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| Other names | NSI-189; NSI189; NeuralStem Inc 189; ALTO-100; ALTO100 |
| Routes of administration | By mouth[1] |
| Drug class | Hippocampalneurogenesis/neuroplasticity stimulant; Indirectbrain-derived neurotrophic factor modulators[2] |
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| Eliminationhalf-life | 17.4–20.5 hours[1] |
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| Formula | C22H30N4O |
| Molar mass | 366.509 g·mol−1 |
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Amdiglurax (INNTooltip International Nonproprietary Name),[3] also known by its former developmental code namesALTO-100 andNSI-189 (short for "NeuroStem Inc. 189"),[4] is adrug described as ahippocampalneurogenesis stimulant and indirectbrain-derived neurotrophic factor (BDNF)modulator which is under development for the treatment ofmajor depressive disorder (MDD),bipolar depression, andpost-traumatic stress disorder (PTSD).[5][6][7][8][9] There has also been interest in amdiglurax for possible treatment ofcognitive impairment andneurodegeneration.[10][11][12] It is takenby mouth.[1]
Amdiglurax's exactmechanism of action is unknown.[4][7][8] However, it is thought to work through indirectly enhancing BDNF signaling and increasingneuroplasticity andneurogenesis in thehippocampus.[12][13][14][15] The drugdose-dependently increases hippocampal volume at sufficiently high doses in rodents.[1][13] However, it did not significantly affect hippocampal volume in humans in a clinical study.[1] Amdiglurax is afirst-in-class drug and asmall molecule.[2]
As of July 2024, amdiglurax is inphase 2clinical trials for MDD, bipolar depression, and PTSD.[5] Aphase 3 trial for MDD is being planned.[5] Findings of the effectiveness of amdiglurax in treating MDD inphase 1 and 2 trials have been mixed, although cognitive and memory improvements have been observed.[16][17][18][19][6][5] Amdiglurax is under development by Alto Neuroscience[5][9] and was previously under development byNeuralstem, Inc.[6][20] It has been sold online as anootropic andantidepressant.[21][22][23]
Depression is associated withatrophy of thehippocampus, reduced hippocampalneurogenesis, and smaller hippocampal volumes.[24][25] Major mechanisms thought to contribute to these changes include prolonged exposure tostress (in part mediated by increased hippocampalglucocorticoid signaling),environmental deprivation, andphysical inactivity, among others.[25][26] Reduced hippocampal volume is associated with more severe depressive symptoms, repeated depressive episodes, longer durations of depressive episodes, earlier onset of depression, andearly-life adversity, among other factors.[25][27] The hippocampus is a key structure formemory, and reduced hippocampal volumes in people with depression have been associated withcognitive andmemory impairments.[28]Antidepressant therapy has been associated with reversal of hippocampal atrophy, and hippocampal neurogenesis could be essential in recovery from depression.[29][30][31][32] These changes may be mediated by increased hippocampalbrain-derived neurotrophic factor (BDNF) signaling.[31] The hippocampus is known to project to and regulate themesolimbic dopamine reward pathway, among other areas, and dysregulation of this pathway could be involved in theanhedonia andamotivation seen in people with depression.[28][33] On the basis of the preceding findings, enhancing hippocampal neurogenesis has been of interest for possible pharmaceutical treatment of depression.[34][31]
Amdiglurax was identified through a neurogenesisfunctional screenin vitro with alibrary of 10,269compounds.[12][13][14] It has been found to enhance hippocampalneuroplasticity and neurogenesis in multiplepreclinical models.[14] In addition, the drugdose-dependently increases hippocampal volume in mice.[1][13] In one study, there was an approximate 36% increase at 10 mg/kg and an approximate 66% increase at 30 mg/kg.[13][35] There appears to be abell-shapeddose–response curve, with 100 mg/kg being less effective than 30 mg/kg in stimulating hippocampal volume.[36][35] Themorphological effects of amdiglurax are confined to thedentate gyrus of the hippocampus and thesubventricular zone (SVZ) and there are no known morphological effects elsewhere in the brain.[1][37][11] It is unknown whether the hippocampal volume increase exclusively represents neurogenesis or also includesneuropil augmentation.[1]
The exactmechanism of action orbiological target of amdiglurax is unknown.[4][10][12] Amdiglurax does not interact with anymonoamine transporters,monoamine receptors, oramino acidtargets (e.g., theNMDA receptor or theAMPA receptor).[1] Screening against 52 neurotransmitter-relatedreceptors,ion channels, andenzymes and screening against 900 kinases was negative.[36] Amdiglurax is said to work in part through indirectly modulating BDNF and its signaling.[1][15][5] It has also been found to upregulateglial-derived neurotrophic factor (GDNF),vascular endothelial growth factor (VEGF), andSkp, Cullin, F-box (SCF)in vitro, with more robust effects on BDNF and SCF than on VEGF or GDNF.[1] Amdiglurax has been found to increase signaling of thetropomyosin receptor kinase B (TrkB) pathway, andantibodies against BDNF and SCF have been found to oppose effects of amdiglurax inpreclinical models.[38][39]
In a small phase 1 clinical study, amdiglurax (40–150 mg/day) for 4 weeks had no impact on hippocampal oramygdalar volume measured bymagnetic resonance imaging (MRI) in people with major depressive disorder.[1] There was a modest numerical increase in left hippocampal volume (b=0.35), but it was not statistically significant (p=0.12).[1] 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.[1][36][13][35] 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.[16][19] 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.[16]
Amdiglurax isorally active and is administered orally in the form oftablets.[1]Peak levels of amdiglurax are reached 1 to 2 hours after administration.[1]Area-under-the-curve levels of amdiglurax increase linearly across a dosing range of 40 mg one to three times per day (i.e., 40–120 mg/day).[1]Steady state levels of amdiglurax are reached within 4 to 5 days.[1] Theelimination half-life of amdiglurax has ranged from 17.4 to 20.5 hours in a few different clinical studies.[1]
Unpublished in vitro studies of amdiglurax have shown limited metabolism to oxidized and glucuronidated products.[40]
Amdiglurax is asmall molecule andbenzylpiperazine-aminopyridinecompound.[2][6][41]
Amdiglurax was first described by 2010.[42][43] Early development of amdiglurax was supported by theDefense Advanced Research Projects Agency (DARPA) and theNational Institutes of Health (NIH).[44]
NSI-189 completed aphase I clinical trial for MDD in 2011, where it was administered to 41 healthy volunteers.[45] 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.[11][46]
In July 2017, it was announced that aphase IIclinical trial with 220 patients failed to meet its primary effectiveness endpoint (MADRSTooltip Montgomery–Åsberg Depression Rating Scale) in MDD.[47][19] However, statistically significant improvements have been reported on a number of secondary depression and cognition endpoints.[48][49][19] Upon the announcement of the unsuccessful trial, Neuralstem stock plummeted by 61%.[50] 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 40 mg/day dose.[19] Of particular note are improvements inmemory (effect sizeCohen's d = 1.12, p = 0.002),working memory (d = 0.81, p = 0.020), andexecutive functioning (d = 0.66, p = 0.048) as measured by the CogScreen computerized test.[19][49]
In August 2020 another phase 2 study with 220 participants was done. An 80 mg dose of NSI-189 showed significant benefit over placebo in the subgroup of patients who were moderately depressed (MADRS < 30) but was not significant in patients who were severely depressed (MADRS ≥ 30). 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.[51]
In addition to MDD, Neuralstem had said that it has intended to pursue clinical development of NSI-189 for a variety of otherneurological conditions, includingtraumatic brain injury,Alzheimer's disease,post-traumatic stress disorder,stroke, and to preventcognitive and memory decline in aging.[10]
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.[52] 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.[20][4]
Preliminary effectiveness of amdiglurax in the treatment of MDD has been demonstrated in new phase 2 trials.[53][54][55] A significantly larger improvement in depressive symptoms (~46%) was observed in patients with a cognitivebiomarker compared to patients without the biomarker profile in phase 2 studies published in 2023.[53][54][55][13] This cognitive biomarker was determined by a web-based memory test.[13]
Other drugs under development by Alto Neuroscience as of August 2024 include ALTO-203 (histamineH3 receptorinverse agonist), ALTO-300 (agomelatine reformulation—melatoninMT1 andMT2 receptoragonist andserotonin5-HT2C receptorantagonist), and ALTO-202 (NR2B subunit-containingNMDA receptor antagonist).[56][57] As with amdiglurax, they are all under development for treatment of major depressive disorder.[56][57]
NSI-189 was additionally under development by Neuralstem for treatment of a variety of conditions besides major depressive disorder, includingAlzheimer's disease,Angelman syndrome,brain injuries,cognition disorders,diabetic neuropathy,neurodegenerative disorders,post-traumatic stress disorder (PTSD),stroke, anddiabetes, but no recent development has been reported for these indications as of September 2022.[6]
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.[5]
ALTO-100, formerly known as NSI-189, is a small molecule that has been shown to induce neurogenesis via the brain-derived neurotrophic factor (BDNF) pathway. The mechanism of action on BDNF by ALTO-100 is not clear, but preclinical studies brought about an increase in the volume of the hippocampus of healthy mice.
The brains of treated mice showed significantly increased neurogenesis in the dentate gyrus and significantly increased hippocampal volume (Data on file, Neuralstem, non-peer-reviewed). NSI-189 is believed to have a highly specific effect in the hippocampus and subventricular zone, the two well-known neurogenic regions in adult central nervous system, and nowhere else in the central nervous system (Data on file, Neuralstem, nonpeer-reviewed).
Prior to the Merger, Seneca exclusively licensed certain patents and technologies, including a sublicense covering a synthetic intermediate, of our NSI-189 assets (189 License), along with a purchase option through December 16, 2023 (Purchase Option). On October 22, 2021, Alto Neuroscience ("Alto") agreed to terms of an early exercise of the Purchase Option under the 189 License and entered into an asset transfer agreement ("ATA").
The small molecule NSI-189 stimulates cell proliferation in the hippocampus and — to a lesser [extent] — in the [subventricular zone (SVZ)]. Rat preclinical study unravelled its protective role following stroke [48]. In a small clinical phase Ib study on patients with major depressive disorder (MDD), treatment with NSI-189 associates with significant improvements in depressive and cognitive symptomatology with no alterations in hippocampal volume (Table 1 and [49]). In 2019, a clinical phase II study confirms the efficacy of NSI-189 in improving cognitive impairments in MDD patients, while no clear positive effect on depression was detected [50]. Despite the mechanism of action of NSI-189 is unknown, these results suggest that human [adult hippocampal neurogenesis (AHN)] is involved primarily in cognitive alterations rather than depressive symptoms in MDD.
[NSI-189] progressed to Phase-II clinical trials for evaluation of its effects on mitigating depression (Papakostas et al., 2020). Although the drug was well tolerated over 12 weeks at daily doses of either 40 or 80 mg, the primary endpoints for the clinical trial were not met. Interestingly however, cognitive benefits were noted at 40 mg, which included response accuracy on executive function testing mental flexibility, response speed on a measure of choice reaction time, and accuracy on a measure of delayed recall for symbol digit paired associates (Johe et al., 2020). The failure of the NSI-189 to get FDA approval for use in MDD and/or cognitive decline highlights the need for development of drugs based on specific targets and not phenotypic screens.
Prior to the Merger, Seneca exclusively licensed certain patents and technologies, including a sublicense covering a synthetic intermediate, of our NSI-189 assets ("189 License"), along with a purchase option through December 16, 2023 ("Purchase Option"). On October 22, 2021, Alto Neuroscience ("Alto") agreed to terms of an early exercise of the Purchase Option under the 189 License and entered into an asset transfer agreement ("ATA"). [...] In addition, Alto will be required to pay us up to an aggregate of $4.5 million upon the achievement of certain development and regulatory approval milestones for NSI-189 (or a product containing or otherwise derived from NSI-189), which is now known as ALTO-100. [...] Alto has successfully completed a Phase 2a clinical trial of ALTO-100 and is currently enrolling a Phase 2b clinical trial from which topline data is expected in the second half of 2024.
In Japan, the company came to terms with the wholly owned subsidiary of Sumitomo, Summit Pharmaceuticals (www.summitpharm.com), to market development and licensing rights for NSI-189, Neuralstem's lead small molecule neurogenic compound. It is currently in an FDA-approved Phase I trial for major depression. The company has said it intends to take NSI-189 through Phase II trials before seeking a partner for worldwide rights.
NSI-189 stimulated neurogenesis of human hippocampus-derived neural stem cells in- vitro. In mice, NSI-189 both stimulated neurogenesis of the hippocampus and increased its overall volume as well. Therefore, NSI-189 may reverse the human hippocampal atrophy seen in major depression and schizophrenia. This program has received significant support from both the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH).
