Anavex Life Sciences, a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases including Alzheimer’s disease, other central nervous system (CNS) diseases, pain, and various types of cancer, has announced new preclinical data for ANAVEX 2-73 in the neurodevelopmental disorders Angelman syndrome, Fragile X syndrome and Rett syndrome.
The company presented at the Antiepileptic Drug Trials XIV 2017 Conference in Aventura, Florida.
Characterized as an autism spectrum disorder, Angelman syndrome is a rare neuro-genetic disorder that occurs in one in 15,000 live births. Individuals with Angelman syndrome exhibit severe cognitive and physical impairments, including ataxia, intellectual disability, speech impairment, sleep disorders, and seizures (the latter being present in over 80 percent of affected individuals).
ANAVEX 2-73 (10 mg/kg IP dosed daily for 14 days) was assessed in the Ubiquitin-protein ligase E3A (Ube3a) mouse model of Angelman syndrome for the development of audiogenic seizures in 3-4-month-old animals. Sponsored by FAST (Foundation for Angelman Syndrome Therapeutics) and conducted in the laboratory of Associate Professor Anne Anderson, MD, at Baylor College of Medicine in Houston, Texas. The results indicated that ANAVEX 2-73 administration significantly reduced audiogenic-induced seizures (p<0.01).
“We are impressed with the positive anti-seizure signal of ANAVEX 2-73,” said Paula M. Evans, Chairperson of FAST. “Most people with Angelman syndrome have recurrent seizures throughout their lives, which is a serious challenge for the individual and caretakers.”
ANAVEX 2-73 has previously been shown to normalize an array of behavioral impairments in a mouse model of Fragile X (see announcement from June 6, 2016). In a recent study sponsored by Fraxa Research Foundation (FRAXA), the effects of ANAVEX 2-73 (1 mg/kg IP dosed twice daily for 14 days) on potential biomarkers were evaluated in Fragile X mental retardation 1 knockout (Fmr1 KO) mice. Vehicle-treated Fmr1 KO mice demonstrate significantly lower brain-derived neurotrophic factor (BDNF) expression in the hippocampus compared to wild-type mice. The experiments demonstrated that ANAVEX 2-73 restored hippocampal BDNF expression to normal levels (p<0.05). BDNF under-expression has been observed in many neurodevelopmental and neurodegenerative pathologies. BDNF signaling promotes maturation of both excitatory and inhibitory synapses. ANAVEX 2-73 normalization of BDNF expression could be a contributing factor for the positive data observed in both neurodevelopmental and neurodegenerative disorders.
In addition, ANAVEX 2-73 has been further evaluated in the MECP2 Rett syndrome disease mouse model. In an experiment sponsored by Rettsyndrome.org, ANAXEX 2-73 was evaluated in automatic visual response and respiration tests in 7-month old mice, an age at which advanced pathology is evident. Vehicle-treated methyl-CpG binding protein 2 (MECP2) mice demonstrated fewer automatic visual responses than wild-type mice. Treatment with ANAVEX 2-73 (30 mg/kg/day PO) for four weeks significantly increased the automatic visual response in the MECP2 Rett syndrome disease mouse (p<0.05).
In Rett syndrome there are disturbances in respiration characterized by an irregular breathing pattern and frequent apnea that are common and debilitating. A trend was observed in MECP2 mice treated with ANAVEX 2-73 – that is, a reduction in apnea counts to levels comparable to those observed in wild-type animals.