Update Compendium 2023

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.