AAIC 2024

Bottom-line Up Front (BLUF): Dr. Sabbagh, Chief of Anavex's Scientific Advisory Board, delivered Anavex's 2b/3 clinical trial results with efficiency and a touch of commanding swagger. After listening to his presentation and seeing the accompanying slide deck, our understanding of the drug's efficacy in the A/T/N construct (amyloid, tau, and neurodegeneration [atrophy]) and in clinical measures is clearer than ever before. Notably, of the few less impressive measures that failed to reach statistical significance, it is more likely that low patient population (N) and possibly timeframe were the primary causes and not the drug itself. We will explore a few of those facets within this 'quick look' report, dive into some of the new and more impressive data pieces, and next steps. Overall, Dr. Sabbagh and Anavex look at Blarcamesine as part of an adjunctive medication, to be taken in combination with available monoclonal antibodies (when able, as the antibodies are quite limited to certain patient populations), and as part of whole-lifestyle intervention. It is our opinion that this approach is the most compelling method to garner scientific support from die-hard amyloid hypothesis scientists/physicians and the FDA. We believe this is the best approach for the company, and would increase Anavex's market penetration in the long run.

Trial Enrollment & Design: 

Dr. Sabbagh begins by explaining the trial's baseline demographics, showcasing excellent diversification through the three arms. Gender, race, ethnicity, and APOE status were all relatively standard and balanced across the population. The same could be said for baseline demographics for ADAS-COG, ADCS-ADL, CDR-SB and MMSE. And finally, the same with p-Tau (phosphorylated tau - the purportedly bad stuff!) 181 and 231.

ADAS-COG13

• ADAS-COG cognitive scores were broken out by dose (30mg and 50mg).

• 30mg at 48 weeks comparing dosed to placebo: delta of -1.934 with a p-value of 0.026

• 50mg at 48 weeks comparing dosed to placebo: delta of -2.149 with a p-value of 0.021

• Dose-dependence = achieved, statistical significance = achieved 

• Observing the efficacy slopes, it is clear that some churn occurred during the first 12 weeks - likely due to titration and maintenance - as the first 12 weeks was the titration phase. Importantly, at no point when dosed patients appeared to fare worse than placebo was the divergence statistically significant. 

• The 50mg slope here is particularly impressive and would likely foretell a significant longitudinal saving to a patient over a robust time period.

• The 50mg group slowed cognitive decline by 38.5% and the 30mg group slowed cognitive decline by 34.6%. This does not account for APOE gene analysis or S1R WT analysis which would likely narrow down a super-responder sub-population.

ADCS-ADL

• ADCS-ADL functional scores were broken out by dose (30mg and 50mg).

• 30mg at 48 weeks comparing dosed to placebo: delta of +0.890 with a p-value of 0.354

• 50mg at 48 weeks comparing dosed to placebo: delta of +0.652 with a p-value of 0.527

• Dose-dependence = not achieved, statistical significance = not achieved

• While both dosed cohorts beat placebo and trended positively, both cohorts failed to reach statistical significance. It is possible that early-stage patients with too few functional detriments bogged down the score, especially as the company didn't use the ADCS-MCI-ADL variant to measure function. Verbatim from the company: "A possible explanation is that the ADCS-ADL scale is designed for AD with overt dementia and is less sensitive for early AD".

• New draft guidance by the FDA will omit the need for a successful functional endpoint such as ADCS-ADL.

CDR-SB

• CDR-SB functional & cognitive (global) scores were broken out by dose (30mg and 50mg).

• 30mg at 48 weeks comparing dosed to placebo: delta of -0.502 with a p-value of 0.020

• 50mg at 48 weeks comparing dosed to placebo: delta of -0.465 with a p-value of 0.045

• Dose-dependence = not achieved [relatively equal], statistical significance = achieved 

• Both 30mg and 50mg cohorts performed with margin of each other on the global CDR-SB. Both cohorts beat Lecanemab's (Leqembi) results here, which was a -0.45 delta over a significantly longer dosing regimen. 

• The 50mg group slowed cognitive decline by 26.5% and the 30mg group slowed cognitive decline by 28.6%. This does not account for APOE gene analysis or S1R WT analysis which would likely narrow down a super-responder sub-population.

CGI-I

• CGI-I global impressions scores were broken out by dose (30mg and 50mg).

• 30mg at 48 weeks comparing dosed to placebo: delta of -0.248 with a p-value of 0.024

• 50mg at 48 weeks comparing dosed to placebo: delta of -0.314 with a p-value of 0.008

• Dose-dependence = achieved, statistical significance = achieved

• Dr. Sabbagh really enjoyed discussing the CGI-I. Physicians were blinded and interviewed the patient while assessing benefit of treatment. Response in the 50mg group was exceptionally strong with a slope indicating a possible reversal.

• The CGI-I measures were met with very strong statistical significance.

Brain Atrophy

• Blarcamesine significantly slowed brain atrophy in key regions of interest, including the whole brain by 37.6%, total grey matter by 63.5%, and lateral ventricles by 25.1%. These were all statistically significant. 

• Atrophy reduction and prevention indicates an effect on the underlying neurodegeneration in early-Alzheimer's patients.

• White matter rates saw no change from placebo. It is notable that white matter is one of the last areas to experience degeneration in early-stage patients, so little change between placebo and dosed groups is perhaps unsurprising.

• Because MRI was only conducted at baseline and at week 48, it is difficult to visualize the slope change progressively over time. It is possible that with additional measures over a longer timeframe, whole brain, grey matter, and lateral ventricles could continue slowing decline, and perhaps even return to normal aging rates (effectively halting atrophy). Again, this measure does not take into account APOE status or S1R WT measures. We also haven't seen whether or not vascular comorbidity sub-populations have an effect on Blarcamesine efficacy for atrophy. 

Plasma Amyloid 42/40, NFL, P-Tau

• As previously elucidated, plasma amyloid 42/40 goes up tremendously over placebo, indicating an aggressive removal of the protein from the brain. This is a very positive outcome and had a p-value of 0.048. 

• Blarcamesine trended positively in NFL, p-Tau 181 and p-Tau 281 but failed to reach statistical significance in all three measures. This is surprising as these measures are strongly associated with neuronal injury and brain atrophy. With that said, a larger trial over a longer timeframe probably would have seen statistical significance. 

Safety

• As we have known, most safety concerns were mild and consisted of dizziness. They were mostly transient (temporary) and subsided by the end of the titration phase. Most patients that discontinued the trial did so before week 24, and is probably related to up-titration. In the compassionate use phase (post-OLE), Anavex slowed titration further and increased use of nighttime dosing to reduce these adverse events.

• There was no ARIA noted in this trial. 

Conclusion and Next Steps: Anavex continues to impress with holistic improvements across the A/T/N construct - to our knowledge this is a first for any registrational level drug. From todays presentation in particular we were most piqued by very strong dose-dependent improvements in ADAS-COG13 (cognition), dramatically reduced grey matter degeneration, robust physician assessment as quantified on CGI-I, and trending improvements on other markers like NFL and tau. It is our opinion that Anavex's recent qualification of autophagy as SIGMAR1's main therapeutic outcome and their openness to act synergistically with existing monoclonal antibodies like Leqembi and Donanemab likely acts to increase liklihood of scientific buy-in and market penetration post-approval. Considering Leqembi's recent failure to garner a foothold in the European Union, we look forward to Anavex submitting for European approval in Q4 2024. Additionally, we are excited for further data in Anavex's landmark Alzheimer's study, including information on super-responder analysis, S1R WT & APOE analysis, and full genome analysis which will drive future precision medicine approaches. Spirit of the Coast Analytics will likely publish follow-on analysis to this report in the future. Thank you for your support as always.

Question: Why would the Tau measure possibly meet statistical significance over a longer trial with more participants?

Answer: Amyloid and Tau are both proteins associated with Alzheimer's disease. Amyloid is found extracellularly (outside the neuron) and Tau is found mostly intracellularly (inside the neuron) - at least in early disease stages. Because of this, amyloid is more accessible to intervention over Tau. Tangled up Tau inside the neuron make the protein less accessible to intervention and also complicates its clearance. Separately, Tau accumulation is less common and in less abundance in early disease stages than amyloid, making it more difficult to assay in smaller trials. With that said, overall mean score for p-Tau 181 and 281 trended extremely favorably so we do know some patients saw marked reduction of the protein. It is possible that a longer trial would allow Blarcamesine's upstream mechanism to change the intracellular landscape more favorably than a shorter trial. As noted in Harald Hampel's peer review for Anavex's 2a trial, "time on drug" was a key predictor of effect. In the case of Tau, which is strongly tied to injury and atrophy, it may be that atrophy slows/halts first, and then Tau formations are able to be prevented and cleared afterwards. In Biogen's BIIB080 1b trial targeting Tau (Blarcamesine's MOA does not hyperfocus on Tau - improvement in Tau for Anavex is a secondary outcome of its upstream mechanism), it took approximately 25 weeks to show effect, and up to 72 weeks before major success was seen.