Special Edition: CTAD 2022

This report outlines Spirit of the Coast Analytics' findings at CTAD 2022 in San Francisco. Within will highlight the Anavex 2b/3 Alzheimer's data reveal, subsequent webcast, interactions with Dr. Macfarlane, conversations with a senior BP representative, and other general findings at CTAD 2022. This should be seen as a preliminary analysis until further data is released.

Anavex 2b/3 Data Bottom-line Up Front (BLUF): On 1 Dec 2022, Dr. Macfarlane unveiled the highly anticipated Anavex 2b/3 Alzheimer's data. Sitting in the front row directly behind the podium, I was utterly shocked as he revealed statistically significant outcomes in all three primary and secondary endpoints with clinically meaningful outcomes in the ADAS-COG cognitive scores & ADCS-ADL activities of daily living. To my knowledge, this represents the finest clinical outcomes in a 2b/3 Alzheimer's trial to date - far surpassing the Aducanumab (Aduhelm) trial data from 2020 and the Lecanemab trial data revealed this year (partially in Oct and the rest at CTAD open). Despite a modest patient population (509 total patients), Anavex was able to show exceedingly strong results with extremely high effect sizes (exact effect size unknown at this time). We are looking forward to Anavex analyzing the differentiation between the 30mg and 50mg scores, the genomic data-sets, and biomarker data (amyloid, T-tau, P-tau, NfL, YKL-40, neurogranin, & BACE-1). Ultimately, we believe Anavex has a good chance for conditional approval for Blarcamesine with regulatory agencies, especially as their data is directly comparable to Aducanumab and Lecanemab; the former receiving approval with lackluster data, and the latter likely to receive approval with clinical outcomes worst than Blarcamesine - not to mention less desirable delivery methods (IV vs. oral), tendency for brain swelling/bleeding, and probably higher cost. Despite some public sentiment, this trial was a complete success and all primary and secondary endpoints were met.

Figure 1. Primary Endpoint Clinical Outcomes

Anavex 2b/3 Cognitive/Activities of Daily Living Data & Comparisons to Aducanumab & Lecanemab: While full analysis is still ongoing, we believe the most important information regarding the Anavex primary endpoints can be found in Figure 1. Dr. Missling explained the rationale for utilizing odds ratio (used for Aduhelm approval), and Anavex's deviation from Biogen in choosing vastly higher 'responder' thresholds. For both endpoints, Biogen sought outcomes in which patients slowed decline, while Anavex sought outcomes in which patients improved (over baseline). These are the most important facts regarding Anavex's primary endpoints [remember that negative scores in ADAS-COG are better, and positive scores in ADCS-ADL are better]:

  • Anavex was looking for improvement, not reduction in decline like the Aducanumab trials (EMERGE & ENGAGE).

  • Anavex proved that patients have a very high chance (84%) to at least mildly improve over baseline by -0.5 or better ADAS-COG cognition points, over placebo group.

  • Biogen proved that patients have a relatively low chance (25%) to slow cognitive decline by 3.0 points, over placebo group.

  • Anavex proved that patients have an exceedingly high change (167%) to greatly improve over baseline by 3.5 ADCS-ADL or better activities of daily living points, over placebo group.

  • Biogen proved that patients have a moderate chance (60%) to slow daily living decline by -3.0 points, over placebo group.

  • Anavex: Among responders (those that improved by at least -0.5), the mean score was -4.03 ADAS-COG cognition points.

      1. This far exceeds any cognitive data from any phase 3 trial.

      2. This score is clinically meaningful (expected to actually positively impact someone's life).

      3. This score represents the combined 30mg and 50mg cohorts - a 50mg only breakout would likely be substantially higher; perhaps 5-to-6 points.

      4. Unlike Aducanumab & Lecanemab, Blarcamesine scores indicate true disease modification in the majority of patients.

  • Overall, in all patients (responder or not), Blarcamesine reduced cognitive decline measured with ADAS-COG by 45%, a treatment difference in mean score change of -1.85 ADAS-COG cognition points.

      1. For reference, Lecanemab garnered a score of approximately -1.25 at 48 weeks and -1.442 at 18 months. These scores weren't as robust as Anavex (higher negative scores = better), and show that a long trial was needed in order to garner a somewhat decent score. If the Lecanemab trial ended at 48 weeks like Blarcamesine's, their ADAS-COG data would have been relatively weak. As it stands, Eisai and Biogen were able to ebb out a moderate effect by 18 months. For Aducanumab, in the EMERGE trial only (ENGAGE failed), the low dose group garnered a score of -0.7 and the high dose group garnered a score of -1.40 at 18 months.

  • Finally, as evaluated by CDR-SB (secondary endpoint), Blarcamesine slowed cognitive and functional decline by 27%, or -0.42. This score is very similar to Lecanemab, and beat Aducanumab scores of -0.26 and -0.39 in the EMERGE low & high dose groups at 18 months.

      1. Recently published in Alzheimer's & Dementia: Translational Research & Clinical Interventions, authors conclude that CDR-SB is limited in its ability to consistently detect a treatment effect in clinical trials compared to ADAS-COG. This is important, and we will discuss later the rationale for including CDR-SB.

Primary endpoint summary: Blarcamesine's cognitive and activities of daily living scores as assessed by ADAS-COG and ADCS-ADL in the combined 30+50mg groups represent the likelihood for true disease modification. While we await 30mg and 50mg breakout charts and further ADCS-ADL data, we are overwhelmingly pleased with the topline results. Not only did Anavex garner better scores, they did so in less time, with an oral method, and had a better safety profile than both Aducanumab and Lecanemab (next section). The 50mg-only responders once broken out and analyzed should dramatically exceed the already clinically meaningful outcomes demonstrated with -4.03 ADAS-COG cognitive points. The majority of patients were up-titrated to their top end doses (30mg or 50mg), and at a glance, at least half of patients at their top end dose maintained that dosing until the end of the trial.

Safety: It should be important to note that in these fragile patients, TEAE are extremely common. In the placebo group 70.2% of patients experienced at least a single adverse event, and in the dosed groups at least 82.4% of patients experienced at least one adverse event. For Lecanemab, there was an 81.9% and 88.9% incidence respectively. In Blarcamesine and Lecanemab dosed groups, serious adverse event incidence was similar at 15.6% and 14% respectively. In addition to serious adverse events, Anavex has not reported any brain swelling or bleeding, unlike relatively widespread cases in both the Aducanumab trials and the Lecanemab CLARITY trial. Dizziness and confused states were reported in Blarcamesine dosed groups with dramatically higher incidence than placebo - and higher than Lecanemab safety reports. Anavex has stated their remedy to this will be nighttime dosing. Despite these incidents, falls were reported less than placebo (7% vs. 9.9%) and was lower than the Lecanemab dosed cohort at 10.4%. It is possible that these patients are reaping some of the motor improvements seen in the Parkinson's Disease Dementia (PDD) trial which is reducing falls.

Safety Summary: Pending a complete list of adverse events, Blarcamesine has an exceptional safety profile with remedies for its highest incident events (dizziness and confusion). Falls are lower than placebo and Lecanemab dosed groups which may indicate therapeutic effect to motor skills as seen in the PDD trial. Most importantly, no brain bleeding or swelling has been reported for Blarcamesine which is the primary differentiation between it and a-beta anti-bodies. Some safety observations related to Lecanemab specifically will be commented upon later in the CTAD notes section from Day 1.

Anavex 2b/3 Alzheimer's Topline Data Conclusion: Anavex data indicates overwhelming cognitive and functional improvement. To our knowledge there has never been reversal of cognitive loss (-4.03 ADAS-COG) in large patient cohorts (84%). We hope Anavex will break out the ADAS-COG chart to show dose-dependency and we believe the most robust presentation would include a combined (30+50mg) vs. placebo chart, a separate broken out cohort (30mg vs. 50mg vs. placebo), and a final chart showing 20mg vs. 30mg vs. 40mg vs 50mg (rounded) in order to account for all doses due to up/down titrations. Blarcamesine has a plethora of advantages over a-beta antibodies; no IV, lower cost, greater efficacy, and no brain bleeding or swelling. Additionally, there may be evidence of modest motor improvement but that will require additional analysis.

A video of my initial conference call post-data on 1 Dec can be viewed here. Note that my impressions were brand new and some of my analysis has shifted since this video.

Interactions with Dr. Macfarlane & Top-5 Senior BP Representative

Dr. Macfarlane: Just prior to his presentation, I met Dr. Macfarlane. As soon as I walked up he said "you must be Jesse", which of course had me surprised. It seems someone tipped him to my pending interest in conversations after the presentation. He said he would be glad to meet with me after the readout. As soon as his presentation concluded he had at least four individuals (one of which was a panelist from earlier in the day) come over and inquire about the results as well as Blarcamesine's mechanism of action. He answered the questions wonderfully, "Blarcamesine works agnostic as to whether a patient has amyloid or tau, the mechanism of action is way upstream, it is orally active which is a massive advantage of course, and there is no reported brain bleeding or swelling" (paraphrased). After his conversations we went up to the highest bar in San Francisco where I offered to buy us a few cocktails (the man likes Whiskey Sours - people keep asking me this). These are some of the things he had to say:

  • Anavex received the data on 30 Nov, only one day prior to the data release, due to a single clinical site not locking in their data. Dr. Missling was aggressively contacting this site to lock out their data so the company could have more time for analysis.

  • He said the Anavex team was going to be here if they had the data earlier, but because of the rush they stayed behind in New York in order to produce as much topline data as possible.

  • Dr. Macfarlane confirmed that CDR-SB is not as good as ADAS-COG for measuring cognitive changes in clinical trials in his experience. Anavex used CDR-SB as a secondary endpoint simply because of its current trending status with big pharma - which of course began as an approval point for Aduhelm.

  • I asked if there was any evidence at all for super-responders as seen in the 2a Alzheimer's trial (top two patients). He confirmed that despite not having the data (not an Anavex employee) he believed his clinic in Melbourne probably had 10-15% super responders based on observation. His clinic had 60 patients (of course, not all were dosed).

  • We speculated on partnerships and the such. Dr. Macfarlane would be surprised to see a preventative CNS trial initiated without a partner due to the massive costs involved with such a large longitudinal trial. We agreed next steps would reasonably be to find a partner, as this would likely aid their regulatory packages, pave the way for a more seamless commercialization, and allow for more trials to be ran.

  • Overall Dr. Macfarlane was very pleased with the data and also made mention of the PDD motor data. He didn't go into detail about the PDD data but was surprised by the clinical outcome which was double the community standard for clinical meaning.

  • We speculated more that Anavex may require a phase four trial, simply because of the 509 patient population - despite effect sizes being good enough for clinical meaning and statistical significant results.

  • He brought me through the history of the TGA. In early days the TGA would only approve drugs with trials ran in Australia. This of course became a problem because Australia doesn't have a particularly large population despite its size. They eventually swapped to accepting worldwide trials for approval and do regularly approve after the FDA.

      • In my own analysis from a few years ago, I would estimate the TGA approves some 80-85% of drugs after the FDA with the other 15% being unique to Australia or the EMA.

      • As we know, the preponderance of these Alzheimer's trials have been ran in Australia and partially paid for by the Australian government.

      • I am speculating, but I do wonder if the Australian government will approve first. They have a lot to gain from doing so, and if we go back to the TGA's old style of approval (Australian-only) then it would be difficult for the Australians to conduct an Alzheimer's trial much larger than the Blarcamesine 2b/3 in any reasonable amount of time. I have no real opinion either way - I am simply providing some context here.

  • As a final note regarding our conversation (which was well over an hour), Dr. Macfarlane explained why the "responder" metric was so important and pointed out the criticality of the -4.03 ADAS-COG score. Clinicians prescribe drugs to patients and wait to see if they work - do they provide benefit. If they do not provide benefit, usually a patient is taken off that drug. The responders reaping a -4.03 cognitive improvement is massive because it is what a responder could reasonably expect to gain. Most people taking Blarcamesine in the future will see immense benefit or be taken off the drug. Therefore, the -4.03 score is probably the most important score in the future for clinicians and their patients.

Senior Manager at Top-5 BP: I requested to post this conversation with the condition of complete anonymity. During my venture at CTAD I met an enthusiastic representative of a top-5 BP whom has a >$1 million stake in Anavex and had some very nice insights into BP perception of the company amongst other things. He has worked at the BP for 20+ years and is a senior member of a major region.

  • He was aware of his companies interest in Anavex - not to mention their worry of how Anavex may progress and beat them to market in multiple indications. He had further insight that other BP also had interest in Anavex for similar reasons.

  • From his perspective Anavex has no interest in manufacturing and stated that they will partner, question is when - he theorized within 6 months.

  • We agreed that it would be in the best interest for Anavex to tie in amyloid theory with their full data presentation in order to draw in the current medical community interest.

  • I hesitate to provide this, as it is outlandish. We agree that PD/PDD trials may be progressing slowly at this time because Dr. Missling may seek a dual-approval with Alzheimer's and PDD. There are other reasonable explanations of course, but this was a very low confidence thought that had occurred to us both.

  • He had very good insights into slow EXCELLENCE enrollment. He himself has an 'at risk' child and refused to participate in a clinical trial during COVID whereas he would have in other circumstances.

  • We both agree that Dr. Missling should place some additional emphasis on Blarcamesine's and 3-71's extra binding affinities as they likely play a greater role than is presented. We think he may not in order to keep focus on the S1R and Muscarinic receptors which is reasonable.

  • He acknowledged that Anavex should consider paying additional costs in order to hire a better CRO for faster post-trial processes.

  • He applied to work at Anavex in a senior position but declined the offer after the company wanted to move him to New York (didn't want to move for his children's sake). He also personally knows some of the senior management at Anavex and mentioned that these individuals are top-notch, and likely wouldn't have accepted a position there without a level of confidence.

General CTAD Notes [Raw & Unedited]

Day 1 (Tuesday)

1. I was sold on the Lecanemab safety presentation. I am not convinced deaths were really all that related to Lecanemab dosing. At least not directly.

2. Full Lecanemab primary/secondary endpoint scores.

- CDR-SB: 27% slower decline

- Amyloid PET: 59.1 centoids lower than placebo at 18 months (massive)

- ADAS-COG14: 26% slower decline

- ADCOMS: 24% slower decline

- ACDS MCI-ADL: 37% slower decline

3. According the the results above (and a 23-56% lower caregiver burden) the company believes this meets the FDA and EMAs definition of disease modification. I agree - however the results still don’t meet clinical significance scores established which is interesting.

4. There was improvement in ALL CDR-SB domains.

5. There was improvement in ALL co-morbidities patients (51% of patients had at least two other diseases: diabetes, obesity, hypertension, etc).

6. APOE4 rate was high (69% in dosed and comparable in placebo). APOE4 homozygote patients faired far worse overall and was the biggest driver of therapeutic effect. There weren’t too many homozygote patients though. Most are heterozygous. Homozygote patients actually declined similar to placebo in CDR-SB but improved slightly in the other cognitive endpoints like ADAS-COG.

7. 26.4% of dosed patients had an infusion related reaction but most were mild-mod and were cleared up usually in the 1st treatment.

8. Most ARIA-E came from APOE4 carriers, especially homozygote. Usually they were mild cases and 90% of occurrences happened in the first 90-180 days. 81% were resolved within 180 days.

9. Intriguingly, Abeta42 improved, but Abeta40 did not. 66% of patients were amyloid negative by 18 months.

10. The temporal lobe was the only region where tau was removed with stat sig, but all other areas showed a positive trend.

11. No stat sig NFT changes.

12. GFAP and neurogranin both saw stat sig changes which indicate astrocyte/inflammation improvement.

13. Brain atrophy was noted in all regions except the hippocampus which saw less decline than placebo.

14. Neurodegenerative markers gave a bit of a mixed picture but may need more time to play out.

15. 31% lower risk of converting to next stage of severity on CDR-SB in 18 months.

16. It would take 25.5 months for dosed patients to reach placebo degeneration at 18 months.

17. Saves 2-3 years out of late stages overall.

18. Experts overall are looking to begin ultra early trials (preclinical, before even MCI)

19. Combination therapies are going to be critical. All known and accepted biomarkers right now only account for about 50% of patients. About half of all people get dementia for reasons not currently investigated to extent.

20. There was an extremely interesting presentation on insulin pathways (which Blarcamesine does hit on).

21. Paul Aisen was well-spoken. I have made mention before that he is an amyloid fan, but more importantly he is investigating ultra early detection. This was extremely obvious in this forum. He will be important for Anavex’s commercialization and preventative trials IMO.

22. Something that really caught my attention was “intervention of ubiquitous protein clearing” being a needed subject. This is exactly what Blarcamesine directly enables and I wrote about it in-depth during the CTAD precursor report. Proteasome 26S.

Retrospective Notes on Day 1 (Tuesday)

I want to write about the second presentation from Tuesday conducted by Suzanna Craft. She spoke about insulin and metabolism. Her opening was ultra divisive and reminded the room not to fixate on Amyloid and Tau.

1. Amyloid reduction is necessary as it slows disease progression but likely not sufficient. In sporadic AD patients it likely doesn’t help at all in fact.

2. Insulin and metabolic changes occur extremely early in AD patients - even before Amyloid in most cases.

3. She mentions the mitochondrial pathway is also very strong although possibly not quite as direct as insulin and metabolism.

4. Insulin is the master regulator of metabolism and immune function.

5. Regulating insulin has some effect on virtually EVERY gene.

6. Insulin PRE-treatment saves synaptic loss.

7. BACE1 is implicated (Anavex has mentioned BACE1 a few times).

8. Studying intranasal insulin (shooting it through your nose) which crosses the blood brain barrier and doesn’t enter blood - so not hypoglycemia.

9. Another target of interest is Sodium-glucose Co-transporter 2 which inhibits type 2 diabetes. Shown to be effective in preclinical trials.

10. Intermittent keto is good for tau reduction and cognition.

11. Exercise has been proven to be the absolute best insulin regulator - greater than any medication.

12. Senescent cells (zombie cells) are cells that are supposed to be cleared but are not. The stress gene expression. Blarcamesine clears proteins via proteasome 26S, hmm…

13. Midlife insulin resistance predicts amyloid accumulation 15 years later.

Parting thought: insulin pathway targeting should be a part of ANY combination therapy. Interesting that Blarcamesine does partially address this pathway.

Day 2 (Wednesday)

1. Two massive lifestyle trials were presented today; FINGERS and SMARRT. The bottom-line is that changing your lifestyle (quit smoking, exercising more, diet, etc.) DOES have an effect on your memory and other aspects of your life (obviously); however, the Cohens D for effect was low, in the .10-.16 range with statistical significance.

2. From a biomarker perspective, we have advanced far enough that we can predict if someone will contract Alzheimer’s up to 30 years in advance.

3. Lecanemab was brought up; interestingly, after dosing stopped (purposefully) amyloid levels began rising again. To me this indicates that the drug doesn’t really address the actual problem. If it did, the amyloid theoretically wouldn’t come back. At least not to the levels indicated on the chart we viewed.

4. P-TAU217 is emerging as a very good biomarker for both amyloid AND tau aggregation. In fact, it has been tested as the BEST amyloid AND tau (looking for both simultaneously) biomarker. This marker may start to be used in more and more clinical trials and early detection methods. P-TAU217 is useful for Alzheimer’s because it is a good read of Alzheimer’s pathology ONLY, not other dementias. The biomarker is increased 300-700% in Alzheimer’s patients with higher increases correlating to higher decline. This is an important thing to consider due to the next bullet statement (bullet 5).

5. 50-70% of symptomatic AD patients are incorrectly diagnosed by primary care physicians (standard doctor from your local hospital). Only about 20% of primary care physicians have high confidence in their ability to diagnose Alzheimer’s.

6. It was admitted the medical community does not have a real consensus on the best or gold standard biomarker. There are APOE disparities in African American patient populations. Additionally, poor kidney function and high body mass index skews current biomarker readings (plasma ones).

7. TRAILBLAZER-ALZ 4: a study measuring amyloid reduction in Donanemab and Aducanumab (no cognitive scores, amyloid only). Donanemab lowered amyloid much faster than Aducanumab and didn’t increase the rate of ARIA events (was comparable to Aducanumab).

8. MTBR-TAU243 biomarker is being developed and is extremely good (the best?) at identifying TAU but NOT amyloid. So while 217 mentioned earlier is good at measuring tau and amyloid combined, 243 is the best at tau-only detection. It is believed that combining the TAU243 and TAU205 biomarkers is nearly as good as a TAU PET scan in terms of accuracy which is less invasive and costly.

9. Roche topline data of their GRADUATE 1 and 2 studies was a bit of an embarrassment. Amyloid was reduced with statistical significance - and to great effect, but much less of an effect than was predicted based on phase 2 study. CDR-SB, ADAS-COG, and activities of daily living scores all failed to reach statistical significance. CDR-SB was improved by 6-8% (not stat sig), and ADAS-COG/ADCS-ADL was improved 9-16% (not stat sig). If pooling ALL patients from both trials into a single data set, CDR-SB was able to barely ebb out statistical significance. TAU181, tTAU, Neurogranin and a few other biomarkers improved upwards of 24% in dosed patients, but clearly did not correspond with clinical improvements (CDR-SB, etc.)

10. In my opinion the medical community should largely be embarrassed by fixating on amyloid and tau removal. The current hypothesis is that the amount of amyloid removal should relate to clinical benefit and in most cases it does NOT. This was a shining example of that.

11. I skipped 2 hours worth of less important sessions to speak to a senior employee of a big pharmaceutical company. I will see if they are willing to allow me to share anonymously my conversations with them. They were pretty interesting to be sure. The rest of the sessions were relatively uninteresting and while I do have significant notes, most investors would not be interested in them.

Day 3 (Thursday)

Just listened to Lundbecks phase 3 trial on Agitation in Alzheimer’s. The results were statistically significant reduction in agitation and the drug was relatively safe. In fact, 68% of patients improved at least 20% by the end of the trial, and a smaller percentage (~20% of patients) improved upwards of 40% by the end of the trial.

Note: Dr. Macfarland actually commented on this trial and was skeptical to the results. We discussed that agitation is a vague endpoint to measure.

One of the panelists had this to say (paraphrased): “any efficacious and safe drug to address Alzheimer’s is invaluable - even if not addressing cognition”.

This is very exciting because Blarcamesine addresses so many facets of Alzheimer’s including cognition, mood, sleep, and more. The medical community is desperate for safe symptom relief and disease modification.

Anavex notes from Day 3 are above and I chose not to attend Day 4 - although I will likely engage my CTAD resources to look over some of the more interesting Day 4 presentations sometime this week.

Overall CTAD Summary: My overall perception of the Alzheimer's community at CTAD was this; amyloid reduction is necessary, but we are likely approaching the best efficacy that can be rendered from this theory. Now that amyloid can be reduced (negative amyloid levels needed for benefit), the community is looking for other novel pathways like insulin, metabolism, protein clearing, and others. Additionally, there is a new emphasis on combination therapies to address specific needs (precision approach). While the academic medical community is only now coming around to this conclusion, this year represents the first time that over 75% of drugs being developed are non-amyloid in approach. While I think the overall trend of focus is shifting, it would still be extremely beneficial for Anavex to continue comparing efficacies to existing amyloid reduction drugs - to include biomarkers typically associated with the approach (which the 2b/3 does have). If nothing else, it seems that money rules all. Deep pocket BP have a lot to lose by being usurrped by a no-name novel thearpatuc like Blarcamesine. These scholars have bet 30+ year careers on the line for the amyloid thesis. Billions of dollars and robust egos are at stake, and that was apparent when listening to certain panelists at CTAD clutch ever-closely to their long-beloved thesis. Overall I had a fantastic time at CTAD. I learned a lot and appreciated the perspectives of all of the presentors. I hope to go back in future years if warranted. Until then, I will be waiting for further Anavex 2b/3 Alzheimer's data with utmost anticipation and excitement.