Spirit of the Coast Analytics

SOTC Analytics strives to report medical intelligence pertaining to neurodegenerative & neurodevelopmental disorders to include Alzheimer's Disease, Parkinson's Disease, Rett Syndrome, Angelman Syndrome, Fragile X, and more.

We follow ongoing trends in clinical research, recap important peer-reviewed medical journals, and chronicle ongoing events at Anavex Life Sciences corp. ($AVXL), which we believe may have the most promising emerging therapeutics cross-central nervous system (CNS).

Bottom-line Up Front: As predicted in 2023, Anavex chose Europe as their first stop toward Alzheimer's approval. Europe suffers from a serious deficit in imaging offices required for monoclonal antibody (mAb) administration, a large population of 'most optimal' Alzheimer's patients, and a lagging therapeutic toolkit - having not approved Lecanemab or Donanemab as of this writing. An efficacious oral therapy available to most patients without the risk of brain bleeding/swelling and need for expensive monitoring poises Anavex in an attractive position for Europe-wide approval and subsequent capitalization. Depending on approval pathway, Anavex could see approval for Blarcamesine in the European Union by late end of year 2024. Meanwhile, discussions for Rett approval are likely in the near term, and trials with the 3-71 compound are set to begin imminently. 

Summary

• Anavex's full Alzheimer's 2b/3 data is set to be published in a peer-reviewed journal soon.

• The company is likely positioned for Alzheimer's approval in Europe.

• We expect benefit of Blarcamesine over mAbs in cost, safety, administration, and efficacy will allow it to explosively supersede the antibodies in market penetration.

• A phase 2 Schizophrenia trial testing Anavex 3-71 is imminent.

• Further Rett Syndrome guidance is expected in 2024 which may result in approval.

• Further, more in-depth analysis can be found in the 2022 and 2023 archive folders.

Investment Thesis

Anavex Life Sciences Corporation (AVXL) has likely positioned itself for European approval for their lead compound, Blarcamesine, which is currently the most promising remedy for holistic neurodegenerative and neurodevelopmental diseases in development, thanks to its wide-sweeping mechanism of action (MOA) revolving around Sigma-1 receptor (S1R) & muscarinic agonist properties. According to SOTC analysis, and confirmed by Anavex CEO Dr. Christopher Missling, Blarcamesine showed significant cognitive and functional improvement in Alzheimer's patients in greater magnitude, and earlier, than existing mAb therapies Aduhelm, Leqembi, and Donanemab. Additionally, the drug dramatically slowed brain atrophy and improved amyloid biomarker 42/40. Brain preservation has never been shown in a mAb trial and indicates potential preventative action. By the scientific communities own definition, Blarcamesine is a first-in-class Alzheimer's disease modifying drug, showing improvement in patient outcomes and meaningfully changing slope of disease progression. Reported on 7 Feb 24, Anavex maintained $143.8M in cash, which is set to finance the company for at least the next four years. This is the first time in recent memory that the company used its own cash reserves (from $151M) to maintain operations, which indicates a possible expectation for separate cash infusion beyond dilution in the near-to-mid term. Anavex maintains exceptional room for growth beyond Alzheimer's, featuring an extensive pipeline in large unmet needs, a slew of orphan disorders, an immaculate safety profile, and an entire platform of other early-stage drugs like Anavex 3-71, Anavex 1-41, and Anavex-1066 which provide long-term growth potential. 

Monoclonal Antibody Market Penetration Difficulty

On 6 Feb 24, Eisai - owner of the first disease-modifying Alzheimer's drug Leqembi (Lecanemab), reported unexpectedly slow market penetration in the United States. Despite marketing with Biogen, the drug is falling well short of the 10,000 patients expected to be on-drug by Mar 24. As of 26 Jan 24, only 2,000 patients have been prescribed Leqembi. The company had expected to reap some $365M in sales by end of the year, but at the current $1.5M a week, the company could reasonably expect to hit only $78M - $100M. This outcome is unsurprising given Aduhelm market languish - a similar drug developed by Eisai and Biogen, which was recently announced to be an effectively 'dead drug' due to lack of sales and loss of confidence. While Leqembi presented better efficacy than its predecessor, the drugs still present a myriad of issues. For starters, the drugs are expensive. Leqembi costs $19,500 annually, $11,000 of which is out-of-pocket for patients. When you combine the financial burden with marginal cognitive & functional benefit, and the persistent threat of ARIA (brain bleeding/swelling), patients & caregivers have little choice but to accept the therapy or wait for something safer to come along. Due to ARIA concern, the drugs require repeated PET/MRI monitoring, which is unavailable in many rural areas, especially outside of the United States. Beyond these concerns, the drug is only designed to work in a rather limited patient population. In fact, 80% of the patients screened for Leqembi's CLARITY trial were excluded for not meeting optimal requirements. Anavex has a real opportunity to overcome these market penetration challenges. Working far upstream, the drug works agnostic to a patient's individual pathology or disease cause (pathogenesis). Most patients would be able to theoretically take Blarcamesine, which is conveniently orally administered, has a favorable safety profile with no brain bleeding/swelling, and high efficacy without the need for follow-up monitoring. From a cost perspective we assess the drug will likely be far less expensive than Leqembi, somewhere between $8,000 - $14,000 annually. Considering these factors, as well as mAb inability to garner European approval, 2024 is an extremely favorable time to approach the U.S. FDA and European EMA for Alzheimer's approval.

Market Applicability

Based on previous in-depth analysis that can be read here, we assess Blarcamesine is likely able to provide absolute improvement or significant slowing of 237 - 486% in a large population cohort. 

If disease stage is unaccounted for, Blarcamesine could be expected to most optimally treat 48% of all MCI-AD and all-stage Alzheimer's patients. Most optimal treatment could see a 486% improvement over standard of care, in many cases resulting in reversal of pathology.

If disease stage is unaccounted for, Blarcamesine could be expected to second-most optimally treat 13% of all MCI-AD and all-stage Alzheimer's patients. Second-most optimal treatment could see a 237% improvement over standard of care, in most cases substantially stagnating pathogenesis.

We have used all company & independent data available to come to these conclusions. One uncertainty we have that has not been accounted for is cholinergic neuron degradation. Being a dual S1R/M1-M4 agonist, the drug works by synergistically enhancing SIGMAR1 gene expression and muscarinic modulation (one of two cholinergic types). It is known that a moderate-to-large degree of Alzheimer's patients experience significant cholinergic neuron depletion by mid-stages in disease course. It is likely that patients with largely intact cholinergic function would reap greater benefit from the drug than patients with degraded cholinergic function. This has been somewhat implied by Anavex; although, it was noted that while the drug works best from synergistic mechanism, the S1R component and muscarinic components are also beneficial separately. In this case, patients with depleted cholinergic neurons would still benefit to a lesser degree from the S1R component.

Overall, approximately 61% of patients are likely to see significant, disease altering effects from Blarcamesine therapy. The remaining 39% are likely to also benefit to lesser varying degree.

Looking Forward

Anavex is likely pursuing an industry-defining genomic study for their completed Alzheimer's 2b/3 trial. Spirit of the Coast Analytics expects this robust analysis to correlate genomics, disease pathology, dosing, and efficacy to fully elucidate 'responders' (classified as patients with absolute improvement/reversal) and varying level of moderate-to-non responder. We believe Anavex is well positioned to accomplish this task with the assistance of Dr. Marwan Sabbagh, Chairman of the Scientific Advisory Board, whom is a frontrunner in disease classification and biomarker analysis. Whether this data is included in the first forthcoming 2b/3 peer-reviewed journal article is unknown at this time. If not, we expect this data later in 2024 along with 72 and 96 week open label extension data, which is especially important as it directly correlates with mAb trial timeframes for more direct comparison. Separately, we also look forward to the Anavex 3-71 Schizophrenia phase 2 trial which is set to launch imminently, and possibly Fragile-X trial initiation with Blarcamesine. Rett Syndrome progression is dependent on regulator discussions, but in all cases we expect Rett Syndrome to continue being a main focus of the pipeline. 

Ultimately we look forward to the full Alzheimer's data-set and are keen to see the EMA's commentary towards Blarcamesine. Brain preservation is a massively undervalued metric, and its our position the drug could have possibly garnered symptomatic approval for it as a standalone due to its preventative implications. As it stands, tying successful cognitive & functional endpoints to traditional amyloid-beta 42/40 improvement & brain volume preservation, the drug is a clear disease-modifier and we give high odds of approval without an additional trial. We look forward to what's to come in 2024, and don't forget, "Grey Matter Matters".