Jesse Silveira

Jesse Silveira sought clarification on the CHMP's rejection phrasing regarding SIGMAR1 wild type patients, the company's strategy to address the ADCS-ADL endpoint miss using new statistical methodology, the status of the CHMP re-evaluation submission and SAG appointment, and details on Anavex's participation in the ACCESS-AD program for blarcamesine, including its trial design and patient population.

Answer

President and CEO Christopher Missling clarified that while not criticizing regulatory bodies, Anavex's interpretation showed significance in SIGMAR1 wild type for ADAS-Cog13 and CDR-SB, with ADCS-ADL being less sensitive for early Alzheimer's. He confirmed the company is arguing for the scientific invalidation of ADCS-ADL, consistent with regulatory guidances. He stated updates on the CHMP submission and SAG appointment would be provided once results are available, confirming a confirmatory Phase 4 study would run in parallel with conditional approval. Missling detailed the ACCESS-AD program includes a dedicated placebo-controlled blarcamesine trial (AD006) for early Alzheimer's patients, focusing on biomarkers and efficacy, with regulatory goals. He also noted the atrophy paper is pending submission.

Jesse Silveira sought clarity on the CHMP's rejection statement regarding SIGMAR1 wild type patients, the company's strategy using a new p-value threshold to address the ADCS-ADL endpoint, and the status of the new submission to CHMP and SAG appointment. He also asked about the commitment to a confirmatory Phase IV trial if approved under CMA, details on blarcamesine's involvement in the ACCESS-AD program, and the status of the autophagy to clinical improvement analysis paper.

Answer

President and CEO Christopher Missling clarified that while not criticizing regulatory bodies, ADAS-Cog13 and CDR-SB showed significance in SIGMAR1 wild type, and the ADCS-ADL is considered less sensitive for early AD. He stated that the new statistical approach and scientific invalidation of ADCS-ADL for early AD are key arguments. He confirmed that a SAG has been requested for the re-evaluation process and that a confirmatory study would be run in parallel with CMA approval. He detailed blarcamesine's role in the ACCESS-AD program, a placebo-controlled trial for early Alzheimer's patients (AD006), which will contribute to regulatory packages. He also noted that three papers have been submitted, with the atrophy paper to follow soon.

Jesse Silvera asked if Anavex could discuss the reasons for the negative CHMP trending or re-evaluation strategy, sought more details on the biomarker data mentioned in the November 14th press release (specifically brain atrophy and its correlation to cognition), inquired about whether ABCLEAR1, ABCLEAR2, and ABCLEAR3 subpopulations were pre-specified or exploratory and their regulatory implications, questioned the relevance of Leqembi and Kisunla's approvals after CHMP re-examination, asked about the immediate refiling for EMA re-evaluation and a projected April timeline, and whether Anavex has community support for the re-evaluation.

Answer

President and CEO Christopher Missling confirmed that details on the negative CHMP trending and re-evaluation strategy cannot be discussed yet. He reiterated that objective biomarker endpoints, such as brain atrophy, are crucial, drawing an analogy to oncology. He noted that Blarcamesine demonstrated less or halted brain shrinking, which correlates with improved cognitive subdomains, and this data will be presented. He clarified that ABCLEAR1 (wild-type sigma-1 gene) was pre-specified based on Phase 2a findings (70% of the population), while ABCLEAR2 (Collagen 24A1 gene) was an unexpected finding from a pre-planned whole-genome exome analysis of Phase 2b/3, representing 71% of the population. He acknowledged that Lecanemab and Donanemab (Kisunla) underwent re-examination and received approval, emphasizing that benefit must outweigh risk, and Blarcamesine has a good safety profile (no ARIA) and efficacy, though he could not anticipate the outcome. He confirmed Anavex would immediately request re-examination and stated that while the community is aware, Anavex's focus is on presenting data and partnering with regulators.

Jesse Silvera from Spirit of the Coast Analytics asked if Anavex could discuss the reasons for the negative CHMP trend or re-evaluation strategy, and sought further details on the biomarker data, specifically brain atrophy and its correlation to cognition, planned for the re-examination. He also inquired about the pre-specified versus exploratory nature of AbClear 1, 2, and 3 subpopulations, the relevance of Leqembi and Kisunla's re-examination approvals, the timeline for refiling for EMA re-evaluation, and whether Anavex has community support similar to that seen for other Alzheimer's drugs.

Answer

President and CEO Christopher Missling confirmed that details on the negative CHMP trend and re-evaluation strategy cannot be discussed yet. He elaborated on the objective nature of brain atrophy as a biomarker, its historical significance in Alzheimer's pathology, and how Blarcamesine's impact on it, along with its correlation to cognitive improvements, will be presented. Missling clarified that AbClear 1 was pre-specified, while AbClear 2 was an unexpected finding from a pre-planned whole genome exome analysis. He acknowledged the precedent of other drugs gaining approval after CHMP re-examination but stressed that Anavex cannot guarantee an outcome. He confirmed immediate refiling for re-examination and noted that Anavex relies on the community's awareness and its own data presentation rather than actively soliciting external support.

Jesse Silveira of Spirit of the Coast Analytics asked about the theoretical use of CRISPR technology to enhance blarcamesine's efficacy, the company's plans for an Alzheimer's prevention trial, and the strategic objectives behind retaining a lobbying firm and engaging with policymakers. He also inquired about Anavex's interest in the FDA's new accelerated approval voucher program.

Answer

President & CEO Dr. Christopher Missling acknowledged that CRISPR is theoretically possible but stated it's largely unnecessary as most patients have a functional sigma-1 gene. He confirmed Anavex plans a preventative trial based on positive preclinical data but noted it is resource-dependent and will follow the initial drug launch. Regarding lobbying, Dr. Missling described it as a standard industry practice to raise awareness and educate policymakers on the unmet needs in Alzheimer's disease. He affirmed the company's strong interest in the FDA's accelerated voucher program, viewing it as independent of any EMA decisions.

Jesse Silveira of Spirit of the Coast Analytics inquired about the theoretical use of CRISPR technology to enhance blarcamesine's efficacy, plans for an Alzheimer's prevention trial, the strategic objectives of engaging with lobbyists, and the company's interest in the FDA's accelerated approval voucher program.

Answer

President & CEO Dr. Christopher Missling responded that while CRISPR is theoretically possible, it's not necessary for the vast majority of patients who have a functional sigma-1 gene. He confirmed plans for a preventative trial, pending resources, and explained that lobbying efforts are for raising awareness among policymakers. Dr. Missling affirmed the company's strong interest in the FDA's accelerated voucher program, stating it is independent of any EMA decision.