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ALTO-100

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ALTO-100
Clinical data
Other namesNSI-189; NeuralStem Inc 189
Routes of
administration		By mouth[1]
Drug classBrain-derived neurotrophic factor modulators[2]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life17.4–20.5 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
FormulaC22H30N4O
Molar mass366.509 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 ☒N

ALTO-100, previously known as NSI-189 (NeuralStem Inc. 189),[3] is a drug described as a neurogenesis stimulant and 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 treatment of cognitive impairment and neurodegeneration.[9][1][10] ALTO-100 is under development by Alto Neuroscience[4][8] and was previously under development by Neuralstem, Inc.[5][11]

ALTO-100's exact mechanism of action is unknown.[3][6][7] However, it is thought to work through enhancing BDNF signaling and increasing neuroplasticity and neurogenesis in the hippocampus.[10][12][13][14] It is a first-in-class drug, a small molecule, and is taken by mouth.[2]

As of July 2024, ALTO-100 is in phase 2 clinical trials for MDD, bipolar depression, and PTSD.[4]

Pharmacology

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ALTO-100 was identified through a neurogenesis functional screen in vitro with a library of 10,269 compounds.[10][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 animals.[12] ALTO-100 is said to work in part through modulating brain-derived neurotrophic factor (BDNF) and BDNF-dependent signaling.[14][4] The exact mechanism of action or biological target of the compound is unknown.[3][9][10]

Clinical development

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By Neuralstem, Inc.

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NSI-189 completed a phase I clinical trial for MDD in 2011, where it was administered to 41 healthy volunteers.[15] 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.[1][16]

In July 2017, it was announced that a phase II clinical trial with 220 patients failed to meet its primary effectiveness endpoint (MADRSTooltip Montgomery–Åsberg Depression Rating Scale) in MDD.[17] However, statistically significant improvements have been reported on a number of secondary depression and cognition endpoints.[18][19] Upon the announcement of the unsuccessful trial, Neuralstem stock plummeted by 61%.[20] 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. 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.[19]

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 most compelling antidepressant and procognitive benefits noted in patients with moderate depression.[21]

In addition to MDD, Neuralstem had said that it 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

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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.[22] 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.[11][3]

Preliminary effectiveness of ALTO-100 in the treatment of MDD has been demonstrated in new phase 2 trials.[23][24][25] A significantly larger improvement in depressive symptoms (45–47%) was observed in patients with a cognitive biomarker compared to patients without the biomarker profile in phase 2 studies published in 2023.[23][24][25][12] This cognitive biomarker was determined by a web-based memory test.[12]

See also

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References

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  1. ^ a b c d Fava M, Johe K, Ereshefsky L, Gertsik LG, English BA, Bilello JA, et al. (October 2016). "A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients". Molecular Psychiatry. 21 (10): 1372–1380. doi:10.1038/mp.2015.178. PMC 5030464. PMID 26643541.
  2. ^ a b "Alto Neuroscience Receives Funding Award from Wellcome Trust to Accelerate Development of ALTO-100 in Bipolar Depression Leveraging Precision Psychiatry Approach". Nasdaq. 5 April 2024. Retrieved 5 August 2024.
  3. ^ a b c d Osborne R (5 August 2024). "New PTSD fix in the offing? Lykos PDUFA nears, Alto forges ahead". BioWorld. Retrieved 5 August 2024. 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.
  4. ^ a b c d "ALTO 100". AdisInsight. Springer Nature Switzerland AG. 29 July 2024. Retrieved 5 August 2024.
  5. ^ a b "NSI 189". AdisInsight. Springer Nature Switzerland AG. 28 September 2022. Retrieved 5 August 2024.
  6. ^ a b Dejanovic B, Sheng M, Hanson JE (January 2024). "Targeting synapse function and loss for treatment of neurodegenerative diseases". Nat Rev Drug Discov. 23 (1): 23–42. doi:10.1038/s41573-023-00823-1. PMID 38012296.
  7. ^ a b Singewald N, Sartori SB, Reif A, Holmes A (March 2023). "Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder". Neuropharmacology. 226: 109418. doi:10.1016/j.neuropharm.2023.109418. PMC 10372846. PMID 36623804.
  8. ^ a b Brady LS, Lisanby SH, Gordon JA (2023). "New directions in psychiatric drug development: promising therapeutics in the pipeline". Expert Opin Drug Discov. 18 (8): 835–850. doi:10.1080/17460441.2023.2224555. PMID 37352473.
  9. ^ a b c Bouhassira EE (15 June 2015). The SAGE Encyclopedia of Stem Cell Research. SAGE Publications. pp. 843–. ISBN 978-1-4833-4767-7.
  10. ^ a b c d Neuralstem (March 2016), Neuralstem Inc. March 2016 Corporate Presentation (PDF), retrieved 25 March 2016[dead link] Alt URL
  11. ^ a b "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.
  12. ^ a b c d e ALTO Neuroscience (July 2024). "ALTO-100: Phase 2B Development for MDD" (PDF). ALTO Neuroscience. Retrieved 5 August 2024.
  13. ^ a b c "S-1". SEC.gov. 12 January 2024. 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").
  14. ^ a b Anderson S (3 August 2023). "Developing psychiatric drugs with precision focus". Drug Discovery News. Retrieved 5 August 2024.
  15. ^ Clinical trial number NCT01310881 for "Single-Dose Pharmacokinetics (PK) Study of Novel Neurogenic Compound NSI-189" at ClinicalTrials.gov
  16. ^ Clinical trial number NCT01520649 for "Multiple-Dose Pharmacokinetics (PK), and Pharmacodynamic (PD) Effect of NSI-189 Phosphate in Depression Patient Subjects" at ClinicalTrials.gov
  17. ^ "Neuralstem Announces Top-line Phase 2 Data of NSI-189 for Major Depressive Disorder" (Press release). Neuralstem Inc. 25 July 2017.
  18. ^ "Neuralstem: NSI-189 Phase 2 Trial Fails To Meet Primary Efficacy Endpoint". NASDAQ.com. 2017-07-25. Retrieved 2017-09-20.
  19. ^ a b "Neuralstem Inc. Corporate Presentation" (PDF). January 2018.
  20. ^ Court E (July 25, 2017). "UPDATE: Neuralstem stock plummets 61% on news of mid-stage clinical trial miss".
  21. ^ Johe KK, Kay G, Kumar S, Burdick KE, McIntyre RS, Papakostas GI, et al. (August 2020). "NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder". Annals of Clinical Psychiatry. 32 (3): 182–196. PMID 32722729.
  22. ^ "Palisade Bio, Inc. Announces Sale of Seneca Asset NSI-189 for the treatment of Central Nervous System Disorders". 22 October 2021.
  23. ^ a b Bratulic A (10 January 2023). "Alto says depression drug shows 'clear' clinical signal in biomarker-defined patients". FirstWord. Retrieved 5 August 2024.
  24. ^ a b Jordan J, Cooper N, Badami F, Powell J, Wu W, Etkin A, et al. (December 2023). "P229. Identification and Prospective Replication of a Cognitive Biomarker for Predicting the Antidepressant Effect of ALTO-100, a Novel Pro-Plasticity Drug, in Patients With Major Depression: Results From a Large Phase 2a Study" (PDF). Neuropsychopharmacology. 48 (Suppl 1 (ACNP 62nd Annual Meeting: Poster Abstracts P1 – P250)): 63–210. doi:10.1038/s41386-023-01755-5.
  25. ^ a b Jordan J, Cooper N, Badami F, Powell J, Wu W, Etkin A, et al. (2024). "206. Identification and Prospective Replication of a Cognitive Biomarker for Predicting the Antidepressant Effect of ALTO-100, a Novel Pro-Plasticity Drug Candidate, in Patients With Major Depression: Results From a Large Phase 2a Study". Biological Psychiatry. 95 (10): S184. doi:10.1016/j.biopsych.2024.02.441.

Further reading

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  • McIntyre RS, Johe K, Rong C, Lee Y (June 2017). "The neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects". Expert Opinion on Investigational Drugs. 26 (6): 767–770. doi:10.1080/13543784.2017.1324847. PMID 28460574. S2CID 205768353.
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