Shots:
- Neurodegenerative care is at a pivotal inflection point, shifting from symptomatic relief to strategies that restore cellular resilience. Blarcamesine (ANAVEX 2-73) advances this upstream approach by activating SIGMAR1 to rebalance autophagy, targeting a core driver of neurodegeneration
- Phase IIb/III findings demonstrated a statistically significant slowing of cognitive decline, with the most pronounced benefit seen in patients carrying the common SIGMAR1 wild-type genotype, underscoring both the robustness of the mechanism and its precision-based potential
- PharmaShots is pleased to welcome Dr. Christopher Missling, President & CEO of Anavex Life Sciences, for an engaging and insightful exchange with PharmaShots, sharing perspectives on innovation, patient need, and the future direction of neurodegenerative care
Saurabh: Welcome to PharmaShots Viewpoints. To begin, could you briefly outline the SIGMAR1 activation mechanism underlying blarcamesine (ANAVEX️ 2-73) and explain why it plays such a central role in your therapeutic approach?
Christopher: Blarcamesine’s (ANAVEX 2-73) Mode of Action (MoA) was confirmed in several peer-reviewed publications. Blarcamesine in vivo SIGMAR1 agonist confirmation was established in a PET study, demonstrating dose-dependent SIGMAR1 receptor engagement.[1] SIGMAR1 (S1R) is an integral membrane protein involved in restoration of cellular homeostasis. It activates an upstream compensatory process: Autophagy through SIGMAR1 activation. SIGMAR1 receptors are significantly lower expressed in the entire brain of the patient with Alzheimer’s disease compared to that of the normal healthy subject.[2] Hence, activation with selective SIGMAR1 agonists, like blarcamesine could restore the compensatory upstream process of autophagy through SIGMAR1 activation.
Saurabh: How does blarcamesine’s mechanism of action distinguish it from other neurodegenerative therapies currently in development?
Christopher: Impairment of autophagy precedes both amyloid beta and tau tangles and therefore anticipates the neurodegenerative process in Alzheimer’s disease.[3],[4]This differentiates blarcamesine from other therapies in development, which target more isolated downstream targets (abeta, tau, inflammation, etc.), while blarcamesine targets more upstream and likely closer to the origin of the pathology.
Saurabh: Could you summarize the most recent clinical data for blarcamesine, with particular emphasis on the results observed in Alzheimer’s disease?
Christopher: Clinical data re-confirmed the mechanism of action (MoA) of blarcamesine by the prespecified SIGMAR1 gene analysis: While over 48 weeks blarcamesine significantly slowed clinical progression by 36.3% in the primary endpoint ADAS-Cog13 [LS mean ADAS-Cog13 difference of -2.027; P = 0.0079] in the ITT analysis, this signal was even stronger in the prespecified common SIGMAR1 wild-type (WT) population with slowed clinical progression by 49.8% at 48 weeks in the active group vs. placebo, respectively [LS mean ADAS-Cog13 difference of -2.317; P = 0.015]. Equal analysis with CDR-SB led to comparable consistent results. Common SIGMAR1 wild-type (WT) [LS mean CDR-SB difference of -0.601; P = 0.012] was stronger compared to ITT analysis [LS mean CDR-SB difference of -0.483; P = 0.0104].[5]
Saurabh: What key regulatory milestones should stakeholders anticipate for blarcamesine across the U.S., EU, and other global markets?
Christopher: We look forward to proceeding with the dialogue we started with global regulators to advance to address critical unmet needs in neurodegenerative diseases like Alzheimer’s disease.
Saurabh: What is the current neurodegeneration landscape and how does Anavex plan to position blarcamesine from a commercial standpoint?
Christopher: Recent high profile Alzheimer’s disease trial failures (tau, GLP-1) demonstrate: Alzheimer’s disease is very complex – blarcamesine upstream approach of autophagy restoration has consistent clinical data points from the Phase IIb/III. Given the aging population and the lack of near term safe medical solutions – it seems to be important to give options to patients and allow them to make choices with their families and physicians. Alzheimer like cancer is a deadly disease. Given the unmet medical need, safe and accessible medicine would be needed – where delay is not an option.
Saurabh: In what ways is Anavex engaging with patient advocacy organizations to guide future clinical trial designs and broader development strategies?
Christopher: We value the perspectives of patients and caregivers and, consistent with applicable laws and regulations, we engage with patient advocacy organizations in ways designed to inform our science and development while safeguarding independence and compliance.
Saurabh: Finally, is Anavex open to strategic collaborations or partnerships aimed at expanding global access to blarcamesine?
Christopher: Yes, the Company is open to expanding collaborative initiatives and strategic partnership activities.
About the Author:
Dr. Christopher Missling
President and CEO, Anavex Life Sciences
Dr Christopher Missling is President and CEO of Anavex Life Sciences and has over 25 years of healthcare industry experience within the large pharmaceutical and biotech industry. Christopher’s work is dedicated to finding potential treatments for degenerative diseases like Alzheimer’s and Parkinson’s disease, as well as autism spectrum disorder, by utilizing precision medicine. Dr. Missling is working with his team to advance new potential convenient oral treatments with the inclusion of the respective stakeholder groups. He has an MS and a PhD in Chemistry and an MBA from Northwestern University Kellogg School of Management.
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[1] Reyes, S T et al. “Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy.” Scientific reports vol. 11,1 17150. 25 Aug. 2021.
[2] Mishina, M et al. “Low density of sigma1 receptors in early Alzheimer’s disease.” Annals of nuclear medicine vol. 22,3 (2008):151-6.
[3] Christ MG, Clement AM, Behl C. The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy. Trends Neurosci. 2020 Feb;43(2):79-81.
[4] Chen, J. et al. Defective Autophagy and Mitophagy in Alzheimer’s Disease: Mechanisms and Translational Implications. Mol Neurobiol 58, 5289–5302 (2021).
[5] Macfarlane, S. et al. “Blarcamesine for the treatment of Early Alzheimer’s Disease.” J Prev Alzheimers Dis. 2025;12(1):100016.
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