level. In the OLE, we proved that continual dosing is important to response and that by halting intervention, patients worsen but can reverse for the better again by resuming treatment – beyond simple endpoint measures, this was also true at the gene level [new information]. We are now about to conduct the imaging (target engagement) study and Parkinson’s disease pivotal trial which are both still being funded by MJFF.

• 13:20 min: When to Treat PD

  • • Advanced patients responded well in the Parkinson’s disease trial, but we do know that the drug is likely better as a preventative or early-stage treatment. All stages are good intervention, which is similar in patients with Alzheimer’s disease.

• 16:10 min: Rett

  • • Trofinetide was 10 years ahead of us, but we have already caught up. The most overt difference is Blarcamesine’s safety profile, which is superior to Trofinetide. We are looking forward to EXCELLENCE read and then approval.

• 16:50 min: Rett Data to Date

  • • There are two successful Rett studies behind us, both in the more difficult patient-set (adults). Now we wait for EXCELLENCE data which features patients from 5-17 years of age. We expect data clean-up and then lock shortly. Data will be available in the second half of this year. Considering orphan drug designation, pediatric voucher eligibility, fast track designation, and three placebo control studies in a rare disease, we believe this will be a very strong package. Comment by Wainwright Moderator: Pediatric voucher could be garnered which would sell for $80-100mil if desired by the company according to recent historical analysis.

• 20:40 Min: Cash Flow

  • • $153 mil in the bank. We have a 4-year runway currently, and if we sold the voucher, we could have about 250 mil in cash, which would preclude our need to dilute further and allow us to be self-sufficient in marketing Rett.

• 22:40 min: Marketing

  • • Alzheimer’s and Parkinson’s require a larger sales force, so we do look to partnering there. Separately, we believe our reputation in the Rett Syndrome community allows us to market alone. We would look to market the Rett Syndrome indication at ~$500,000 annually, which is about the going rate for Trofinetide. Considering our greater safety profile, we may market for a bit more than $500,000.

• 25:10 min: Additional Note

  • • Gathering commercialization expertise by looking for a Chief Marketing Officer and Chief Commercial Officer positions.

Assessment: Dr. Missling's presentation today was successful in simply detailing distinction between Blarcamesine and other S1R agonists. Beyond muscarinic, sodium channel, and NMDAR, Blarcamesine likely features an extremely effective docking mechanism - enhancing S1R potency over other approved drugs featuring S1R activation. It is clear to us at SOTC Analytics that Anavex is extremely confident in garnering Rett approval dependent on EXCELLENCE results. Indeed, the company is going as far as to hire for Chief Marketing Officer and Chief Commercial Officer positions. We place Anavex's chances of success in this indication at 100%, which would guarantee dramatic upside after Blarcamesine hits the market. Finally, we want to impress upon Anavex's inclusivity during Alzheimer's patient screening. Dr. Missling stated perfectly that their trial represented a true Alzheimer's population. Considering what we know of the 2b/3 efficacy, its amazing Anavex was able to perform as well as they did with such a diverse patient-set. This goes to Dr. Missling's point - and probably one of the most exciting aspects of the drug - which is the drug's ability to perform agnostic to pathology and agnostic to indication. A Spirit of the Coast directed video on Blarcamesine binding affinities can be found below.

Bottom-line Up Front (BLUF): Overall I was impressed by Dr. Missling's breadth of material and exhaustive summary of the companies current stage. Within this report you will find presentation of key-items including gender-specific disease onset, expectations for AD 2b/3 data, drug-to-indication cost methodology, and more. 

Presentation Key-Items:

• 3:05 min: Women that hit early menopause have reduced estrogen and have higher risk of Alzheimer's disease. One of the sigma-1 agonists natural to the body is estrogen. Dr. Missling concludes that due to unnaturally low estrogen levels, women are at heightened risk of Alzheimer's as their ability to create compensatory S1R diminishes as well.

  • • We have previously covered to great extend XLID premutation genes and their impact on men and women. In women, Fragile-X premutation genes result in early menopause. Separately, women begin to rapidly lose the ability to retain calcium at menopause. Perhaps the most important component for nutrient funneling in neurons, compounding calcium loss of ~2% annually surely plays a key role in heightened female neurodegeneration. As it is understood, S1R modulates calcium and provides calcium homeostasis. Herein, we see the criticality of S1R in female-specific cognition, and we here at SOTC assess that Anavex's persistent mention of the subject likely insists that the company will present this data as an additional topic for discussion in their regulatory package for Alzheimer's disease. Note: Some other criteria that lead to early menopause include extremely early child-birth and having multiple (5+) children.

• 3:45 min: Dr. Missling notes that S1R-related research and understanding is at all-time-highs.

• 6:45 min: Full AD 2b/3 data is still expected this year. This will include MRI, biomarkers, blood data, dose-dependent results of ALL measures including cognition, function, quality of life.

• 7:20 min: PD trial update is expected shortly. The trial was also bumped up to a full phase 3 (not phase 2b/3) according to the pipeline chart showed later.

• 8:20 min: Dr. Missling alludes to the fact that EXCELLENCE data will/should be extremely good considering the age of the patients. Later he mentions data is expected 2H 2023.

• 8:55 min: The company still expects to begin a Fragile-X trial, Schizophrenia trial, and the 'undisclosed' rare disease trial. He does not go into exact timeframes here.

  • • When describing the forthcoming Fragile-X trial, Dr. Missling mentions the planned use of S1R as a biomarker as well as an un-named biomarker previously improved in Blarcamesine/Fragile-X preclinical trials. He is certainly referring to this paper, and is likely talking about a BDNF-related biomarker, probably Phosphorylated GSK-3β (pGSK-3β) or Ras-related C3 botulinum toxin substrate 1 (Rac1).

• 8:55 min: The company still expects to begin a Fragile-X trial, Schizophrenia trial, and the 'undisclosed' rare disease trial. He does not go into exact timeframes here. Other publications regarding the Blarcamesine & 3-71 compounds are also expected this year.

• 11:15 min: Dr. Missling discusses potential to expand even further into more indications to include restorative and preventative trials.

• 12:30 min: Dr. Missling mentions that we should expect to see an update on Anavex-1066 very soon, which is interesting as the drug has sat on the sidelines for a long time.

• 12:55 min: Reiterated again, AD 2b/3 data is expected this year. Current annual cost of dementia is $1 trillion and expected to double in the next 7 years. Of this cost, Anavex is targeting $232.2B (current 2023).

• 13:35 min: Very strong improvements in PDD patients, especially in MDS-UPDRS 1-4 (motor & behavioral). Dr. Missling mentions here that another trial is still expected in PDD, but PD will go first. SOTC Analytics assesses the PDD trial may be awaiting special considerations by regulators (such as BTD) and the company is waiting to see if they are granted those considerations. In the event the company is denied special consideration, shareholders are unlikely to hear about it and a trial will continue forth as planned.

• 15:15 min: Pressing towards commercialization is the current focus for both Rett syndrome and Alzheimer's disease.

• 16:30 min: Dr. Missling goes over a key detail regarding the AD 2b/3 trial design - which admittedly had slipped our mind. Anavex has included a pre-specified S1R WT vs. mutation-gene sub analysis which will allow for the exclusion of all mutations in a final analysis. This is obviously extremely important as the drug works best with S1R WT. We look forward to see full dose-dependent, all cohort result (including S1R WT and mutation), as well as a full dose-dependent, all cohort sub analysis excluding mutations to see breadth of efficacy in all patient populations.

• 16:55 min: "Structural and functional MRI" is "about to be released". This will identify disease modification by measuring atrophy (brain shrinking) - especially in the hippocampus. 

• 17:42 min: Dr. Missling goes over use of odds ratio from the preliminary TLD. He goes on to say that these culminative results (ADAS-COG [cognition] and ADCS-ADL [Activities of Daily Living]) are unprecedented and have never been reached by any other drug-maker in the Alzheimer's space.

• 18:30 min: Dr. Missling goes over CDR-SB comparison to Lecanemab, stating that Blarcamesine is likely vastly more potent with better safety profile and much easier administration (oral).

• 21:20 min: Anavex has very good patent protection, including method of use, composition of matter, the drug itself, combinations, and crystallization of the drug. This ultimately provides protection to 2039.

• 22:00 min: Dr. Missling explains how cost of the drug can be separated by indication depending on the formulation of the drug. For example, rare diseases will use oral liquid formulation whereas the classic neurodegeneration disorders will use oral solid (pill) form. This will allow patients to have the most suitable administration (rare disease children need liquid), and maintain cost differentiation (more money for rare disease and less for large-population CNS) - all the while being more cost effective than IV drugs.

• 23:40 min: The company maintains $143.6M in cash.

• 26:55 min: Dr. Missling mentions how Anavex is transforming from a research company to a commercial-stage company. He goes on to hit home the companies readiness to pursue this objective globally.

• Q: What is the fields understanding as to which indications S1R is most important? How is Anavex's approach different to previous work in the space?

• A: S1R activation is a full-body aid, thus S1R can aid most - if not all - indications dramatically. This aid is more effective when intervention starts earlier during disease course. Note: ALS is almost certainly a future indication. In response to the second portion of the question, most drug-makers target downstream targets whereas S1R is very upstream (as are muscarinic receptors). An MIT paper came out last week where researchers reversed Alzheimer's disease by blocking CDK5. We know from previous work (Anavex's genomic paper from 2022) that Blarcamesine specifically downregulates overactive CDK5. So S1R can manage CDK5 and other protein dysfunction simultaneously - thus further elucidation into therapeutic upstream value.

• Q: Traditional approval may come for Lecambi later this year, what are your thoughts on combining Lecambi and Blarcamesine? What are the next steps in the program?

• A: We do believe that Lecambi and Blarcamesine are synergistic because they do not interfere with each other. Additionally, small molecules are trending due to the need for simple oral administration. We look forward to potential with combinations there. As far as next steps go, we are expecting full comprehensive results of the entire AD 2b/3 trial, which will be presented via paper or otherwise. After of course, we look forward to speaking with the FDA, EMA, TGA, and other global regulators. We believe our biomarker suite is compelling for approval. 

My Updated Timeline Projections for 2023

These are my personal projections and trading should not be conducted based on these timelines. Changes are in blue.

• Partnership: I expect this to be nearing completion, if not completed by end of May. Looking forward to a partner that can assist with manufacturing, promoting, and distributing Blarcamesine worldwide once approved for Alzheimer's specifically (which of course I expect based on this 2b/3 with potential for a phase 4).

• Full AD Data: I expect this to be released by April and no later than June.

  • • At this point, AD data is more likely in May or June but cannot rule out potential for end-of-April.

• Parkinson's Disease Dementia OLE Data: I expect this to be released very close to or in conjunction with the full AD data, so in April to June. I have low confidence in this particular timeline however as I believe the data is probably available at this time, so release may be quite soon. 

  • • Preliminary outcome: met.

• Submissions for Alzheimer's Approval to Begin: I expect submissions to the FDA, EMA, and TGA (possibly to include the MHRA [UK] and HPFB [Canada]) by July and no later than August.

• Rett EXCELLENCE Data: I expect data to be complete by June and no later than end of July. It is possible the company may wait until a relevant scientific event to release however.

  • • Considering EXCELLENCE over-enrollment came after my initial projections, it is highly likely data for EXCELLENCE will come between August and December 2023. This projection is accurately based on trial length and the two previous Rett trial timelines. Exact timing is impossible to refine at this time due to large variance between end-of-trial for the first two Rett trials and their data readouts.

• Submissions for Rett Syndrome Approval in Pediatric & Adults to Begin: I expect submissions to the FDA, EMA, and TGA by September and no later than November. I have a feeling Anavex may have interest in attempting to have this indication approved in Japan as well based on previous comments by Dr. Missling.

  • • This will likely push into first half of 2024.

• Fragile X, Schizophrenia, PD (to include imaging trial), PDD, and Undisclosed Indication Trial Commencement: I have no projections for timelines on these trials commencing. I do expect at least 2-3 new trials to begin by the end of 2023. 

Assessment: A clear standout from today's presentation was Dr. Missling's clear proclamation regarding the AD 2b/3s unprecedented cognitive & activities of daily living results. Additionally, we found specific mention of multiple biomarkers (in addition to S1R) to be extremely interesting. Direct mention of CDK5 is especially exciting, as we had previously featured the protein in one of our videos  (starting at 8:40 min). Furthermore, Dr. Missling hinted multiple times to the closeness of full AD data release. Based on his exact comments, we assess there will be a PR with more AD data (partial) before a peer-review publication as the company wants to begin conversations with regulators and possibly wishes to circumvent some of the bureaucratic time constraints that would come with waiting for a peer-reviewed publication. We also assess that Anavex is keenly interested in presenting gender-specific addendum to their regulatory package. This is a unique approach as women's health is commonly neglected in CNS study.

 Other key takeaways include ALS as a likely indication, possible adjunctive therapy testing with Lecambi (certainly little granularity here), dusting off Anavex-1066, and explanation as to how different pricing can occur between rare disorders and common large-population CNS disorders. Dr. Missling hit home numerous times the companies emergence as a commercial-stage company. With full Alzheimer's data and Rett trial suite data expected shortly (EOY), it is likely discussions with regulators will begin towards global commercialization for at least Alzheimer's by the end of 2023. Considering Dr. Missling's commentary on biomarker use, efficacy, administration, and safety, the company clearly has high expectation for subsequent approval.

Bottom-line Up Front (BLUF): Despite COVID-19 disruptions to OLE enrollment, a small patient cohort was able to show clinical benefit in all measured efficacy endpoints at 48 weeks following a substantial (41 week average) unintended washout period being referred to as a 'drug holiday'. The drug holiday caused patients to regress from the therapeutic progress made by the end of the primary trial period (14 weeks). 

COVID-19 in Spain and Trial Relevance: Spain was one of the hardest hit European nations from 2020 - 2021 by COVID-19. Not only did the country have the highest incidence (only surpassed by Russia), Spain also had one of the most under-budgeted healthcare infrastructures - 5.9% lower than European standard. The Anavex PDD primary trial coincided with a State of Emergency announcement on 1 Oct 2020 which ultimately precluded non-essential medical care (Figure 1).

COVID-19 in Spain and Trial Relevance Continued: The preponderance of Anavex's Spanish clinical sites were located in high-infection areas, especially those within the 'Madrid pocket'. This surely had a high impact on patient ability to continue the OLE trial, even after the State of Emergency ended, as the nation exceeded hospital capacities in 80% of responsive medical care facilities for an extended period of time (Figure 2.).

COVID-19 in Spain and Trial Relevance Summary: Due to prolific COVID-19 infection and overwhelmed (and underfunded) healthcare facilities, Anavex PDD patients had little opportunity to continue the OLE. This inaccessibility likely continued past the end of the State of Emergency on 9 May 2021 as local quarantine laws and hospitalization in high-risk zones continued through 2021. Due to COVID-19, enrollment in the OLE was extremely low (N=20 at 48 week) and efficacy in the following section should be viewed cautiously. 

PDD OLE Preliminary Data: All of Anavex's clinical outcomes saw positive trend, especially in MDS-UPDRS Part 3, RSBDQ, and CGI-I.

• MDS-UPDRS Part 3: Items within this battery include: speech, facial expression, rigidity of the neck and four extremities, finger taps, hand movements, pronation/supination, toe tapping, leg agility, arising from chair, gait, gait freezing, postural stability, posture, global spontaneity of movement, hand tremor, resting tremor amplitude, constancy of rest tremor

• MDS-UPDRS Part 2 + 3: Items here are a combination of the part 3 (above) and these new items: speech, salivation and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, hobbies and activities, bed turning, tremor, deep-seat rising, walking and balance, freezing

• MDS-UPDRS Total Score: Combines the sum of Part 1, 2, 3, and 4. Facets in the part 1 and 4 batteries not noted earlier include: cognitive impairment, hallucination and psychosis, depressed mood, apathy, dopamine dysregulation syndrome, nighttime sleep problems, daytime sleepiness, pain, urinary problems, constipation, lightheadedness, fatigue, dyskinesia, time spent in the OFF state, impact of fluctuations, complexity of motor fluctuations, painful OFF-state dystonia

• RBDSQ: A questionnaire for rapid eye movement behavior disorder which is a common ailment in PD patients. Newer data has indicated that reliability of the test is moderate and that better batteries to address this issue should be developed.

• CGI-I: Clinician-assessed battery to assess how much the patient has improved compared to the start (baseline) of treatment. This includes motor function, demeanor, perceived cognitive function, etc.

• MoCA: A rapid screening instrument for mild cognitive dysfunction.

Post-Edit Inclusion of Median Scores (Figure 4.): After conversations with board-poster 'Georgejjl', I decided to include a supplementary median data graphic. Viewers should consider mean data (Figure 3.) as more complete data as it equally weighs outliers and 'average patients'. Median data negates/reduces outlier emphasis (super responders and under-performers), so visualization of median data still plays a role as it displays a more 'average patient' response.

PDD OLE Preliminary Data Main Findings:

• MDS-UPDRS Part 3: Returned nearly entirely to the primary trial EOT score. This is extremely positive and most of the facets within Part 3 are considered 'classic' PD impairments.

• MDS-UPDRS Part 2 + 3: Scores started to improve but didn't make it even close to the primary trial EOT score. Plus, disparity between the 24 and 48 week score add a level of ambiguity to the data. Part 2 + 3 combined make up a lot of the dysfunction seen in Anavex's other indications such as Rett Syndrome, Angelman Syndrome, and Fragile X.

• MDS-UPDRS Total Score: Scores started to improve but didn't make it even close to the primary trial EOT score. Plus, disparity between the 24 and 48 week score add a level of ambiguity to the data. This is a holistic health score as it includes behavioral issues, sleep, motor, cognitive, and activities of daily living.

• RBDSQ: SOTC Analytics previously assessed that patients required longer exposure to the drug to reap greater REM benefit and this appears to be corroborated in the OLE. Despite disparity between the 24 and 48 week outcomes, the 48 week score nearly returned to the primary trial EOT score.

• CGI-I: At 48 weeks the CGI-I score actually exceeded benefit seen at the primary trial EOT. This is the only endpoint with such a result. This is exceedingly positive as CGI-I is a global score with assessment by the clinician and encompasses 'total disease severity'. 

• MoCA: While we have not validated this, Anavex claims that the decline seen in MoCA is slower than placebo or natural disease progression. This is of course beneficial. MoCA is not as good a cognitive endpoint as was CDR from the primary study, but Anavex almost certainly used MoCA for the OLE to cut time and reduce burden on the patient. 

PDD OLE Preliminary Data Bottomline: Despite a small enrollment, Anavex was able to see continued positive trends in all trial endpoints. We are most pleased with MDS-UPDRS Part 3, RSBDQ, and CGI-I. It is pleasing to see continued benefit in the MDS-UPDRS Part 2 + 3 as it foretells potential benefit in some of Anavex's rare/pediatric indications featuring movement disorders, sleep disruption, behavioral problems, and self sufficiency inabilities. Ultimately, we are pleased with the preliminary OLE data. While it is certainly not what we had hoped for in terms of size and execution, positive trends will still likely be used towards various data packages. We noticed in the 30 Mar 2023 PR the mention of the upcoming/expected PD pivotal trial. Interestingly, the company did not make mention of a pivotal trial for Parkinson's disease dementia and we are unsure if that was because of its 'implied' nature or if the company is potentially pursuing accelerated approval pathways. We have no official position on this matter but we found it interesting nonetheless.

Finally, while we are pleased with today's data outcome, we drafted an email to Anavex to express perturbation over the companies willingness to keep investors abreast of important developments in their clinical trials. Specifically, we are displeased that the company did not relay to investors earlier that most PDD patients were unable to continue in the OLE. Additionally, we felt that this data - while preliminary, was incomplete and partially unclear - and we expect better communication (especially if written) at this stage in development. 

SOTC Analytics looks forward to Anavex's next milestones, which we believe will be full AD topline data (in PR or conference) and/or partnership. As macroeconomics continue to deteriorate, we are unsure how this may influence Anavex's ability or willingness to accept certain commercialization partnerships with large (or medium-sized) pharma. Anavex has a good cash position which will prevent them from accepting a low offer - which is more likely as market conditions worsen and valuations drop. It may actually be more benefical to partner with a medium-sized pharma and form a true 'partnership'. We look forward to seeing which route Anavex will take towards this goal.

Bottom-line Up Front (BLUF): It is my belief that Dr. Grimmer was likely shown raw scores post-management CC in Dec 2022 which spurred on his acceptance as Scientific Advisor for the company and increased enthusiasm during our interview. While I want viewers to form their own opinion after watching the interview (below), my key takeaways are as follows:

1. Dr. Grimmer may lean towards an additional trial, but this is based on historic precedence from regulators, and he acknowledges that there are pathways one could take to circumvent this informal expectation - which Anavex is pursuing. He also leaned much more towards this possibility than on the Dec 2022 CC.

2. Dr. Grimmer mentions the importance of activities of daily living (in Anavex's case, assessed by ADCS-ADL), which in his opinion supersedes cognitive improvement. This is interesting to me for two reasons. First, Anavex's data across their trials have shown improvement in both cognition, and activities of daily living (amongst other facets) with the edge typically going to activities of daily living. The second thing that interests me is new data from a cross-dementia study which sought to determine trends in survivability in dementia patients. Over 45,000 patients were analyzed. Independence (function), working memory (including attention), and personal care - or will to live - consistently scored by far the greatest predictors of longevity while debilitated. 

3. Dr. Grimmer was clear that efficacy signals are present. If I had to guess, Anavex will likely be able to relate S1R mRNA and abundance to responders.

4. Touched on lightly, some patients improved in both the dosed and placebo cohorts. Described at CTAD were two large studies describing effects on MCI patients when nutrition and exercise become priorities. The FINGERS and SMARRT studies confirmed that in early-stage patients, becoming healthier with 120-150 minutes of exercise a week, cutting out smoking, and eating more healthy can actually stave off degradation with good effect. In addition, there are other factors that could account for this - including sex of the patient, education levels, and age - all of which have been found in a multitude of studies to have a marked effect of dementia outcomes. We are looking forward to the entire data-set of course.

5. Dr. Grimmer smirked while asked about Lecanemab's early approval by the FDA. He acknowledges that cost, regimen, and safety will all be burdensome, but being a clinician, he would be happy to have something to prescribe to patients as no Alzheimer's therapy has been approved in the EU for decades.

6. We discussed Anavex's trial design and expectation from the EMA. It was agreed that Anavex had desirable trial design and I believe Anavex is strongly invested in gaining approval in Europe - especially as most of the concerns by the EMA regarding Aduhelm are not present for Blarcamesine but largely remain for Lecanemab. Blarcamesine is safe, efficacious, and likely inexpensive. We believe the cost of Blarcamesine is unlikely to exceed $10,000 annually, and won't require additional MRI imaging burden required for MAB treatments.

7. I believe Anavex will utilize their PDD trial data in concert with the Alzheimer's 2b/3 (and 2a OLE) to create a more robust regulatory package. I had indication based on Dr. Grimmer's facial/body language that he agreed with this or had something on his mind but could not comment.

8. Overall, Dr. Grimmer is excited about the cross-CNS implications of Blarcamesine and that is his primary interest. This makes sense as his office primarily focuses on Alzheimer's and Frontotemporal Dementia - a disorder with no approved therapies. Dr. Grimmer is so excited by the prospect of cross-CNS potential that he recommends as many diverse trials as possible to capitalize on Blarcamesine's therapeutic value.

My Timeline Projections for 2023

As the company approaches commercialization, there are a number of key milestones I am anticipating this year. These are my personal projections and trading should not be conducted based on these timelines.

• Partnership: I expect this to be nearing completion, if not completed by May. Looking forward to a partner that can assist with manufacturing, promoting, and distributing Blarcamesine worldwide once approved for Alzheimer's specifically (which of course I expect based on this 2b/3 with potential for a phase 4).

• Full AD Data: I expect this to be released by April and no later than June.

• Parkinson's Disease Dementia OLE Data: I expect this to be released very close to or in conjunction with the full AD data, so in April to June. I have low confidence in this particular timeline however as I believe the data is probably available at this time, so release may be quite soon.

• Submissions for Alzheimer's Approval to Begin: I expect submissions to the FDA, EMA, and TGA (possibly to include the MHRA [UK] and HPFB [Canada]) by July and no later than August.

• Rett EXCELLENCE Data: I expect data to be complete by June and no later than end of July. It is possible the company may wait until a relevant scientific event to release however.

• Submissions for Rett Syndrome Approval in Pediatric & Adults to Begin: I expect submissions to the FDA, EMA, and TGA by September and no later than November. I have a feeling Anavex may have interest in attempting to have this indication approved in Japan as well based on previous comments by Dr. Missling.

• Fragile X, Schizophrenia, PD (to include imaging trial), PDD, and Undisclosed Indication Trial Commencement: I have no projections for timelines on these trials commencing. I do expect at least 2-3 new trials to begin by the end of 2023. 

Assessment: SOTC Analytics assesses 2023 as probably the most important year Anavex will have as a company. We are expecting partnerships, commercialization (or definitive notion towards beginning commercialization), and the completion of Anavex's Rett Syndrome trial suite. Considering recent influxes in investment by funds and institutional investors, as well as key developmental milestones expected, we believe the proverbial launch-pad has been set and this year likely represents the final opportunity to accumulate at discount. 

Blarcamesine Features Dramatically Improved CDR-SB Scores Over Lecanemab When Taking Into Account Disease Stage

Bottom-line Up Front (BLUF): After carefully examining documented thresholds for CDR-SB clinically meaningful improvements and decline, SOTC Analytics came to new conclusions that we believe have not been discussed by any other source to date. Previously mentioned by Anavex, Blarcamesine garnered faster response over Lecanemab. In fact, Blarcamesine attained the same response as Lecanemab but 24 weeks earlier. That is extremely interesting considering disease-stage of enrolled patients in each trial. The Lecanemab CLARITY trial featured significantly less impaired patients (25.6 MMSE) over the Blarcamesine 2b/3 (23.57 MMSE). When considering published clinically meaningful thresholds for CDR-SB, we can come to the conclusion that Blarcamesine was 125% more efficacious than Lecanemab in CDR-SB when it comes to decreasing patient proximity to clinically meaningful worsening (decline) when considering disease stage. In other words - Blarcamesine-dosed patients at the ~1 year mark demonstrated a far greater distance from what is considered to be meaningful decline than Lecanemab. Clinically meaningful status - both improvement & worsening - are thresholds established by clinicians to indicate when a treatment or disease progression begins noticeably effecting a patient for the better or worse. More information is available below. Note: Although it is known that CDR-SB is limited in its ability to consistently detect a treatment effect in clinical trials, todays findings are still extremely interesting as Anavex continues to compare efficacy against competitors whom used CDR-SB and amyloid reduction to garner approval by the FDA.