Anavex Life Sciences Operational Updates in 2024

Anavex Life Sciences is a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome, schizophrenia, and other central nervous system diseases.

In January 2024, Anavex announced a peer-reviewed publication in Clinical Pharmacology in Drug Development, which included findings from the Anavex 3-71 first-in-human study, which achieved its safety objectives, and on March 18, the company announced that the first patient in its U.S. Food and Drug Administration-cleared placebo-controlled Phase 2 clinical study of Anavex 3-71 for the treatment of schizophrenia had been screened.

The company recently published updates on a variety of topics related to its ongoing operations.

Overview of 2b/3 Alzheimer’s Trial and Significance of Responder Analysis

Anavex's recent Alzheimer’s trial focused on meeting co-primary endpoints on the Alzheimer’s Disease Assessment Scale, specifically the ADAS-COG (cognitive) and ADCS-ADL (Alzheimer's Disease Cooperative Study activities of daily living) measures within the 2b/3 trial. The analysis primarily emphasized the combined 30mg and 50mg dosed cohorts versus a placebo. Notably, while the ADAS-COG endpoint was successfully met, the ADCS-ADL did not reach statistical significance. Fortunately, predefined anchoring of ADAS-COG to the key secondary endpoint CDR-SB (global) allowed for a successful trial designation.

The regulatory assessment by bodies such as the FDA and European Medicines Agency will likely prioritize the primary analysis of the pooled 30mg and 50mg cohorts for approval decisions. However, secondary analyses, including specific dosing subgroups (30mg and 50mg versus placebo) and patient characteristics like comorbidity, S1R gene status, and demographics will provide valuable insights for post approval commercialization efforts.

In the context of post approval use, responder analyses will be pivotal in guiding physicians' decisions. By leveraging preestablished gene and disease-stage analyses (e.g., S1R gene analysis), which show high confidence in predicting responders (over 80%), physicians can better inform patients about potential outcomes from treatment, such as cognitive decline reversal.

Although commercialization may benefit greatly from responder analyses, the primary focus for regulatory bodies remains the success of the combined dosing arms during the trial. This means that even if one dosing group (e.g., 30mg) had not shown efficacy while another (e.g., 50mg) did, approval would likely be granted for the successful arm(s) in the pooled analysis. Ultimately, this underscores the significance of combined dosing success in achieving trial objectives.

The Significance of Brain Atrophy Data and Advantages of Blarcamesine Over Big Pharma Monoclonal Antibodies

Research suggests a strong association between brain atrophy and cognitive decline as well as life expectancy. In individuals with Alzheimer's disease, those with atrophied amygdala face over a 315% increased risk of mortality, while those with atrophied hippocampus have a 220% higher likelihood of death compared to healthy aging adults. Furthermore, each 1% increase in annual whole brain atrophy raises the odds of progressing to the next stage of dementia by 30%.

Having reported halting atrophy during a pivotal trial — the only such achievement in the field — Anavex appears to be at the forefront of brain atrophy treatment. In contrast, monoclonal antibodies have been observed to potentially exacerbate brain atrophy. Anavex 2-73 may have even reversed atrophy in some cases. Anavex's focus will likely be on preserving or halting atrophy rather than pursuing full reversal, a concept that remains less understood.

Blarcamesine offers distinct advantages over antibody treatments like Aduhelm, Leqembi, and donanemab. Blarcamesine is a small molecule administered orally, contrasting with the injectable antibodies, and clinical trials have demonstrated improvements across the full spectrum of amyloid, tau, and degeneration biomarkers, showing a strong safety profile without amyloid-related imaging abnormalities such as brain swelling and bleeding. Moreover, the therapy has shown clinically meaningful benefits compared to baseline in a broad range of patients.

An important consideration is the addressable market. Antibody therapies typically set stringent amyloid thresholds for patient recruitment, resulting in the exclusion of tens of thousands of potential patients. This approach ensures successful trials, but limits the eligible patient pool postapproval. Anavex's recruitment process, while confirming amyloid positivity, does not hinge on specific amyloid thresholds, potentially broadening the patient population eligible for treatment.

Considering the black box warnings associated with antibody therapies, blarcamesine presents a more appealing option for a wider patient base, offering a substantial advantage in terms of the addressable market.

EXCELLENCE Trial and Reevaluation

The outcome of the EXCELLENCE Rett trial, which did not meet its endpoints, appears to have been influenced by several factors, including trial design and a significant placebo response. Around two-thirds of the trial participants were administered the drug, leading to an imbalance in the dosed versus placebo groups. This likely created an assumption among caregivers and physicians that their patients were receiving the intervention, given the statistical likelihood of being in the treatment arm.

In contrast, during the trofinetide trial, more than 80% of patients experienced diarrhea, inadvertently revealing who was on the intervention due to this side effect. This pseudo-unblinding reduced the placebo response, particularly within the close-knit Rett syndrome community, where trial outcomes were actively discussed.

Blarcamesine, however, did not exhibit such telltale side effects, allowing for complete blinding in the trial. Unfortunately, despite showing efficacy in previous Rett trials, blarcamesine also fell short of endpoints in the EXCELLENCE trial. Nonetheless, this setback does not signal the end of research in the Rett syndrome field or related rare diseases.

Considering the unmet need highlighted after trofinetide, and the announcement of a forthcoming follow-on trial, it is evident that there remains a demand for new treatments. Future trials will likely address the shortcomings of previous designs, aiming for a more balanced distribution between placebo and intervention groups to enhance statistical power. While the EXCELLENCE trial outcome poses a significant challenge, it represents a hurdle rather than a conclusion for Rett syndrome research and related rare diseases.

On Future Partnerships

The SIGMA-1 (SIGMAR1, S1R) mechanism remains a unique and novel approach. The forthcoming peer-reviewed study on Alzheimer's disease, phase 2b/3, is poised to significantly enhance Anavex’s credibility and solidify its innovative mechanism within the field. This paper, likely led by Missling and Marwan Sabbagh, M.D., chairman of Anavex’s Scientific Advisory Board, holds pivotal importance for securing future partnerships. Sabbagh's anticipated prominent role underscores his reputation and dedication to advancing promising therapeutics.

It is speculated that a future collaboration with Eli Lilly or Sanofi is probable, potentially culminating around the time of EMA/FDA submission or approval. Although specifics on the deal structure are to be determined, it's anticipated to involve upfront payments and royalties, typical for such partnerships in the pharmaceutical industry.

Week 12 Divergence in ADAS-COG and CDR-SB Linear Charts

The company's decision to up-titrate until Week 12 likely contributed significantly to the observed divergence, creating the appearance of placebo outperforming blarcamesine. Fortunately, this divergence was not statistically significant and resolved once the up-titration phase concluded.

In Alzheimer’s trials today, patients are more knowledgeable than in previous years, partly due to landmark studies like FINGERS, which promote lifestyle changes to slow disease progression. During early trial stages, patients and caregivers can be influenced by the placebo effect. Caregivers closely monitor their loved ones for any changes, and lifestyle modifications such as diet and exercise can temporarily improve outcomes, especially in mild cognitive impairment and early Alzheimer's. Therefore, longer trials are preferable in Alzheimer's research.

Looking ahead, it will be interesting to see similar analyses for the 50mg-only and responder-only subgroups. This data will provide deeper insights into blarcamesine's effects in these specific populations.

On the European Medicines Agency Approval for Blarcamesine Alzheimer’s Indication

Anavex's drug approval process is advancing steadily, with expectations of EMA submission by December 2024 or more likely in the first or second quarter of 2025. There's an estimated 89% likelihood of approval under accelerated assessment conditions. Anavex is anticipated to delay its FDA filing until the conclusion of its 2b/3 OLE study and the finalization of the early Alzheimer's draft guidance. However, various administrative factors could potentially extend the approval timeline beyond our projections, prompting investors and stakeholders to evaluate their own timelines for drug approval.

Spirit of the Coast Analytics specializes in the scientific facets of company development and employs probability language as outlined in ICD 203, which may not be widely familiar to all observers.

Anavex is eagerly anticipating the forthcoming publication of a peer-reviewed paper, expected to significantly enhance the company's reputation and partnership opportunities. Given recent Annovis data disclosures and available information on antibody trial outcomes, Anavex is positioned as having the most compelling validated cognitive data in Alzheimer's research. SOTC Analytics plans to integrate later this year, continuing its examination of Anavex Life Science Corporation and emerging developments in the CNS sector.

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