Amdiglurax
Amdiglurax, also known by its former developmental code names ALTO-100 and NSI-189, is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor modulator which is under development for the treatment of major depressive disorder, bipolar depression, and stress disorder">psychological stress">stress disorder. There has also been interest in amdiglurax for possible treatment of cognitive impairment and neurodegeneration. It is taken by mouth.
Amdiglurax's exact mechanism of action is unknown. However, it is thought to work through indirectly enhancing BDNF signaling and increasing neuroplasticity and neurogenesis in the hippocampus. The drug dose-dependently increases hippocampal volume at sufficiently high doses in rodents. However, it did not significantly affect hippocampal volume in humans in a clinical study. Amdiglurax is a first-in-class drug and a small molecule.
As of July 2024, amdiglurax is in phase 2 clinical trials for MDD, bipolar depression, and PTSD. A phase 3 trial for MDD is being planned. Findings of the effectiveness of amdiglurax in treating MDD in phase 1 and 2 trials have been mixed, although cognitive and memory improvements have been observed. Amdiglurax is under development by Alto Neuroscience and was previously under development by Neuralstem, Inc. It has been sold online as a nootropic and antidepressant.
Pharmacology
Pharmacodynamics
is associated with atrophy of the hippocampus, reduced hippocampal neurogenesis, and smaller hippocampal volumes. Major mechanisms thought to contribute to these changes include prolonged exposure to stress, environmental deprivation, and physical inactivity, among others. Reduced hippocampal volume is associated with more severe depressive symptoms, repeated depressive episodes, longer durations of depressive episodes, earlier onset of depression, and early-life adversity, among other factors. The hippocampus is a key structure for memory, and reduced hippocampal volumes in people with depression have been associated with cognitive and memory impairments. Antidepressant therapy has been associated with reversal of hippocampal atrophy, and hippocampal neurogenesis could be essential in recovery from depression. These changes may be mediated by increased hippocampal brain-derived neurotrophic factor signaling. The hippocampus is known to project to and regulate the mesolimbic dopamine reward pathway, among other areas, and dysregulation of this pathway could be involved in the anhedonia and amotivation seen in people with depression. On the basis of the preceding findings, enhancing hippocampal neurogenesis has been of interest for possible pharmaceutical treatment of depression.Amdiglurax was identified through a neurogenesis functional screen in vitro with a library of 10,269 compounds. It has been found to enhance hippocampal neuroplasticity and neurogenesis in multiple preclinical models. In addition, the drug dose-dependently increases hippocampal volume in mice. In one study, there was an approximate 36% increase at 10mg/kg and an approximate 66% increase at 30mg/kg. There appears to be a bell-shaped dose–response curve, with 100mg/kg being less effective than 30mg/kg in stimulating hippocampal volume. The morphological effects of amdiglurax are confined to the dentate gyrus of the hippocampus and the subventricular zone and there are no known morphological effects elsewhere in the brain. It is unknown whether the hippocampal volume increase exclusively represents neurogenesis or also includes neuropil augmentation.
The exact mechanism of action or biological target of amdiglurax is unknown. Amdiglurax does not interact with any monoamine transporters, monoamine receptors, or amino acid targets. Screening against 52neurotransmitter-related receptors, ion channels, and enzymes and screening against 900kinases was negative. Amdiglurax is said to work in part through indirectly modulating BDNF and its signaling. It has also been found to upregulate glial-derived neurotrophic factor, vascular endothelial growth factor, and Skp, Cullin, F-box in vitro, with more robust effects on BDNF and SCF than on VEGF or GDNF. Amdiglurax has been found to increase signaling of the receptor [kinase">receptor (biochemistry)">receptor [kinase B] pathway, and antibodies against BDNF and SCF have been found to oppose effects of amdiglurax in preclinical models.
In a small phase 1 clinical study, amdiglurax for 4weeks had no impact on hippocampal or amygdalar volume measured by magnetic resonance imaging in people with major depressive disorder. There was a modest numerical increase in left hippocampal volume, but it was not statistically significant. The doses of amdiglurax used in humans are lower than those that have been found to increase hippocampal volume in some studies in mice although not in other studies. Despite the preceding, although no antidepressant effect over placebo was apparent in a phase 2 study, amdiglurax nonetheless produced significant cognitive and memory improvements in the study. The mixed effectiveness of amdiglurax in treating depression but its apparent cognitive benefits in clinical studies has been interpreted as suggesting that reduced hippocampal volumes are more associated with cognitive alterations in depression rather than with the mood effects of depression.
Pharmacokinetics
Amdiglurax is orally active and is administered orally in the form of tablets. Peak levels of amdiglurax are reached 1 to 2hours after administration. Area-under-the-curve levels of amdiglurax increase linearly across a dosing range of 40mg one to three times per day. Steady state levels of amdiglurax are reached within 4 to 5days. The elimination half-life of amdiglurax has ranged from 17.4 to 20.5hours in a few different clinical studies.Unpublished in vitro studies of amdiglurax have shown limited metabolism to oxidized and glucuronidated products.
Chemistry
Amdiglurax is a small molecule and benzylpiperazine-aminopyridine compound.History
Amdiglurax was first described by 2010. Early development of amdiglurax was supported by the Defense Advanced Research Projects Agency and the National Institutes of Health.Clinical development
By Neuralstem, Inc.
NSI-189 completed a phase I clinical trial for MDD in 2011, where it was administered to 41 healthy volunteers. A phase Ib clinical trial for treating MDD in 24 patients started in 2012 and completed in July 2014, with results published in December 2015.In July 2017, it was announced that a phase II clinical trial with 220 patients failed to meet its primary effectiveness endpoint in MDD. However, statistically significant improvements have been reported on a number of secondary depression and cognition endpoints. Upon the announcement of the unsuccessful trial, Neuralstem stock plummeted by 61%. More detailed analysis of the trial results was released in December 2017 and January 2018. It revealed statistically significant improvements on patient-reported depression scales and in aspects of cognition for the 40mg/day dose. Of particular note are improvements in memory, working memory, and executive functioning as measured by the CogScreen computerized test.
In August 2020 another phase 2 study with 220participants was done. An 80mg dose of NSI-189 showed significant benefit over placebo in the subgroup of patients who were moderately depressed but was not significant in patients who were severely depressed. The study concluded that NSI-189 is effective as a safe adjunctive therapy, with the most significant antidepressant and pro-cognitive benefits noted in patients with moderate depression.
In addition to MDD, Neuralstem had said that it has intended to pursue clinical development of NSI-189 for a variety of other neurological conditions, including traumatic brain injury, Alzheimer's disease, post-traumatic stress disorder, stroke, and to prevent cognitive and memory decline in aging.
By Alto Neuroscience
In 2021, Neuralstem merged with another company to become Palisade Bio, who in 2021 sold NSI-189 to an unknown buyer for up to $4.9 million. In 2024, it was revealed that this buyer was Alto Neuroscience, which is now developing NSI-189 under the new developmental code name ALTO-100.Preliminary effectiveness of amdiglurax in the treatment of MDD has been demonstrated in new phase 2 trials. A significantly larger improvement in depressive symptoms was observed in patients with a cognitive biomarker compared to patients without the biomarker profile in phase 2 studies published in 2023. This cognitive biomarker was determined by a web-based memory test.
Other drugs under development by Alto Neuroscience as of August 2024 include ALTO-203, ALTO-300, and ALTO-202. As with amdiglurax, they are all under development for treatment of major depressive disorder.
Research
NSI-189 was additionally under development by Neuralstem for treatment of a variety of conditions besides major depressive disorder, including Alzheimer's disease, Angelman syndrome, brain injuries, cognition disorders, diabetic neuropathy, neurodegenerative disorders, post-traumatic stress disorder, stroke, and diabetes, but no recent development has been reported for these indications as of September 2022.Amdiglurax is being developed by Alto Neuroscience exclusively for treatment of major depressive disorder, bipolar depression, and post-traumatic stress disorder as of July 2024.