Blarcamesine

Part A of the placebo-controlled Phase 2 study has been completed ANAVEX®3-71 demonstrates a dose-dependent pharmacodynamic effect on objective EEG biomarkers of schizophrenia Patients are currently being dosed in Part B of the Phase 2 study which will investigate a longer treatment duration Oct. 17, 2024 -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, neurodevelopmental, neurodegenerative, and rare diseases, including Rett syndrome, and other central nervous system (CNS) diseases, today announced encouraging preliminary electroencephalography (EEG) biomarker results from the Part A of the ongoing placebo-controlled Phase 2 clinical study of ANAVEX®3-71 for the treatment of schizophrenia. Part A of the Phase 2 study ANAVEX®3-71-SZ-001 (NCT06245213), was a multiple ascending dose study in 16 participants treated with either oral placebo, oral ANAVEX®3-71 90 mg daily, or oral ANAVEX®3-71 180 mg daily for 10 days. Preliminary results demonstrated a dose-dependent effect of ANAVEX®3-71 on two key EEG biomarkers in patients with schizophrenia. Treatment with ANAVEX®3-71 compared to placebo resulted in improvements in 40 Hz Auditory Steady-State Response (ASSR) Inter Trial Coherence (ITC) and Resting State Alpha Power, both of which were increased. These effects were most pronounced in the higher dose group demonstrating a dose-dependent pharmacodynamic effect. These results provide evidence of CNS target engagement and potential therapeutic effects of ANAVEX®3-71 in schizophrenia. The observed changes reversed known EEG and ERP biomarker abnormalities associated with schizophrenia1. These EEG biomarkers correlate with positive, negative, and cognitive symptoms of schizophrenia. Individuals with schizophrenia typically have reduced neural synchrony as measured by 40 Hz ASSR ITC. Improvements in 40 Hz ASSR ITC indicate enhanced neural synchronization, potentially leading to reduced auditory hallucinations (positive symptom), improved executive function, and working memory (cognitive symptoms).2 Individuals with schizophrenia also typically have decreased resting state alpha power correlating with sensory and behavioral problems. Increases in Resting State Alpha Power reflect improvements in thalamocortical circuits and sensory gating, potentially resulting in reduced irritability and anxiety (negative symptoms).3 “We are pleased to see an initial effect of biomarkers changing in people with schizophrenia treated with our oral M1/SIGMAR1 therapy ANAVEX®3-71, which could eventually help patients address both positive, negative, and cognitive symptoms of schizophrenia,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. “The results are encouraging for further development of ANAVEX®3-71 for people with schizophrenia.” ANAVEX®3-71 was well tolerated, with no serious adverse events reported. Oral ANAVEX®3-71 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 of schizophrenia without the side effects of standard of care antipsychotics. ANAVEX®3-71 has previously demonstrated long-lasting, pro-cognitive effects and behavioral improvements in animal models of neurodegenerative diseases4,5, an ability to prevent cognitive decline in animal models6,7, and has shown robust safety signals in healthy volunteers at single doses ranging from 5 to 200 mg once daily.8,9 Recent research into the genetic underpinnings of schizophrenia has revealed links between this psychiatric disorder and neurodegenerative disease, suggesting the disorders may share certain mechanisms.10 Oral ANAVEX®3-71, in addition to the M1 muscarinic receptor activity, the combined SIGMAR1 receptor activity might offer a novel mechanism of action that may address multiple symptom domains without the motor side effects associated with traditional antipsychotics. The currently ongoing Part B of the placebo-controlled Phase 2 study, which includes more participants and a longer treatment duration, will provide more comprehensive data on the efficacy and safety of ANAVEX®3-71 in schizophrenia. Anavex expects data from Part B of the placebo-controlled Phase 2 study in the first half of 2025. 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 34% of people do not respond to therapy, 11 with an additional 50-60% experiencing only a partial improvement in symptoms or unacceptable side effects.12 Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of novel therapeutics for the treatment of neurodegenerative, neurodevelopmental, and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, Rett syndrome, 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 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 and one Phase 2/3 study in pediatric patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate designed to restore 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. We believe that 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. 1 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 2 Parker DA, Hamm JP, McDowell JE, et al. Auditory steady-state EEG response across the schizo-bipolar spectrum. Schizophr Res. 2019;209:218-226. doi:10.1016/j.schres.2019.04.014 3 Newson JJ, Thiagarajan TC. EEG Frequency Bands in Psychiatric Disorders: A Review of Resting State Studies. Front Hum Neurosci. 2019;12:521. Published 2019 Jan 9. doi:10.3389/fnhum.2018.00521 4 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:10.1159/000440864 5 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.2017.11.009 6 https://www.anavex.com/post/anavex-life-sciences-reports-new-publication-in-scientific-journal-demonstrating-the-potential-of 7 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.2023.09.010 8 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.1303 9 Fadiran EO, Hammond E, Tran J, Missling CU, Ette E. Population-Based Characterization of the Pharmacokinetics and Food Effect of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer Disease. Clin Pharmacol Drug Dev. 2024;13(1):21-31. doi:10.1002/cpdd.1323 10 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.2023.109802 11 Potkin SG, Kane JM, Correll CU, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr. 2020;6(1):1. Published 2020 Jan 7. doi:10.1038/s41537-019-0090-z 12 Nucifora FC Jr, Woznica E, Lee BJ, Cascella N, Sawa A. Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol Dis. 2019;131:104257. doi:10.1016/j.nbd.2018.08.016 The content above comes from the network. if any infringement, please contact us to modify.

iStock/ wildpixel The next generation of Alzheimer’s therapeutics is moving away from amyloid plaques and tau tangles, offering multiple approaches to slow cognitive decline. Over the past two years, Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla, both anti-amyloid antibodies, made history as the first real options to slow cognitive decline associated with Alzheimer’s disease. For years, amyloid plaques and tau tangles have been a primary target of Alzheimer’s disease research and drug development, but while affecting these proteins may yield some benefit, the illness continues to progress. Today, multiple therapeutics are in Phase III trials with other targets, suggesting that within the next few years it may become possible to treat Alzheimer’s via multiple pathways. There are currently 32 Alzheimer’s therapeutics in 48 Phase III trials, according to a recent paper by neuroscientist Jeffrey Cummings, a professor at the University of Nevada. Six of those target amyloid-β and one targets tau, but the others aim to affect neuroprotection growth factors, neurotransmitters, neurogenesis, inflammation and proteinopathies. Of those, 21 are meant to be disease-modifying. “Alzheimer’s disease is quite complex in its biology and diagnosis,” Rebecca Edelmayer, vice president of scientific engagement for the Alzheimer’s Association, told BioSpace. “We’re moving to a point where we have better understanding of the disease and what contributes to its symptomology, so those biological underpinnings become targets.” These approaches won’t necessarily replace Leqembi and Kisunla, but they could increase therapeutic options to better manage the disease. The First Anti-Amyloid Antibodies for Alzheimer’s In January 2023, the FDA approved Leqembi as the second disease-modifying treatment for Alzheimer’s disease. The third, Kisunla , followed in July 2024. (The first drug, Eisai and Biogen’s Aduhelm, was discontinued earlier this year.) While Leqembi and Kisunla are a positive step forward, experts suggest there is room for improvement. As measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), Leqembi reduced clinical decline by 27%, whereas Kisunla reduced clinical decline by 29%. In addition to limited efficacy, the drugs both have notable side effects, specifically, the risk of amyloid-related imaging abnormalities (ARIA), the increase in lateral ventricular volume and the simultaneous loss of whole brain volume. A finding of ARIA on imaging tests is indicative of a brain bleed or swelling. When physician online community Sermo questioned 268 neurologists, it found a diversity of opinion on how to best determine clinical benefit. Forty percent of those surveyed have treated Alzheimer’s patients with Leqembi or Kisunla. “There’s debate about whether the two already approved therapeutics are that compelling, so the bar is low,” Andrew Tsai, senior vice president of equity research for the biopharma analyst Jefferies, told BioSpace . A major difference between the two is that Leqembi is infused intravenously twice monthly, while Kisunla is infused only once per month. But any infusion is a pain point for many patients, not to mention a cost to the healthcare system, so easier administration is the goal for several next- gen Alzheimer’s therapeutics. Lilly’s drug is also designed to stop treatment once plaque clearance is achieved. Phase III Alzheimer’s Candidates Athira’s Fosgonimeton Athira Pharma’s fosgonimeton is a small-molecule therapeutic that may be injected daily at home. The company recently reported data from a Phase II/III trial of the drug, which enhances signaling by neurotrophic hepatocyte growth factor (HGF). The trial, which included 315 patients with mild-to-moderate Alzheimer’s disease, failed to meet its primary and key secondary endpoints regarding improvements in cognition and function at the 26-week point. However, pre-specified subgroups experienced rapid disease progression, while both cognition and function either stabilized or improved. Biomarkers also showed improvement, according to the company. In preclinical models of Alzheimer’s disease, fosgonimeton has “been shown to reduce inflammation, improve mitochondrial and synaptic function and reduce amyloid toxicity and p-tau aggregation,” Chief Medical Officer Javier San Martin told BioSpace in an email. “[While] Leqembi and Kisunla are monoclonal antibodies targeting removal of amyloid plaque from the brain with the expectation that by removing amyloid the neurons will be preserved . . . fosgonimeton focuses on improving neuronal health regardless whether the insult is amyloid, tau or other misfolded proteins,” he said. Anavex’s ANAVEX 2-73 In New York, Anavex Life Sciences Corp. is targeting neuronal homeostasis in an ongoing Phase IIb/III study with blarcamesine, an oral, once-daily therapeutic that works “through autophagy through SIGMAR1 activation .” “Blarcamesine’s ability to reduce pathological brain volume loss could be defined as disease-modifying,” Andrew Barwicki, company spokesperson, told BioSpace . In the Phase IIb/III trial , blarcamesine slowed clinical progression of Alzheimer’s by 38.5% at 48 weeks, compared to placebo. Analysis of the Phase IIb/III trial showed no associated neuroimaging adverse events and, unlike Kisunla and Leqembi , blarcamesine is not expected to require routine MRI monitoring. “Blarcamesine could be appealing because of its route of administration and good comparative safety profile,” Barwicki suggested. Anavex anticipates submitting a full regulatory package to the European Medicines Agency by the end of this year. Novo Nordisk’s Semaglutide Novo Nordisk is testing semaglutide , its wildly popular glucagon-like peptide-1 (GLP-1) receptor agonist for weight loss and other indications, in patients with early Alzheimer’s. Completion of the Phase III study is expected in October 2026. Early studies by independent scientists suggest semaglutide reduces neuroinflammation , which impairs cell signaling. It also may improve vascularization. Neurim’s Piromelatine At Neurim Pharmaceuticals, a Phase III trial in Alzheimer’s patients with mild dementia will determine whether piromelatine can improve cognition and function by improving sleep quality. The hypothesis is that sleep disturbances increase synaptic and metabolic activity, impairing the brain’s ability to clear wastes, which then increases amyloid beta aggregation. Piromelatine works by activating certain melatonin and serotonin receptor agonists. Cassava Sciences’ Simufilam Finally, Austin, Texas–based Cassava Sciences seeks to restore the brain’s shape and function by stabilizing the scaffolding protein filamin A (FLNA), thus purportedly blocking signaling from soluble amyloid beta. But Cassava’s conduct around simufilam has spurred an investigation by the U.S. Department of Justice. The company’s former science advisor, Hoau-Yan Wang, was indicted in June for allegedly falsifying scientific data that led to the awards of some $16 million in NIH grants between 2015 and 2023. The charges include allegedly misconstruing data about how “a potential treatment” and its diagnostic test would work. The company’s August corporate overview reiterates a February news release , noting that patients with mild Alzheimer’s who were treated with its oral therapeutic, simufilam , continuously for two years had no decline in their ADAS-Cog scores. Non-continuous treatment resulted in a one-point ADAS-Cog decline. In late July, Cassava added an open-label extension to its ongoing Phase II and III clinical trials for Alzheimer’s, which attracted 89% of its Phase III patients. According to August’s corporate overview, Cassava expects topline results from its 804-patient RETHINK-ALZ trial by year’s end. Combinations Are Key Alzheimer’s is a very hetergeneous disease and there is no magic bullet for treatment. Given the many different mechanisms of action of emerging Alzheimer’s therapeutics, “there may be a case for teaming up and using certain therapeutics in combination,” Tsai said. “We’re excited to see the clinical trial pipeline diversity over time,” Edelmayer added, but the solution may involve more than therapeutics. Ultimately, “Treatment may require a combination of powerful, FDA-approved therapies in conjunction with brain-healthy lifestyles. We envision a future where there are many treatments that address the disease in multiple ways.”