Analysis of information sources in references of the Wikipedia article "NSI-189" in English language version.
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).
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).
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.
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.
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).
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.
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").
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.
