Anavex Life Sciences Announces U.S. Phase 2 Clinical Trial of ANAVEX®3-71 in Schizophrenia
Anavex Life Sciences Corp. announces the initiation of a placebo-controlled Phase 2 trial of ANAVEX®3-71 for the treatment of schizophrenia, which is expected to begin in Q2 2024. ANAVEX®3-71 is a dual SIGMAR1 receptor agonist and M1 positive allosteric modulator with agonistic effects, offering the potential to treat all symptom domains of schizophrenia without the side effects of standard antipsychotics. The trial will study positive, negative, and cognitive domains of schizophrenia based on ANAVEX®3-71’s ability to synergistically activate both SIGMAR1 and M1 muscarinic receptors.
The initiation of a Phase 2 clinical trial for ANAVEX®3-71 marks a critical juncture in the development of new treatments for schizophrenia. The compound's dual mechanism, targeting both SIGMAR1 and M1 muscarinic receptors, is a noteworthy deviation from typical antipsychotic treatments, which primarily act on dopamine receptors. This novel approach could potentially address the full spectrum of schizophrenia symptoms—positive, negative and cognitive—more effectively than current standard care, which often fails to adequately manage the negative and cognitive symptoms associated with the disorder.
From a medical research perspective, the use of established clinical outcomes like the PANSS, combined with novel electrophysiological biomarkers, could enhance the robustness of the trial's findings and may facilitate a more nuanced understanding of the drug's efficacy. The reference to genetic links between schizophrenia and Alzheimer's disease further underscores the potential broader application of ANAVEX®3-71, which could be significant given the high comorbidity and shared pathophysiological features of these diseases.
For investors, the progression of ANAVEX®3-71 into Phase 2 trials is a pivotal event that could influence Anavex Life Sciences Corp.'s market valuation. The success of Karuna Therapeutics' similar compound, KarXT, suggests a receptive market and a proven pathway for muscarinic agonists in treating schizophrenia. This could bode well for Anavex if ANAVEX®3-71 demonstrates efficacy and safety in the upcoming trials.
However, it's important to note that clinical trials are inherently risky and the outcomes are uncertain. The investment community will be closely monitoring the trial's progress and results, as positive data could lead to significant appreciation in Anavex's stock price, while failure could have the opposite effect. Moreover, the potential for ANAVEX®3-71 to treat Alzheimer's disease adds another layer of speculative value, given the size and unmet needs of the Alzheimer's treatment market.
The pharmacological profile of ANAVEX®3-71 is particularly intriguing due to its dual action as a SIGMAR1 receptor agonist and M1 positive allosteric modulator . SIGMAR1 receptors are involved in neuroprotection and neuroplasticity, while M1 receptors play a critical role in cognitive function. The combination of these effects could theoretically provide a more holistic treatment approach for schizophrenia, which is often characterized by a disruption in neuronal homeostasis.
The reference to ANAVEX®3-71's pro-cognitive effects and behavioral improvements in animal models, as well as its ability to prevent cognitive decline in an Alzheimer's disease model, suggests that if these effects translate to humans, it could represent a significant advancement in the treatment of neurodegenerative and neurodevelopmental disorders. The pharmacological community will be keen to analyze the trial's data upon completion to assess the clinical relevance of these preclinical findings.
01/16/2024 - 07:30 AM
Placebo-controlled Phase 2 trial cleared by the FDA – Trial to begin in Q2 2024
Trial to include Schizophrenia validated clinical outcomes PANSS and EEG/ERP biomarkers
Trial to study positive, negative, and cognitive domains of Schizophrenia based on ANAVEX® 3-71’s ability to synergistically activate both SIGMAR1 and M1 muscarinic receptors
NEW YORK, Jan. 16, 2024 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), 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, and schizophrenia, today announced the initiation of the U.S. FDA cleared placebo-controlled Phase 2 trial of ANAVEX® 3-71 for the treatment of schizophrenia, which is expected to begin in Q2 2024. ANAVEX® 3-71 positive initial Phase 1 results in healthy volunteers were previously reported.1
ANAVEX® 3-71 (formerly AF710B) is a dual SIGMAR1 receptor agonist and M1 positive allosteric modulator with agonistic effects. This novel mechanism of action offers the potential to treat all symptom domains (positive, negative, and cognitive) of schizophrenia without the side effects of standard of care antipsychotics.2
The selective nature of ANAVEX® 3-71’s dual synergistic mechanism of action has previously demonstrated long-lasting, pro-cognitive effects and behavioral improvements in animal models of neurodegenerative diseases.3 ANAVEX® 3-71 has also previously demonstrated the ability to prevent cognitive decline in an animal model of Alzheimer’s disease.4
New research into the genetic underpinnings of schizophrenia has revealed links between this psychiatric disorder and Alzheimer’s disease, suggesting the disorders may share certain mechanisms.5
A recent successful trial of Karuna Therapeutic’s dual M1/M4 muscarinic receptor agonist KarXT in individuals with schizophrenia demonstrated efficacy in treating both positive and negative symptoms.6 , 7 Muscarinic agonists have previously been investigated in Alzheimer’s disease8 and schizophrenia.9
Positive, negative, and cognitive symptoms associated with schizophrenia are strongly associated with poor social and functional outcomes. As currently approved treatments only control a subset of symptoms, patients continue to exhibit severe impairments in social and occupational functioning and poor quality of life. ANAVEX® 3-71’s ability to modulate both SIGMAR1 and M1 receptors synergistically are expected to address disruptions to neuronal homeostasis observed in individuals with schizophrenia, upstream of the targets leveraged by standard of care medications which do not adequately address all domains of symptoms in schizophrenia.
The placebo-controlled Phase 2 ANAVEX® 3-71-SZ-001 study, will consist of two-parts to explore multiple ascending doses in individuals with schizophrenia followed by a 28-day treatment period in a larger cohort. The study will utilize standard clinical outcome measures for schizophrenia including the Positive and Negative Symptoms Scale (PANSS) and novel electrophysiological biomarkers identified by the ERP Biomarker Qualification Consortium for use in schizophrenia clinical trials.10
“Schizophrenia is a serious mental illness affecting 24 million people worldwide. While current antipsychotic therapies can be effective in managing positive symptoms, like hallucinations and delusions, they may not fully address persistent negative symptoms or cognitive difficulties. Often, available treatments are limited by side effects, e.g., movement disorders, sedation, weight gain, and other metabolic side effects,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. “We are excited to build on our diverse Precision Medicine Platform, which advanced blarcamesine (ANAVEX® 2-73) onto a regulatory pathway for potential treatment of Alzheimer’s disease and to now also study ANAVEX® 3-71, another small molecule from our drug portfolio with selective SIGMAR1 receptor activity as a novel pharmacological approach to potentially provide a new schizophrenia treatment option for patients and their physicians.”
About Schizophrenia Schizophrenia is a persistent and often disabling mental illness impacting how a person thinks, feels, and behaves, and affects nearly 24 million people worldwide, including 2.8 million people in the U.S. It is characterized by three symptom domains: positive symptoms (hallucinations and delusions), negative symptoms (difficulty enjoying life and withdrawal from others), and cognitive impairment (deficits in memory, concentration, and decision-making). In part due to limitations with current treatments, people living with schizophrenia often struggle to maintain employment, live independently, and manage relationships. While current treatments can be effective in managing select symptoms, approximately 30% of people do not respond to therapy, with an additional 50% experiencing only a partial improvement in symptoms or unacceptable side effects.
About Anavex Life Sciences Corp. Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, schizophrenia and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex's lead drug candidate, ANAVEX® 2-73 (blarcamesine ), has successfully completed a Phase 2a and recently a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX® 2-73 is an orally available drug candidate that restores cellular homeostasis by targeting SIGMAR1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's disease. ANAVEX® 2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX® 2-73 for the treatment of Parkinson's disease. ANAVEX® 3-71, which targets SIGMAR1 and M1 muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX® 3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com . You can also connect with the Company on Twitter, Facebook , Instagram , and LinkedIn .
Forward-Looking Statements Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks set forth in the Company’s most recent Annual Report on Form 10-K filed with the SEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof.
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1 Fadiran EO, Hammond E, Tran J, et al. Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease. Clin Pharmacol Drug Dev. 2023;12(9):888-901. doi:10.1002/cpdd.13032 Fisher A, Bezprozvanny I, Wu L, et al. AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease. Neurodegener Dis. 2016;16(1-2):95-110. doi:10.1159/0004408643 Hall H, Iulita MF, Gubert P, et al. AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer's disease. Alzheimers Dement. 2018;14(6):811-823. doi:10.1016/j.jalz.2017.11.0094 Orciani C, Do Carmo S, Foret MK, et al. Early treatment with an M1 and sigma-1 receptor agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology [published online ahead of print, 2023 Sep 26]. Neurobiol Aging. 2023;132:220-232. doi:10.1016/j.neurobiolaging.2023.09.0105 Guo P, Meng C, Zhang S, et al. Network-based analysis on the genes and their interactions reveals link between schizophrenia and Alzheimer's disease. Neuropharmacology. 2024;244:109802. doi:10.1016/j.neuropharm.2023.1098026 Weiden PJ, Breier A, Kavanagh S, Miller AC, Brannan SK, Paul SM. Antipsychotic Efficacy of KarXT (Xanomeline-Trospium): Post Hoc Analysis of Positive and Negative Syndrome Scale Categorical Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study. J Clin Psychiatry. 2022;83(3):21m14316. Published 2022 May 11. doi:10.4088/JCP.21m143167 Kidambi N, Elsayed OH, El-Mallakh RS. Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia. Neuropsychiatr Dis Treat. 2023 May 10;19:1145-1151. doi: 10.2147/NDT.S406371. PMID: 37193547; PMCID: PMC10183173.8 Bodick NC, Offen WW, Levey AI, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 1997;54(4):465-473. doi:10.1001/archneur.1997.005501600910229 Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033-1039. doi:10.1176/appi.ajp.2008.0609159110 Cecchi M, Adachi M, Basile A, et al. Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers. Schizophr Res. 2023;254:178-189. doi:10.1016/j.schres.2023.02.018
What is the Phase 2 trial for ANAVEX®3-71?
The Phase 2 trial is for the treatment of schizophrenia and is expected to begin in Q2 2024.
What is the mechanism of action of ANAVEX®3-71?
ANAVEX®3-71 is a dual SIGMAR1 receptor agonist and M1 positive allosteric modulator with agonistic effects, offering the potential to treat all symptom domains of schizophrenia without the side effects of standard antipsychotics.
What are the expected outcomes of the trial?
The trial will study positive, negative, and cognitive domains of schizophrenia based on ANAVEX®3-71’s ability to synergistically activate both SIGMAR1 and M1 muscarinic receptors.
Who is the President and CEO of Anavex?
Christopher U Missling, PhD is the President and Chief Executive Officer of Anavex.
