ALTO-100

Last updated

ALTO-100
NSI-189 structure.svg
Clinical data
Other namesNSI-189; NeuralStem Inc 189
Routes of
administration 		By mouth [1]
Drug class Hippocampal neurogenesis/neuroplasticity stimulant; Indirect brain-derived neurotrophic factor modulators [2]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 17.4–20.5 hours [1]
Identifiers
  • (4-Benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H30N4O
Molar mass 366.509 g·mol−1
3D model (JSmol)
  • CC(C)CCNC1=C(C=CC=N1)C(=O)N2CCN(CC2)CC3=CC=CC=C3
  • InChI=1S/C22H30N4O/c1-18(2)10-12-24-21-20(9-6-11-23-21)22(27)26-15-13-25(14-16-26)17-19-7-4-3-5-8-19/h3-9,11,18H,10,12-17H2,1-2H3,(H,23,24)
  • Key:DYTOQURYRYYNOR-UHFFFAOYSA-N X mark.svgN

ALTO-100, previously known as NSI-189 (NeuralStem Inc. 189), [3] is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD). [4] [5] [6] [7] [8] There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration. [9] [10] [11] It is taken by mouth. [1]

Contents

ALTO-100's exact mechanism of action is unknown. [3] [6] [7] However, it is thought to work through indirectly enhancing BDNF signaling and increasing neuroplasticity and neurogenesis in the hippocampus. [11] [12] [13] [14] The drug dose-dependently increases hippocampal volume at sufficiently high doses in rodents. [1] [12] However, it did not significantly affect hippocampal volume in humans in a clinical study. [1] ALTO-100 is a first-in-class drug and a small molecule. [2]

As of July 2024, ALTO-100 is in phase 2 clinical trials for MDD, bipolar depression, and PTSD. [4] A phase 3 trial for MDD is being planned. [4] Findings of the effectiveness of ALTO-100 in treating MDD in phase 1 and 2 trials have been mixed, although cognitive and memory improvements have been observed. [15] [16] [17] [18] [5] [4] ALTO-100 is under development by Alto Neuroscience [4] [8] and was previously under development by Neuralstem, Inc. [5] [19]

Pharmacology

Pharmacodynamics

Depression is associated with atrophy of the hippocampus, reduced hippocampal neurogenesis, and smaller hippocampal volumes. [20] [21] Major mechanisms thought to contribute to these changes include prolonged exposure to stress (in part mediated by increased hippocampal glucocorticoid signaling), environmental deprivation, and physical inactivity, among others. [21] [22] 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. [21] [23] The hippocampus is a key structure for memory, and reduced hippocampal volumes in people with depression have been associated with cognitive and memory impairments. [24] Antidepressant therapy has been associated with reversal of hippocampal atrophy, and hippocampal neurogenesis could be essential in recovery from depression. [25] [26] [27] [28] These changes may be mediated by increased hippocampal brain-derived neurotrophic factor (BDNF) signaling. [27] 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. [24] [29] On the basis of the preceding findings, enhancing hippocampal neurogenesis has been of interest for possible pharmaceutical treatment of depression. [30] [27]

ALTO-100 was identified through a neurogenesis functional screen in vitro with a library of 10,269 compounds. [11] [12] [13] It has been found to enhance hippocampal neuroplasticity and neurogenesis in multiple preclinical models. [13] In addition, the drug dose-dependently increases hippocampal volume in mice. [1] [12] In one study, there was an approximate 36% increase at 10 mg/kg and an approximate 66% increase at 30 mg/kg. [12] [31] There appears to be a bell-shaped dose–response curve, with 100 mg/kg being less effective than 30 mg/kg in stimulating hippocampal volume. [32] [31] The morphological effects of ALTO-100 are confined to the dentate gyrus of the hippocampus and the subventricular zone (SVZ) and there are no known morphological effects elsewhere in the brain. [1] [33] [10] It is unknown whether the hippocampal volume increase exclusively represents neurogenesis or also includes neuropil augmentation. [1]

The exact mechanism of action or biological target of ALTO-100 is unknown. [3] [9] [11] ALTO-100 does not interact with any monoamine transporters, monoamine receptors, or amino acid targets (e.g., the NMDA receptor or the AMPA receptor). [1] Screening against 52  neurotransmitter-related receptors, ion channels, and enzymes and screening against 900  kinases was negative. [32] ALTO-100 is said to work in part through indirectly modulating BDNF and its signaling. [1] [14] [4] It has also been found to upregulate glial-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and Skp, Cullin, F-box (SCF) in vitro, with more robust effects on BDNF and SCF than on VEGF or GDNF. [1] ALTO-100 has been found to increase signaling of the tropomyosin receptor kinase B (TrkB) pathway, and antibodies against BDNF and SCF have been found to oppose effects of ALTO-100 in preclinical models. [34] [35]

In a small phase 1 clinical study, ALTO-100 (40–150 mg/day) for 4 weeks had no impact on hippocampal or amygdalar volume measured by magnetic 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 ALTO-100 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] [32] [12] [31] Despite the preceding, although no antidepressant effect over placebo was apparent in a phase 2 study, ALTO-100 nonetheless produced significant cognitive and memory improvements in the study. [15] [18] The mixed effectiveness of ALTO-100 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. [15]

Pharmacokinetics

ALTO-100 is orally active and is administered orally in the form of tablets. [1] Peak levels of ALTO-100 are reached 1 to 2 hours after administration. [1] Area-under-the-curve levels of ALTO-100 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 ALTO-100 are reached within 4 to 5 days. [1] The elimination half-life of ALTO-100 has ranged from 17.4 to 20.5 hours in a few different clinical studies. [1]

Chemistry

ALTO-100 is a small molecule and benzylpiperazine-aminopyridine compound. [2] [5] [36]

History

ALTO-100 was first described by 2010. [37] [38] Early development of ALTO-100 was supported by the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH). [39]

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. [40] 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. [10] [41]

In July 2017, it was announced that a phase II clinical trial with 220 patients failed to meet its primary effectiveness endpoint (MADRS Tooltip Montgomery–Åsberg Depression Rating Scale) in MDD. [42] [18] However, statistically significant improvements have been reported on a number of secondary depression and cognition endpoints. [43] [44] [18] Upon the announcement of the unsuccessful trial, Neuralstem stock plummeted by 61%. [45] 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. [18] Of particular note are improvements in memory (effect size Cohen's d = 1.12, p = 0.002), working memory (d = 0.81, p = 0.020), and executive functioning (d = 0.66, p = 0.048) as measured by the CogScreen computerized test. [18] [44]

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. [46]

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. [9]

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. [47] 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. [19] [3]

Preliminary effectiveness of ALTO-100 in the treatment of MDD has been demonstrated in new phase 2 trials. [48] [49] [50] A significantly larger improvement in depressive symptoms (~46%) was observed in patients with a cognitive biomarker compared to patients without the biomarker profile in phase 2 studies published in 2023. [48] [49] [50] [12] This cognitive biomarker was determined by a web-based memory test. [12]

Other drugs under development by Alto Neuroscience as of August 2024 include ALTO-203 (histamine H3 receptor inverse agonist), ALTO-300 (agomelatine reformulation—melatonin MT1 and MT2 receptor agonist and serotonin 5-HT2C receptor antagonist), and ALTO-202 (NR2B subunit-containing NMDA receptor antagonist). [51] [52] As with ALTO-100, they are all under development for treatment of major depressive disorder. [51] [52]

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 (PTSD), stroke, and diabetes, but no recent development has been reported for these indications as of September 2022. [5]

ALTO-100 is being developed by Alto Neuroscience exclusively for treatment of major depressive disorder, bipolar depression, and post-traumatic stress disorder as of July 2024. [4]

See also

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References

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  15. 1 2 3 Beckervordersandforth R, Rolando C (February 2020). "Untangling human neurogenesis to understand and counteract brain disorders". Curr Opin Pharmacol. 50: 67–73. doi:10.1016/j.coph.2019.12.002. PMID   31901615. 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.
  16. ↑ McNerlin C, Guan F, Bronk L, Lei K, Grosshans D, Young DW, et al. (November 2022). "Targeting hippocampal neurogenesis to protect astronauts' cognition and mood from decline due to space radiation effects". Life Sci Space Res (Amst). 35: 170–179. doi: 10.1016/j.lssr.2022.07.007 . PMID   36336363. [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.
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  19. 1 2 "FORM 10-K" (PDF). Retrieved 5 August 2024. 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.
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  37. ↑ "Neuralstem files FDA application for first drug therapy". EurekAlert!. 17 November 2010. Retrieved 10 August 2024.
  38. ↑ Philippidis A (15 September 2011). "U.S. Stem Cell Firms Partnering Overseas: Companies Find It Easier to Navigate Regulatory Requirements in Asia and Europe". Genetic Engineering & Biotechnology News. 31 (16): 16–18. doi:10.1089/gen.31.16.05. ISSN   1935-472X. 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.
  39. ↑ "Neuralstem Files FDA Application For First Drug Therapy NSI-189 For The Treatment Of Major Depression". Bioprocess Online for bioanalytics, biopurification, bioproduction. 19 November 2010. Retrieved 16 August 2024. 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).
  40. ↑ Clinical trial number NCT01310881 for "Single-Dose Pharmacokinetics (PK) Study of Novel Neurogenic Compound NSI-189" at ClinicalTrials.gov
  41. ↑ Clinical trial number NCT01520649 for "Multiple-Dose Pharmacokinetics (PK), and Pharmacodynamic (PD) Effect of NSI-189 Phosphate in Depression Patient Subjects" at ClinicalTrials.gov
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  43. ↑ "Neuralstem: NSI-189 Phase 2 Trial Fails To Meet Primary Efficacy Endpoint". NASDAQ.com. 2017-07-25. Retrieved 2017-09-20.
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