Published in Scientific Reports, Results Highlight Reversal of Hyperactivity and Restoration of Associative Learning and Reduction of Anxiety, Phenotypes Associated with Fragile X Syndrome
Positron emission tomography (PET) Establishes ANAVEX®2-73’s Dose Dependent SIGMAR1 Receptor Occupancy
Study Provides Proof-of-Concept for Advancing ANAVEX®2-73 (blarcamesine) into Phase 2/3 Fragile X Syndrome Clinical Trial
NEW YORK – August 26, 2021
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 other central nervous system (CNS) diseases, today announced that preclinical data of ANAVEX®2-73 (blarcamesine) in Fragile X Syndrome were published in the peer-reviewed journal, Scientific Reports.
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and the most frequent single gene cause of autism spectrum disorder with an estimated population of approximately 62,500 in the US and 1,088,500 worldwide. At present, there is no approved treatment for Fragile X Syndrome.
The study evaluated doses of ANAVEX®2-73 in Fmr1 knockout (KO) mice, a validated animal model for the disease, which resulted in the reversal of hyperactivity and restoration of associative learning as well as reduction in anxiety-like and perseverative behaviors. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective SIGMAR1 PET ligand [18F]FTC-146, demonstrated ANAVEX®2-73’s dose dependent receptor occupancy. Additionally, ANAVEX®2-73 also restored pAkt and BDNF levels in the hippocampus, which are signaling pathways particularly affected in Fragile X Syndrome. ANAVEX®2-73 also showed a good safety profile.
“Testing novel drugs that can safely improve the symptoms of Fragile X Syndrome is a high priority,” said Walter E. Kaufmann, M.D., Chief Medical Officer of Anavex and corresponding author of the paper. “The present findings support the viability of SIGMAR1 as a therapeutic target in Fragile X Syndrome, and the clinical potential of ANAVEX®2-73 (blarcamesine) in Fragile X Syndrome and other neurodevelopmental disorders.”
The study, “Effects of the Sigma-1 Receptor Agonist Blarcamesine in a Murine Model of Fragile X Syndrome: Neurobehavioral Phenotypes and Receptor Occupancy,” is the basis for a Phase 2/3 ANAVEX®2-73 study in Fragile X Syndrome. The fact that the investigation involved chronic administration, as opposed to acute dosing, provides additional evidence in favor of the clinical use of ANAVEX®2-73. Since the behavioral paradigms reflect the involvement of multiple cortical and subcortical regions, their marked improvement by ANAVEX®2-73 suggest widespread activation of SIGMAR1 by the drug and modulation of multiple neural pathways. Indeed, the observation of normalization of pAkt and BDNF levels after ANAVEX®2-73 administration, in a brain region critical for cognition and behavior, is also a finding with important implications for Fragile X Syndrome and other synaptic disorders.
Altogether, these neurobehavioral, biochemical, and imaging data demonstrate that corresponding doses of ANAVEX®2-73 that yield measurable receptor occupancy are effective for substantially correcting key synaptic and behavioral phenotypes in Fmr1 KO mice. The data also suggest that these positive effects are mediated by SIGMAR1 activation in multiple brain regions, where ANAVEX®2-73 binds to the receptor in a dose-dependent and genotype-independent manner. The study was supported by the FRAXA Research Foundation.
“We look forward to initiating a double-blind, placebo-controlled Phase 2/3 ANAVEX®2-73 study in Fragile X Syndrome,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. “We are intrigued about the clear preclinical data providing potential to expand the therapeutic profile of ANAVEX®2-73 into the largest portion of addressable market of autism spectrum disorder, Fragile X Syndrome. This is further evidence of the potential of ANAVEX®2-73 as a platform technology of precision medicine.”
The full paper can be accessed online at: www.nature.com/articles/s41598-021-94079-7.
Anavex Life Sciences’ product portfolio platform includes orally available small molecule drug lead candidate ANAVEX®2-73 for the treatment of Alzheimer’s disease, Parkinson’s disease and Rett syndrome and ANAVEX®3-71 for frontotemporal dementia.
About Fragile X Syndrome and Autism Spectrum Disorder
Fragile X Syndrome is the most common form of inherited intellectual disability and the most frequent single gene cause of autism, affecting approximately 1 in 4,000 males and 1 in 6,000 females. The disorder is caused by the unstable expansion of a CGG repeat in the FMR1 gene that leads to abnormal methylation and suppression of FMR1 transcription with the resulting decrease in protein levels in the brain and other tissues. The average age of Fragile X Syndrome diagnosis for boys and girls are 35 to 37 months and 42 months, respectively. Behavioral abnormalities, including autism spectrum disorder, are common.
Autism spectrum disorder is a behavioral diagnosis while Fragile X Syndrome is a medical/genetic diagnosis. Many studies have evaluated the link between Fragile X Syndrome and autism spectrum disorder over the last few decades. Since many children with Fragile X Syndrome are interested in social interactions, they may not meet the diagnostic criteria for autism spectrum disorder, even though they exhibit some features such as poor eye contact, shyness, social anxiety, hand-flapping and sensory issues. Autism is much more common in boys than in girls with Fragile X Syndrome. According to the CDC, a national parent survey found that 46% of males and 16% of females with Fragile X Syndrome have been diagnosed or treated for autism spectrum disorder.
About FRAXA Research Foundation
FRAXA’s mission is to find effective treatments and ultimately a cure for Fragile X Syndrome. FRAXA directly funds research grants and fellowships at top universities around the world. FRAXA partners with biomedical and pharmaceutical companies, large and small, to bridge the gap between research discoveries and actual treatments. Treatments for Fragile X Syndrome are likely to help people affected by autism, Alzheimer’s, and other brain disorders. More information is available at www.fraxa.org.
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), successfully completed a Phase 2a clinical trial for Alzheimer’s disease and recently a Phase 2 proof-of-concept study in Parkinson’s disease dementia and a Phase 2 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 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 sigma-1 and 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.
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