Anavex2-73 Shows Efficacy in Fragile X Mouse Study, Phase 2/3 Trial Planned
Note: This story was updated Aug. 12, 2022, to reflect that blarcamesine is an experimental activator.
Treatment with Anavex2-73 (blarcamesine) safely and significantly eased behavioral symptoms of fragile X syndrome (FXS), and normalized some aspects of brain chemistry, in a preclinical study in mice.
Anavex Life Sciences, the company developing this treatment candidate, is now looking to begin clinical testing of the medication in fragile X patients.
Results were in the study “Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy,” published in Scientific Reports. Anavex supported the research in part; additional funding was provided by the FRAXA Research Foundation.
Blarcamesine is an experimental agonist (activator) of the protein sigma-1 receptor (S1R). This protein is involved in mitochondrial function and calcium signaling; through this, it helps to regulate the activity of synapses — the connections between neurons (nerve cells). By blocking S1R, blarcamesine may improve synapse health, which could be therapeutic in fragile X and other neurological diseases characterized by synapse dysfunction.
Led by a team at Sanford University, researchers at Anavex and other institutions in the U.S. and Chile tested the effects of Anavex2-73 treatment in a mouse model of fragile X. The investigational medication was administered by injection into the abdomen twice daily for two weeks.
Results showed that Anavex2-73 treatment eased several aspects of behavior. For example, untreated fragile X mice have abnormally high scores on the open field test, indicative of hyperactivity.
“Chronic treatment with blarcamesine significantly reduced the [hyperactivity] behavior in [fragile X] mice to levels indistinguishable from those observed in” healthy mice, the researchers reported.
Similar results were observed in a fear conditioning test. Mice treated with Anavex2-73 mice showed normal “freezing behavior” again comparable to healthy mice, known as wild-type animals.
In a species-specific behavior test assessing the mouse tendency to bury marbles, fragile X mice initially buried significantly fewer marbles than their wild-type counterparts. Anavex2-73 treatment partially rescued this behavior, though not to the same level seen in the healthy mice.
“Administration of blarcamesine to Fmr1 KO2 [fragile X] mice for two weeks led to correction of two key neurobehavioral phenotypes and marked improvement of a third one,” the researchers wrote. (Frm1 knockout, or KO, mice lack the FRMP protein — much like people with this disorder — due to induced disruptions in the Fmr1 gene responsible for its production.)
To understand the biochemical basis for these changes, the researchers assessed levels of various signaling molecules in the mice’s brains. Fragile X mice were found to have abnormally low levels of brain-derived neurotropic factor (BDNF), a signaling molecule involved in synapse formation. Treatment with Anavex2-73 restored BDNF levels to near those seen in wild-type mice. (Synapses are the junctions between two nerve cells that allow them to communicate.)
“A major neuronal signaling abnormality in mouse models of FXS, namely decreased BDNF levels, was restored to [wild-type] levels in the hippocampus of [fragile X] mice,” the team wrote. (The hippocampus is part of the brain that plays a key role in learning and memory.)
“Since BDNF is a converging point of several synaptic regulators disrupted in FXS [fragile X], these findings suggest that blarcamesine corrects [fragile X] mouse behavioral phenotypes through multiple synaptic signaling mechanisms known to be affected” by the disease, they added.
In further imaging experiments and examining brains post-mortem, the researchers demonstrated that the investigational medication was binding to the S1R protein in various brain regions as expected, and this was not affected by the mutation that causes fragile X in this model.
“Altogether, these neurobehavioral, biochemical, and imaging data demonstrate that corresponding doses of blarcamesine that yield measurable receptor occupancy are effective for substantially correcting key synaptic and behavioral phenotypes in [fragile X] mice,” the researchers concluded.
Anavex2-73 has shown some evidence of efficacy in early clinical trials of other neurological diseases, namely Rett syndrome and Parkinson’s disease dementia. Later-stage clinical studies of the medication in Rett syndrome and Alzheimer’s disease are ongoing.
“Continued findings from these clinical studies with blarcamesine, combined with the presented data strengthens the rationale for potentially a dependable and effective treatment strategy for FXS and other neurological disorders targeting the S1R with blarcamesine,” the researchers wrote.
Anavex is planning a Phase 2/3 clinical trial to test the investigational therapy in people with fragile X, it announced in a press release.
“We are intrigued about the clear preclinical data providing potential to expand the therapeutic profile of Anavex2-73 … into Fragile X Syndrome,” said Christopher Missling, PhD, president and CEO of Anavex. “We look forward to initiating a double-blind, placebo-controlled Phase 2/3″ study in patients.
“Testing novel drugs that can safely improve the symptoms of Fragile X Syndrome is a high priority,” added Walter Kaufmann, Anavex’s chief medical officer and a study author. “The present findings support the viability of SIGMAR1 as a therapeutic target in Fragile X Syndrome, and the clinical potential” of Anavex2-73 in the disorder.