Update Compendium 2024

Bottom-line Up Front (BLUF): The 9 May 2024 second quarter financial call was a step above in breadth and quality over most previous conference calls. There are a number of exciting developments & milestones expected over the next few months that should keep most investors interested. Within the conference call, Dr. Missling hits on operation timelines, EMA filing status, biomarkers and FDA guidance, Rett syndrome trial rework, and more. We apologize for the late report and thanks for reading.

Big Rocks:

1. Anavex 2b/3 Alzheimer's interim genomic data expected mid-year (2024)

2. Anavex 2b/3 Alzheimer's OLE data expected 2H 2024

3. Rett Syndrome expected to continue in a P3 12-week trial

4. Parkinson's 2b/3 6-month initiation expected 2H 2024

5. Fragile-X biomarker data is set to be presented from 25 - 28 July 2024

6. Anavex 3-71 Schizophrenia trial ahead of schedule, and the Part A cohort has been enrolled

Q&A Segment:

7. In the first question by Jones Research, the analyst inquires into the forthcoming FDA Early Alzheimer's Draft Guidance. Specifically, the draft guidance allows for ADL omission at the cost of "strong biomarker data". So is the plasma amyloid 42/40 improvement (p=0.05) strong enough to meet this guidance threshold? Dr. Missling does a really nice job answering this question, explaining that there was a positive amyloid effect in all patients, and that the company was surprised by the effect simply because Blarcamesine is not a monoclonal antibody with an anti-amyloid mechanism of action - it's not designed to address amyloid. However, the drug works upstream of amyloid, meaning it addresses the root issues of downstream pathological effects like amyloid even without direct confrontation. He goes on to say that whether the amyloid 42/40 data hits the undefined draft guidance threshold is currently unknown; however, the company boasts another biomarker with high statistical significance - brain preservation through dramatically reduced atrophy (p=0.0001 in whole brain). Dr. Missling then states that the brain atrophy data is really impressive because it is a direct measure of disease progression, and is an underlying cause of disease, whereas the amyloid is more of a biproduct. In all cases, the company can combine amyloid and brain preservation to come to some very strong synergistic conclusions with compounding effects. Finally, he impressed that these benefits have all been seen over standard of care, making this effect even more impressive.

8. In the second question, the Jones Research analyst asks about open label data and filing timelines. Dr. Missling states that having 96 week safety data would be favorable when approaching the FDA, and that because it is open label they could expedite this by looking at interim safety data at say 76 or 82 weeks rather than waiting for all 96 weeks. For the EMA, the Anavex team is working overtime to complete the package modules. He states that the company is well on track to file this year and will provide better update the closer they are to filing. In the 6 May 2024 Spirit of the Coast update, we left it open to slight possibility that the company was nearing completion of the EMA package. With this likely not being the case, we quickly redact our EMA approval timeline, no longer seeing a real possibility of approval in 2024. With accelerated assessment - with which we assess the company has a high chance (89%) of garnering - we believe 2nd or 3rd quarter 2025 approval looks most likely. 

9. For the third question the HC Wainwright analyst doubles down on EMA filing, when will it be filed and how deep is the CHMP currently involved in review? What are the main criteria they will use for approval in the EU? Dr. Missling states that the company is filing as soon as possible and will be done definitively this year. There have been interactions with EMA to ensure the company is building the package in congruence with their standard. It is notable that the EMA saw most of the 2b/3 data and the EMA requested the company files for approval expeditiously, "immediately". Dr. Missling mentions that the EMA probably requested this due to unmet need in the EU, and lack of MRI/PET centers in many EU nations like Romania and Poland. There are copious peer review articles over the last 5 years confirming the EU's need for a safe, cost effect, non-monitored Alzheimer's therapeutic to address these very facets. Romania is an excellent example, and one that I am familiar with. Viewers with more interest would find this article helpful published in Feb 2024. The following excerpt is especially helpful to understand the situation: 

"If European regulators impose similar eligibility conditions as the FDA, patients will require biomarker confirmation of amyloid pathology in the brain, currently measured using PET scans or lumbar puncture tests. There may also be a requirement for genetic testing, to establish patient ApoE4 status. In addition, European payers may ask that patients are enrolled in a registry to obtain coverage, similar to payers in the US. Treatment with current formulations of anti-amyloid drugs will involve monthly or bi-weekly intravenous infusions in specialist clinics, with regular monitoring involving MRI scans and other medical evaluations. If infusion reactions or side-effects such as ARIA occur, hospitals and emergency medicine teams will be required to manage and treat symptoms. Together, these clinical interventions will require a range of specialised personnel and infrastructures, from neurologists, neuroradiologists and genetic counsellors to PET scanners, MRI units and infusion centres. Defined clinical care pathways, standardised ARIA detection, monitoring and management protocols, as well as tools, training and guidelines for healthcare professionals, will also be required to ensure timely and effective treatment.

Currently, European healthcare systems are not resourced, equipped or organised to provide equitable access to anti-amyloid drugs for all people with early AD. Access to approved, symptomatic treatments for Alzheimer’s dementia already varies between countries, with only 26% of low- and middle-income countries and 76% of high-income countries including these drugs in national schemes for full reimbursement."

10. For the fourth question, the HC Wainwright analyst inquires as to how the company will monitor 3-71's efficacy in Schizophrenia, and how different 3-71 is expected to be from current anti-psychotic medications. Will the drug be more efficacious, easier to prescribe, safer, or perhaps a combination of these? Dr. Missling states that company is focusing on EGERP as a biomarker. This was an outcome tested in the COGNISION consortium Anavex participated in a few years ago. The company hopes that the outcomes of the ongoing phase 2 trial will inform how the drug will be differentiated from existing molecules.

11. For HC Wainwright's last question the analyst wonders if the EMA approves Blarcamesine for Alzheimer's in the EU, what will Anavex's strategy be to commercialize or partner, and does the current cash runway provide enough startup funds if they are to solely commercialize without a partner. At this point, Dr. Missling says that they are most interested in shareholder value. If the company can find a very active partner with large bandwidth and ability to maximize sales while incentivizing the company with upfront payments, milestone payments, and royalties, then this is the route to take. However, if this is not the case, there are split marketing opportunities. Based on how Dr. Missling answers this question, it is likely the company is waiting until approval to finalize a deal, as this would secure the most favorable terms for Anavex and its shareholders. Currently the company is not including advertising or commercialization startup costs in the cash runway, but there are non-dilutive ways to garner such funds in the event the company commercializes alone. 

12. BI Research then asks the sixth question, inquiring into the Schizophrenia trial design and data expectation. Dr. Missling states that there are several cohorts in the Szhiophrenia trial and the first such cohort has been fully enrolled - and well ahead of schedule. The first part of the trial is a dose finding trial, and the second part is an efficacy portion with optimized dose. The data timeline will be coming later when the trial is closer to completion.

13. The BI Research analyst then asks about the upcoming Rett trial and expectations there. Dr. Missling confirms that the trial really only failed due to a high placebo effect and 2:1 dosed vs. placebo arm. Because of this 2:1 ratio, caregivers assumed they were on the drug, thus increasing caregiver and physician placebo rates. For the upcoming trial the company will swap to a 1:1 ratio to reduce placebo noise, and will also refine clinical outcomes. The trial is expected to be 12 weeks and the company is engaging the Rett community to garner interest in the trial. If interest is high, the company will accelerate trial initiation and possibly bump the trial enrollment numbers accordingly. 

14. To highlight Fragile-X, the BI Research analyst asks where the company is at with the indication and if more can be said about the upcoming 2b/3 trial. Dr. Missling states that the biomarker they have correlates very clearly with Fragile-X pathology, and this data is expected to be presented in July. It is likely Dr. Missling is referencing peripheral lymphocyte signaling, which was first elucidated in the 8 June 2022 company PR with accompanying peer review article reference - though we leave the possibility of a second biomarker previously unmentioned. The biomarker allows the company to initiate a 2b/3 with Fragile-X. Having a firm, scientifically sound, and measurable biomarker helps enrollment processes as patients have a molecular outcome to spur on excitement. 

15. Finally, BI Research opines over the AVXL share price and pontificates that the company should consider insider-buying. Dr. Missling is obviously less-than-pleased over the share price, but the company has no debt, has a great team, continues hiring, and continues expanding their pipeline and trial progress. Additionally, the company is currently in a closed buying window, preventing insiders from purchasing at this time. 

Conclusion: As mentioned in the BLUF, there is a lot to look forward to for the rest of the year. Spirit of the Coast Analytics is most excited for the finished 2b/3 peer review and early genomic data (which could both come as early as mid-2024, a window we are currently in). Another standout milestone would be EMA submission, and possibly even FDA submission by the end of the year. It is refreshing to see Fragile-X and Rett Syndrome continue, and of course we can look forward to the long-awaited Parkinson's disease trial initiation and Anavex 3-71 Schizophrenia data. Over previous calls, this financial call gave good insight into current Anavex operations with better defined timelines and expectations. Based on new EMA filing progress and the company's continued module compilation, we assess it is likely the company will see EMA approval mid-2025, likely with accelerated assessment as the EU struggles to equip physicians with safe, efficacious therapies. 

Bottom-line Up Front (BLUF): The following Q&A covers a variety of topics related to ongoing Anavex operations. I have been asked many of these questions privately. These answers are my absolute best guess based on extensive research and conversations with industry experts. 

1Q: Can you provide an overview of the 2b/3 Alzheimer’s trial? What is the significance of responder analysis? 

1A: Anavex needed to meet co-primary endpoints in the 2b/3 Alzheimer’s trial. These endpoints were ADAS-COG (cognitive) and ADCS-ADL (activities of daily living). The primary statistical analysis was for combined 30mg+50mg dosed cohorts vs. placebo. The ADAS-COG was met nicely, while the ADCS-ADL failed to meet statistical significance. Luckily, it was pre-established that ADAS-COG could be anchored to the key secondary endpoint - CDR-SB (global) – which was met, and thus allowed for a successful trial designation. 

As previously mentioned, the primary statistical analysis was for pooled 30mg+50mg cohorts. Because the anchored endpoints were met, further pre-established sub-analysis can be explored. Primarily, this sub-analysis would include breaking out 30mg and 50mg vs. placebo, as well as a patient co-morbidity analysis, S1R gene analysis, sex & age, etc. 

Regulators like the FDA and EMA are most likely to base approval decisions off the primary analysis (pooled 30mg+50mg), but valid pre-established sub-analysis will likely play a smaller piece in their conclusions. Where sub-analysis for responders really shines is in the commercialization stage post-approval. Physicians will be able to prescribe Blarcamesine to a vast array of patients based on previously established gene/disease-stage analysis (80%+). By breaking out a high-confidence responder criteria, physicians can inform patients early on as to their odds of improving (reversing cognitive decline). 

So again, while responder analysis is important for commercialization-stages, the primary analysis being analyzed by the FDA and EMA is the pooled 30mg+50mg cohort. It is almost certain the earlier disease stage, higher dose (concentration), S1R WT, and time-on-drug, are primary factors as to whether a patient improves over baseline during therapeutic intervention. In a totally unlikely hypothetical case, if all 30mg patients totally failed the trial, but the 50mg patients carried the pooled group to success, only the 50mg dosing would be approved in the clinic. What’s important is that the combined dosing arms passed the trial. 

Additional note: It is likely that ADCS-ADL trended favorably, but simply failed to meet statistical measures in MMRM.

2Q: In your opinion, what is the significance of brain atrophy data? What are the biggest delineations or advantages of Blarcamesine over big pharma monoclonal antibodies? 

2A: Quite simply, brain atrophy has significant ties to cognitive loss and life span. Compared to healthy aging adults, Alzheimer’s patients with atrophied amygdala have a 315%+ greater likelihood of death and similarly a 220%+ greater likelihood with atrophied hippocampus. Every 1% of annual whole brain atrophy over standard aging humans increases the odds of progressing to the next stage of dementia by 30%. To my knowledge, Anavex is the only company to halt brain atrophy during a pivotal trial. In fact, monoclonal antibodies exacerbate further brain atrophy. Dr. Missling mentioned a few investor conferences ago that the company may have even reversed atrophy in some cases. In my studies, there is very little literature mentioning atrophy reversal, so it’s likely that Anavex will focus on the preservation/halting over reversal which hasn’t been fully elucidated. Beyond brain preservation, other advantages setting Blarcamesine over the antibodies (Aduhelm, Leqembi, Donanemab) is the fact that the therapy is a small molecule and orally available. There have been improvements in the full ATN (amyloid, tau, biomarkers of degeneration) with a good safety profile void of ARIA (brain swelling and brain bleeding) and the ability to show substantial clinically meaningful benefit over baseline in ideal patients - which is theoretically most people. 

Something especially key to hone in on is addressable market. The antibodies established amyloid thresholds as part of their recruitment process. Tens of thousands of patients were excluded from these trials to enroll only the most ideal patients for the drug mechanism of action. While this resulted in ‘successful’ trials, it also resulted in a very small addressable market, because the drug can only be prescribed to patients meeting the stringent threshold tested in their respective pivotal trials. Meanwhile, while Anavex tested for amyloid+ confirmation during enrollment, none of their analysis was dependent on specific amyloid enrollment threshold – thus, the drug will be feasibly prescriptible to all patients in early stages. Combining an antibody black box warning (safety warning), you can see how advantageous Blarcamesine is in comparison to the antibodies for addressable markets. 

More can be read about brain preservation here.

3Q: What is Dr. Sabbagh’s (Chair of the Scientific Advisory Board) relevance at this stage?

3A: Dr. Marwan Sabbagh has been involved in hundreds of Alzheimer’s-related peer reviewed publications. His prolific reach and influence in the field is certain to carry a heavy weight during the 2b/3 paper publication. Based on my personal experience meeting Dr. Sabbagh at AAIC 2023, I see him as a strong asset with dominant opinions and the willpower to pursue strategies he feels will extrapolate a best outcome for Anavex. He likes to attach himself to emerging technologies and medicines in the Alzheimer’s space and being brought on as the SAB Chair speaks volumes to the talent Anavex can garner. It is likely that he was enticed by Anavex’s unpublished data and wanted to be a part of something exciting. 

4Q: Why do you think the EXCELLENCE trial missed its endpoints, what do you think next steps will be?

4A: The EXCELLENCE Rett trial likely missed its endpoints due partially to trial design and strong placebo response. Factually, 2/3 of the trial participants were on the drug due to the lopsided dosed vs. placebo arm weighting. This likely prompted caregivers and physicians to assume their child/patient was on the intervention – as it was statistically more likely to be so. It is notable that during the Trofinetide trial, over 80% of patients experienced diarrhea, which unintentionally resulted in a pseudo-unblinding. If patients experienced diarrhea, caregivers knew that they were on the intervention, resulting in a much lower placebo response as Rett communities are tight-knit and were certainly discussing results mid-trial. Blarcamesine has no such ‘tell’ and therefore a complete blinding was maintained. It is extremely unfortunate that Blarcamesine missed endpoints in EXCELLENCE, as the drug already showed efficacy in two prior Rett trials. It is likely that the company weighed whether an unmet need still existed post-Trofinetide. Considering Dr. Missling recently confirmed a follow-on trial, a need certainly still exists, and I assume the next trial will have higher power with a more even placebo vs. intervention grouping. I look at the EXCELLENCE miss as a roadblock, not an end to the Rett indication or follow-on rare diseases. 

5Q: Why do you think Anavex hasn’t partnered yet, do you have any thoughts on partnership?

5A: Quite frankly the SIGMA-1 (SIGMAR1, S1R) mechanism of action is still unique/novel. The peer-reviewed 2b/3 Alzheimer’s paper will be extremely important to cementing Anavex’s mechanism and reputation. It is my opinion that the paper – probably headed by Dr. Missling and Dr. Sabbagh – will be of absolute criticality to a future partnership. It is likely that Dr. Sabbagh’s probable prominent role in the paper will be instrumental in this goal considering his reputation and rigor in pursuing promising therapeutics. It is my best guess that Eli Lilly or Sanofi will be Anavex’s eventual partners and partnership is possibly to be solidified sometime around EMA/FDA submission or EMA/FDA approval. I have very little to go on as far as how the deal will be structured but will most likely include some sort of upfront payment and royalties.

6Q: Have you noticed the strange divergence at week 12 in the ADAS-COG and CDR-SB linear charts featured in the company update presentations?

6A: Yes, it is notable that the company was up-titrating up until week 12, which probably had a lot to do with this divergence – making it appear as though placebo was performing better than Blarcamesine. The good thing is this divergence was not statistically significant and subsided as soon as the up-titration phase ended. As a general note for all Alzheimer’s trials, modern patients are more learned than in the past - even a decade ago. As a result of excellent whole-intervention trials like FINGERS, patients now more than ever begin sweeping lifestyle changes to stave off disease progression. During early stages of a clinical trial, patients and caregivers are more likely to succumb to placebo effect. Caregivers are hypervigilant to changes in their loved ones, and lifestyle changes including diet and physical fitness improve patient outcomes for a time, especially in MCI and early-Alzheimer’s stages. This is why longer trials are better in the Alzheimer’s indication. I look forward to seeing similar charts in the 50mg-only, and responder-only sub-analysis. 

7Q: What do you think about Parkinson’s trial initiation speed?

7A: The pivotal Parkinson’s trial has certainly been initiated in less than spectacular time; however, this is probably due to emerging biomarkers and assays in that field. This is probably related to a desire to be thorough, rather than an inability of management to execute. 

8Q: Have you made any recommendations or suggestions to Anavex recently or in the past?

8A: I have sent email suggestions a few times in the past. One of the topics I've emailed about was tying brain atrophy to life extension or ‘’time saved in early disease stage’. The FDA representative at AAIC 2023 mentioned this metric was a going interest to the agency. In addition, I have emailed the company my opinion about drug pricing, public perception, 2b/3 data release methodologies, and facets revolving around emerging FDA guidance on early Alzheimer’s clinical trials. 

9Q: When do you think the EMA may approve the Alzheimer’s indication?

9A: Considering what I believe to be true regarding Anavex’s regulatory submission and progress, I believe at an earliest the drug may be approved by the EMA in December 2024; and more likely, in the first or second quarter 2025. I believe the chances of approval are high and give about 89% likelihood it will be done under accelerated assessment conditions. Separately, it is likely Anavex will wait to file with the FDA until their 2b/3 OLE concludes, and the pending early Alzheimer’s draft guidance is finalized. Note: SOTC Analytics focuses primarily on scientific aspects of company development. Any number of administrative actions could push approval to the right of our proposed timeline. Investors and stakeholders should assess their own timelines for drug approval. Additionally, we use likelihood language established in ICD 203, which is perhaps not well known by many viewers. It can be found on page 3 here.

Conclusion: I look forward to the peer review paper – which is likely headed in part by Dr. Sabbagh – and believe its publication will be of massive benefit to the company’s reputation and partnership prospects. I have high confidence this paper will be released in 2024. With the recent Annovis data release and all publicly available information on antibody trial data, it is resoundingly obvious that Anavex currently boasts the most promising proven cognitive data in Alzheimer’s. I have personally made stock purchases over the last month in support of this belief. Spirit of the Coast Analytics will likely incorporate later this year, and we look forward to continuing analysis of Anavex Life Science Corporation and emerging sciences in the CNS-sector. 

Bottom-line Up Front (BLUF): The following are first impressions of Annovis's most recent Alzheimer's data. My impression of their previous Alzheimer's data released at AAIC 2021 was mixed but mostly negative on account of presentation disorganization and data inconsistencies. The company had a chance to refine their approach with this phase 2/3 trial, which appears to have suffered similar blunders by management, primarily in trial design. Not all aspects of the data release were negative - despite the 56% hit to the company market cap at time of writing - so let's explore and see what kind of conclusions we can draw. The PR released 29 April 2024 can be found here.

Trial Enrollment & Design: 

Perhaps the most perplexing aspect to the 2/3 trial design was the enrollment process. Below you will find an excerpt from the PR verbatim:

"Our initial recruitment did not prescreen patients for AD biomarkers in plasma. When we became aware of issues from other AD studies with sites recruiting non-AD patients, we fast-tracked biomarker measurements by collaborating with C2N Diagnostics. This enabled us, when we unblinded the data, to tell which patients had confirmed AD and which did not (Ashton et al. JAMA 2024, Barthelemy et al. Nat. Med 2024, Meyer Alzheimer’s Dement 2024). Out of 325 patients who completed the Phase II/III trial, 202 had a ratio of pTau217/tTau≥4.2% that indicates AD. We further subdivided the patient population into moderate (MMSE 14-20; 112 patients) and mild (MMSE 21-24; 90 patients) AD patients. These two selections were not pre-specified analyses."

The company expedited enrollment by skipping initial biomarker analysis. Biomarkers, primarily amyloid - and tau to a lesser degree - are often used to confirm Alzheimer's diagnosis in patients and is a standard screener for Alzheimer's trials. Instead of screening immediately, the company enrolled 353 patients without the biomarker screening and screened them as they progressed through enrollment, thus masking the results which could be uncovered during the post-trial analysis. 

Notably, Annovis used tau (lesser used biomarker for Alzheimer's confirmation) as the biomarker, and found that of the 325 patients to complete the trial, only 62% (202 patients) met the criteria for Alzheimer's. This indicates the company enrolled 151 patients that did not have Alzheimer's by their own metric analysis. Additionally, the 202 actual Alzheimer's patients were subdivided into mild and moderate stages (90 mild, 112 mod), but this was not a part of pre-specified analysis which is surprising.

Primary Endpoints: 

The company used ADAS-COG (cognitive) and ADCS-CGIC (global) as their co-primary endpoints. For those not familiar with endpoints, the ADCS-CGIC global endpoint tests cognitive and activities of daily living. If it is helpful, the reader can compare it similarly to CDR-SB used in many large Alzheimer's trials.

Remember that the subdivided mild and moderate stages mentioned earlier were not a part of pre-specified analysis. Based on the PR, the drug failed to meet statistical significance in the primary analysis (pooled mild and moderate Alzheimer's patients). However, the drug did meet statistically significant improvement in all doses (7.5mg, 15mg, 30mg) against placebo in the early Alzheimer's group. The results in early Alzheimer's showed dose-dependent effect, with the largest dose of 30mg showing a -3.3 point improvement (reversal). However, the placebo group also improved, and so compared to placebo this improvement is reduced to something around -2.4 point improvement over placebo. This is very respectable; however, notable that the primary analysis failed and the sub analysis was not a part of pre-specification. 

The ADCS-CGIC global endpoint failed entirely, showing only minor, non-statistically significant improvement in the 15mg and 30mg group.

Key Secondary Endpoints & Biomarkers: 

The company used ADCS-ADL (activities of daily living) as a key secondary endpoint, which failed. It is not uncommon for ADL to fail in very early Alzheimer's patients; however, in the 202 Alzheimer's patients enrolled, more than half were in the moderate stage. Because of this, a beneficial result theoretically should have been possible. There is no mention of the moderate-only stage effect; therefore we can conclude that it is likely there was no meaningful benefit even in the moderate group.

The tTau biomarker (neuronal or axonal damage) was improved in all 3x doses in the 202 Alzheimer's patients when compared to placebo. There is no mention as to whether the improvement was statistically significant, but this metric is not as important in my opinion for the tTau measure. Overall, I see the tTau biomarker as a positive. The company says they will present some other biomarker data in inflammation, axonal, and synaptic function. We can theorize these biomarkers would include possibly NFL, GFAP, and a few others. Intriguingly, the company did not make mention of assaying amyloid and it is not listed on clinicaltrial.gov. 

Responders & Safety: 

The company showcases dose-dependent response compared to placebo, which does look promising. At 30mg, the number of responders vs. non-responders is extremely obvious, with 87.5% response rate as opposed to 12.50% non-response rate. Once again however, this is only considering the early Alzheimer's patients. When combining all 3x dosing groups and assessing for only early Alzheimer's patients, 72% of patients were 'responders', which without explicitly stating so, we take to mean that they improved on ADAS-COG over baseline.

The drug was reported to be safe and consistent with previous trials. Adverse events were comparable between dosed and placebo, and were mild or moderate in severity.

Conclusion: Annovis's unusual trial enrollment scheme and non-inclusion of disease-severity sub analysis really hindered their ability to showcase clinical efficacy. Only 62% of the enrolled patients even had Alzheimer's at all as quantified by the company's analysis of tau screening. Positively, the drug appeared to show very nice improvement over baseline in the ADAS-COG cognitive assay, as well as compared to placebo - albeit in a very short trial. Tragically, the co-primary global endpoint failed to show statistical significance, and the key secondary endpoint of ADCS-ADL failed to show statistical significance as well, even in the moderate-stage patients that likely were capable of showing variance. Unfortunately, most efficacy appeared to be found solely in the 90x patients early-stage Alzheimer's group. Due to unusual enrollment, sample size for the trial and ideal patient population was low. It is also unusual that the company did not seemingly plan to assay the amyloid biomarker. Overall, Annovis has an absurdly lacking cash fund and in order to run a larger planned phase 3 trial, they will likely require further dilution or partnership. It is possible that success in their current Parkinson's disease trial will help them accomplish this goal. In all cases, the company appears to need assistance in trial design and may be a reflection of management.

Bottom-line Up Front (BLUF): A few weeks ago, the FDA published draft guidance for Early Alzheimer's disease. The guidance makes marked improvements for very early stage trials by placing greater emphasis on pathophysiological changes (measurable changes in the brain as a cause of disease), and negates the need for the activities of daily living metric. Overall, the draft is favorable to Anavex Life Sciences and a myriad of other developers. Below you will find a link to the draft guidance (downloadable), as well as a link to Spirit of the Coast's official comment to the FDA in order to improve upon the draft. Our feedback primarily revolves around specificity on desirable physiological changes with emphasis on those that are most likely to extend patient lifespan (brain atrophy).

• Draft Guidance

• Spirit of the Coast Comment

Bottom-line Up Front (BLUF): Within this report we make comment on various points of interest: ADCS-ADL success, the tau biomarker, the arterial spin labeling endpoint, possible gender-dependent effect, SIGMAR1 mRNA levels, odds ratio and effect sizes, placebo effect, and time-saved as result of therapeutic intervention. These are subjects we've researched over the last couple of weeks and wanted to wrap up here as separate-but-related points of interest. We hope to spark interest in readers as we all wait for Anavex's full 2b/3 dataset.

Gate Keeping

To clarify SOTC stance on the ADCS-ADL endpoint, it is our opinion that ADCS-ADL more likely than not met statistical significance as a standalone primary endpoint (p=0.05 or better), but did not meet the threshold needed as a co-primary endpoint (combining ADAS-COG and ADCS-ADL to reach p=0.05 together). Based on our research, it appears that the results are a waterfall. What is meant by this is, for the ADAS-COG to be combined with CDR-SB, the ‘first measure’ must be met. In this case, the first measure being both ADAS-COG and ADCS-ADL were met at the p-value of 0.05 (separately). 

Gate keeping procedures indicate that both ADAS-COG and ADCS-ADL did in fact reach 0.05 separately; however, that’s not good enough to claim success outright because the scores are supposed to be combined to meet 0.05 (i.e. both need to be 0.025 to add up to 0.05).

Thus, as was pre-prescribed in the SAP, Anavex could use the gate keeping measure (because both co primary endpoints were stat sig separately) to try to come to a truly successful trial (0.05 or lower when combining two endpoints). They were able to do this with the CDR-SB and ADAS-COG because the first measure (ADAS-COG and ADCS-ADL meeting at least 0.05 separately) was met. 

Gate Keeping Conclusion: it is more likely than not that ADCS-ADL met statistical significance somewhere between 0.05 and 0.0275. Our confidence is increased by the fact that the company's latest 10-series filings reiterate that the ADAS-COG and ADCS-ADL endpoints were both met. 

There are two fundamental truths:

1. According to the CTAD PR and subsequent 10-series filings, the trial met both co-primary endpoints; ADAS-COG and ADCS-ADL. This implies both endpoints were met with at least 0.05.

2. The second truth is that the trial was a success because of the ADAS-COG and CDR-SB reaching 0.05 combined. This implies that ADAS-COG and ADCS-ADL could not reach 0.05 when combined.

We look forward to the eventual release of the mean-scores for ADCS-ADL in the pooled dosed cohorts as has already been released for ADAS-COG and CDR-SB.

Tau Levels

Plasma (blood) T-tau and CSF P-tau/T-tau were collected as biomarkers in Anavex's 2b/3 Alzheimer's trial. We have yet to receive any information regarding tau and Blarcamesine's therapeutic effect on the proteins. Tau association to brain atrophy has now been elucidated in multiple peer reviewed papers - not just for Alzheimer's, but also in other tauopathies like stroke, corticobasal degeneration, lewy body dementia, frontotemporal dementia, and more. In all of these tauopathies, tau increase is correlated to an increase in brain atrophy. This is unsurprising as tau is largely associated with 'brain injury'. With the knowledge that Blarcamesine dramatically slowed or ceased atrophy in the whole brain, it is likely that the drug had a beneficial effect on tau as well. In preclinical studies, Blarcamesine has already shown to block or decrease tau levels by altering p35 levels, and thereby reducing CDK5 dysfunction. Further information on CDK5 can be found throughout the SOTC site; but as a brief reminder, dysfunctional CDK5 is disastrous to the CNS and its substrates are related to at least 39 key functions such as BACE1 expression, Parkin activity, synaptic plasticity, axon formation, tau, and more. Blarcamesine has been shown to correct or reverse CDK5 levels in Alzheimer's and PDD patients.

Tau Levels Conclusion: By virtue of known atrophy prevention/slowing and corrected CDK5 levels in earlier patients, it is highly likely that tau levels were improved in the 2b/3 Alzheimer's study.

Arterial Spin Labeling 

Beyond structural MRI, the company assayed cerebral blood flow (CBF) utilizing arterial spin labeling (ASL). ASL is an ingenuitive way to quantitatively and objectively track blood flow in a patient's brain by magnetizing water in the blood and then tracking the blood. The blood amount is then divided against the mass of the brain tissue it was tracked to in order to compute a value. Blarcamesine has demonstrated effect towards hypertension normalization, having corrected systolic blood pressure in the 2a trial participants. Irregular systolic blood pressure damages arteries, causes heart disease, kidney damage, and stroke, and has been implicated in an increased risk of cognitive decline and dementia. 

Arterial Spin Labelling Conclusion: Efficient CBF is needed for proper brain function, ensuring supply of oxygen and energy substrates. In addition, and possibly more importantly, efficient blood flow helps to clean out the accumulation of dead or misfolded proteins in the brain. Accumulation of dead, misfolded, or zombie (senescence) proteins impair energy (ATP) output and cause neuroinflammation. Healthy CBF reduces brain atrophy, and it is likely this measure was successful in the 2b/3 trial - especially in the 'responder' population.

Gender-dependent Effect

We feel we’ve done a good job in previous reports explaining factors influencing Blarcamesine’s efficacy. Most of these factors were discovered in the Alzheimer’s 2a trial such as: S1R WT gene, earlier disease stage, APOE3 genes, drug concentration, and time on drug. It was also indicated that males had a higher tendency to perform better than females; however, this was not statistically significant. Because of this, it’s likely that males do perform better or have higher odds of responding to treatment, but both genders maintain good/excellent compatibility with the drug.

As we know, females have higher odds of all-cause dementia over males, especially as they reach menopause. We also know that S1R mRNA expression is reduced in women, and S1R expression appears to be enhanced by estrogen. As menopause reduces estrogen, S1R also lowers in conjunction.

Newer evidence published on 25 Jan 2024 revealed gender-based differentiation in the basal forebrain cholinergic system (BF / BFCS) during CNS degeneration. The cholinergic system is important to Anavex’s MOA as the muscarinic receptor agonism is dependent on the health/state of cholinergic regions. If the basal forebrain cholinergic system is atrophied, there is less acetylcholine to stimulate muscarinic and nicotinic receptors. Luckily, even with significant atrophy, Blarcamesine would still be partially effective with its S1R role and dampened M1-M4 ability. Within the report it was noted that:

• Normal aging has minimal effect on basal forebrain volume 

• Basal forebrain volume reduction is a biomarker for diagnosing neurodegenerative disease 

• Asymmetric atrophy was observed in subregions of the basal forebrain in female patients as opposed to male patients 

Below are various excerpts from the research, with especially important portions highlighted in red. A brief synopsis will follow.

“Research combining structural MRI (sMRI) and cerebrospinal fluid (CSF) examination has revealed that cognitively normal older adults with abnormal amyloid beta and tau pathology in CSF biomarkers exhibit a reduction in gray matter (GM) volume within the Ch4 subregion of the BF. A longitudinal sMRI study found that in cognitively normal participants destined to develop AD, the BF area exhibited significant atrophy as early as 4.5 years before the onset of clinical symptoms, indicating that atrophy in the BF is a biomarker that predicts the likelihood of asymptomatic elderly subjects developing AD.”

“It has been reported that approximately two–thirds of patients with AD are females, and they tend to experience faster cognitive decline compared to males. This could be due to the brain of female patients with AD undergo more severe pathological damage, leading to more pronounced hippocampal atrophy and cognitive decline. Extensive brain imaging studies have provided evidence that males with MCI and AD tend to experience slower rates of brain atrophy over time compared to females. In addition, it has been observed that males with MCI show less atrophy in multiple brain regions, and once diagnosed with AD, they exhibit less atrophy in various regions as well. It has been proposed that cholinergic basal forebrain cortical projection neurons within the nucleus basalis, which mediate memory, attention, and the degeneration in AD, may exhibit greater vulnerability in elderly females compared to males.”

“Animal experiments have further revealed significant sex differences in estrogen receptors within BF cholinergic neurons.”

“Our findings indicated a significant reduction in BF volume, specifically in the Ch4 region, even before the diagnosis of AD. Most of the cholinergic innervation of the cortex, which is involved in attention and memory, originates in the Ch4 (nucleus basalis of Meynert) and in the horizontal limb of the diagonal band nucleus of the basal prosencephalon. Functional alterations in this system have been implicated in neurocognitive disorders as well as the cognitive changes described in Parkinson’s disease and AD. The atrophy of BF in patients with AD and MCI has been widely reported. A study utilizing a large multicenter dataset found that all of the subregion volumes of the BFCS were significantly reduced in the AD group.”

“The survival and maintenance of BFCS neurons rely on the nerve growth factor (NGF) and its homologous receptors (trkA and p75[NTR]). Compared to HC, p75(NTR) mRNA levels in BF cholinergic neurons decreased by approximately 40% in females with AD, while the p75(NTR) expression in males remained unchanged. Additionally, compared to HC and MCI individuals, males with AD demonstrated a 45% decrease in trkA mRNA levels in BF cholinergic neurons, while females exhibited a 50% decrease, and reduced trkA mRNA levels were associated with poorer global cognitive performance in females. These findings suggested that females may be at a higher risk of cholinergic BF neuron degeneration.”

"An animal experiment showed that estrogen had a protective effect on both male and female BF cholinergic fibers, and the therapeutic potential of estrogen decreased with increasing age."

Gender-dependent Effect Conclusion: There is a complex relationship between estrogen, SIGMAR1 expression, APOE, cholinergic atrophy, and neurodegeneration. So far, monoclonal antibodies have showed reduced efficacy in female patients. Considering Blarcamesine's wide-sweeping MOA and the relationship between estrogen and SIGMAR1 reduction in female patients, we expect the drug to be more efficacious in females than the MABs by boosting endogenous protection and restoration. Multiple studies have now demonstrated that SIGMAR1 confers/interacts with p75 noted in one of the excerpts above, further lending credence to SIGMAR1/estrogen axis of effect. Nonetheless, due to more pronounced BFCS degeneration innate to female patients, it is not likely female and male patients with see an equal response. Perhaps more than anything, we find the sex-dependent effect of Blarcamesine's therapy to be forefront of interest. More information can be found in the "gender and estrogen" portion of the SOTC AAIC 2023 readout here.

SIGMAR1 (S1R) mRNA Levels

A driver of clinical success is attributing drug MOA to clinical efficacy. For the MABs for instance, the goal is to show reduction of amyloid and correlate those results to improvements in CDR-SB (or slowing effect). In the Alzheimer's 2a trial, PDD trial, and Rett suite, increased SIGMAR1 mRNA corresponds to higher clinical output. While a minor note, we expect this trend to continue in the 2b/3 final analysis. This ties in nicely with the next section below.

Odds Ratio + Effect Size:

According to Anavex's 4 Nov 2017 PR, of the 30 patients that completed the primary phase 2a Alzheimer's study to 57 weeks, a strong drug concentration / response relationship was first identified. Drug concentration in the upper tertile (1/3) increased the probability of improved MMSE score 2.1 fold (110%) and ADCS-ADL score 1.6 fold (67%). It was stated in the 25 Jul 2018 PR that 80% of patients were "responders" resulting in improved MMSE and ADCS-ADL.

As shown in the 2a supplementary materials, higher drug dose nearly always (although not exclusively) correlated to higher drug concentration. For these intents and purposes, high dose = high concentration. 

Pulled directly from Anavex's 1 Dec 2022 PR: "ANAVEX®2-73 demonstrated visible improvement in patients with Alzheimer’s disease. Patients treated with ANAVEX®2-73 were 84% more likely, to have improved cognition by ADAS-Cog score change of -0.50 points or better from baseline to end of treatment than patients on placebo, Odds Ratio = 1.84 (p = 0.015). On average, patients, who improved cognitively with ANAVEX®2-73 treatment, improved by ADAS-Cog cognition score of -4.03 points. ANAVEX®2-73 treatment was 167% more likely to improve function compared with placebo, at a clinically meaningful improvement of ADCS-ADL score change of +3.5 points or better, Odds Ratio = 2.67 (p=0.0255). This reflects a robust improved and clinically meaningful outcome in cognition and function from baseline."

As was found in the 2a trial, it is highly likely that the higher dose/concentration group had better scores in both memory (ADAS-COG) and function (ADCS-ADL). 

According to the CTAD 2022 presentation given by Dr. Macfarlane, 287 dosed patients (85.7%) were titrated to 30mg or 50mg. Of those patients, 263 (78.5) did not need to down-titrate from their set 30mg or 50mg dose. The presentation did not breakout the 30mg and 50mg separately; however, we assess it is likely more 50mg patients down-titrated over the 30mg cohort due to higher odds of increased dizziness/headache. It's very difficult to project a meaningful outcome without the exact numbers, but we hypothesize somewhere between 110-120 patients on the 50mg dose maintained the objective dose until end of study. Based on my previous analysis considering patient severity, dose, APOE genes, and S1R WT, there is possibly up to 98 "responders" [+/- 10%] as defined by Anavex's own description (ADAS-COG of -.5 points or better and/or ADCS-ADL +3.5 points of better). Most of these responders would be from the 50mg group with a much lower percentage from the 30mg group. 

Odds Ratio + Effect Size Conclusion: While the pooled data presented so far is positive and met necessary statistical weight for success, the real anticipation comes with broken out subgroups - especially the 30mg vs. 50mg subgroup. As it stands, it is possible to equate an effect size to the pooled odds ratios, as they can be a little bit difficult to understand on their own.

• ADAS-COG ODDS RATIO: 1.84 = a small+ effect size

• ADCS-ADL ODDS RATIO: 2.67 = a medium+ effect size

Keep in mind that Anavex's responder threshold was improvement over baseline, which is unique to Anavex, with predecessor competitors always opting for 'slower decline' as their responder threshold. With this knowledge, the odds ratio and respective effect sizes are more impressive than what meets the eye. A 50mg only analysis would also certainly garner higher odds ratios and effect sizes. 

Time Saved and Placebo Improvement [Donanemab]:

In MCI and early-Alzheimer's stage patients, placebo improvement is a common phenomenon. In the Donanemab trial, the following was noted:

• Low/Medium Tau Group [ideal patients]: 47% of dosed patients saw no progression on CDR-SB, 29% of placebo patients saw no progression

• Pooled Groups [all dosed vs. placebo]: 36% of dosed patients saw no progression on CDR-SB, 23% of placebo patients saw no progression

We do not currently have data on placebo response in Anavex's 2b/3 Alzheimer's trial, but there was surely placebo response as patients are susceptible to placebo effect and earlier-stage patients can still see benefit from diet, exercise, and lifestyle improvements. CDR-SB is scored on a 0.5-point scale, so it's not the best tool to use for progression analysis, but there is no ADAS-COG or ADCS-ADL progression analysis publicly available for progression. In addition to the progression metric, time-saved will be another key output we hope to be included in the final data set. Time-saved was all-the-rage at AAIC 2023, and according to analysis presented there featuring unique calculation methods the following was elucidated:

• Donanemab: saved 5.5 months in 18 mo dosing cycle

• Lecanemab: saved 5.1 months in the same

• Aducanumab: saved 2.6 months in the same

Time Saved and Placebo Improvement [Donanemab] Conclusion: There is still a lot of useful data expected from the 2b/3 trial. At AAIC 2023, Dr. Jeffrey Cummings mentioned how time-saved may be the most useful metric for approval going forward, and that odds ratio analysis will be instrumental in determining which patients are right for each drug. SOTC previously attempted a time-saved analysis using brain atrophy, that analysis can be found in graphic 5, here. We thought it necessary to share Donanemab's placebo response in order to set expectation for the final Anavex data release and put forth the understanding that placebo response, while robust, can be overcame with drug efficacy - even when threshold for efficacy was set as high as Anavex's.

Bottom-line Up Front (BLUF): Two years ago on 6 Feb 22, ForestFoxes asked me a question related to doubts of another poster to Blarcamesine's long-term efficacy. The other poster stated "....the gist of it was that it [S1R agonist] will work and do so quite dramatically-at the beginning, but over time it will become less effective as the person's S1R levels continue to drop (or the patient will require increasing doses with declining improvement over multiple years) and it's therefore not going to prove a viable long-term therapeutic strategy..."

Yesterday, 6 Feb 24, ForestFoxes requested an update to my initial repsonse. Below you will find my response two years ago, as well as my response yesterday. At the least, I believe some followers will find the conversation interesting.

Reply on 6 Feb 22:

First, I don’t believe his point to have merit. The AD 2a trial extended through 5 years with at least half of the patients still taking the drug. (These people were quite old, it is likely that some actually died - not Blarcamesine related).

Secondly, I found in my analysis that most AD drugs dropped efficacy dramatically somewhere around the 35-45 week range (need to go back and find the exact number). Anavex did not see a drop here, in fact, it increased further. With this being the case, Anavex already beats SOC in multiple arenas. 

Of course many drugs lose efficacy after bodies attenuate to the response. But we haven’t seen meaningful evidence towards this at the 5 year mark. And what’s more, it is my hypothesis that the preventative CNS trial Anavex is planning will begin patients at 30mg. If people take 30mg to stave off CNS disorders but begin losing efficacy, the dose can be titrated up to 50 (and in some cases 60mg) to account for that loss.

Reiteration on 6 Feb 24:

Indeed, based on slope change for ADAS-COG and CDR-SB in the 2b/3 trial, Blarcamesine efficacy appears to increase with time, especially the longer the trial went on (week 36-48). 

I was going through the 2a supplementary material the other day and found some interesting tidbits. Primarily, it was found that TIME on drug was the lead indicator of therapeutic value in both cognition, and activities of daily living. 

This was especially true in patients with APOE4 genes (the majority of AD patients). Patients with high blood concentrations of the drug found the most therapeutic benefit. While not exclusively high dose patients, MOST high concentration was found in high dose cohort. High concentration and time on drug were especially important for patients with S1R variant. 

Lastly, COMT gene variant also needed more time, which correlated to higher activities of daily living scores but not necessarily cognition.

As we know, the most ideal patient type for blarcamesine are patients with S1R WT, early in disease stage, with APOE3 genes and high drug concentration. These patients, ESPECIALLY over a long trial period, will do very well in the trial and represent most likely ‘responders’ or ‘super responders’. I have done analysis prior to determine the odds of being one of these such patients. It was 48% of all MCI and early stage Alzheimer’s patients. When combining the ‘second best’ patient group, blarcamesine can optimally treat 61% of ALL MCI and early AD patients. Which is significant. Nearly all other patients (remaining 39%) respond well to treatment, but simply slow degradation instead of halt/improve.

One of my key takeaways is that ADCS-ADL may not have seen enough separation from placebo during the trial. Which isn’t necessarily surprising as activities of daily living are hardly affected in very early stages. More so than cognition, it was found in the 2a supplementary data that ADCS-ADL was improved most by patients on the trial longest. This makes sense, as cognition and brain degradation are the two drivers of reduced patient function. By improving brain function and halting atrophy (or slowing in both cases) activity scores would have a trailing effect that would take longer to record. 

I’m looking forward to 72-week OLE data, as this is congruent with both Lecanemab and Donanemab trials, and is likely more than enough time to garner ADCS-ADL separation.

I’m also looking forward to a 50mg-only chart, a “responder-only” chart, and oppositely, a total non-responder chart of the worst performing patients to better define what small percentage of patients respond worst to the therapy. Perhaps it is a specific co-morbidity, pathology, or gene keeping those patients behind. 

We have still only seen pooled data for the trial, with responder analysis in “odds ratio” and mean change data for ADAS-COG and CDR-SB. And only for a short 48 weeks. I emphasize “pooled” because in theory, most patients could likely titrate up to 35-45mg. This is why I’m most interested in high dose or high concentration-only charts. Even if the drugs quadruple muscarinic modulation causes transient dizziness or headaches, I believe it is a risk most patients would take if foretold that the drug would provide MEANINGFUL benefit. We already have evidence of this as the vast majority of patients continued to OLE and continued even further to the extended-OLE.

Phase 2 Trial for Anavex 3-71 in Schizophrenia is Imminent 

Bottom-line Up Front (BLUF): On 7 Feb, the trial design for Anavex's 3-71 Schizophrenia trial became available on clinicaltrials.gov. The trial is set to assess approximately 40 patients over 10 or 28 days with two doses (30mg & 60mg), in the United States. The trial features a vast array of endpoints (38) and is supported by the COGNISION consortium, the Cognitive Research Corporation, and Hassman Research Institute. While the trial is exploratory in nature, the inclusion of fluid biomarkers is exciting, and positive outcome there would propel the indication through to a well-deigned phase 2b/3 or phase 3.

Trial Design Notes: 

After analyzing other phase 2 Schizophrenia trials, we found that both the size and length of Anavex's trial to be within established norms (15-125 patients, 2-6 weeks). Looking at the trial endpoints, we most look forward to the PANSS, BACS, CGI-SCH, and biomarkers YKL-40, GFAP, amino metabolites, and of course the Anavex-standard DNA/RNA & whole genome analysis. The biomarkers and genome analysis will objectively correlate PANSS, BACS, and CGI-SCH efficacy to molecular improvement via gene up-regulation. 

Anavex 3-71: 

Having explained differences between Blarcamesine and Anavex 3-71 in the past, below is a brief refresher on why Anavex 3-71 was chosen over Blarcamesine for Schizophrenia. 

• Pros for 3-71:

  • • Massively increase S1R and M1 agonism. Of all the muscarinic receptors, M1 is known to be highly concentrated in the CNS with ties to motor, learning, and memory.

    • Eliminating M3-M4 reduces safety concerns as quadruple modulation of muscarinic receptors has historically been tied to dizziness, headaches, and in some rare cases psychiatric problems.

    • Access to a slew of 5-HT serotonin secondary receptors for psychiatric benefit.

    • Retains good M2 agonism for motor function.

• Con Differentiators from Blarcamesine: 

  • • Lacks SCN2A which is probably the biggest component for autism & seizures.

    • Lacks M3 agonism which is probably one of two greatest factors influencing blood pressure/endothelial aid.

    • Lacks NMDAR, probably the second biggest component for autism.

Overall, as mentioned in previous publications, Blarcamesine is an excellent 'whole body' therapy and has special considerations for autism disorders and epilepsy. Meanwhile, Anavex 3-71 is an ultra-focused cognitive enhancer and psychiatric aid, making it more ideal for Schizophrenia.