NSI-189

Overview

NSI-189 (INN: amdiglurax; developmental code ALTO-100) is a non-peptide small-molecule benzylpiperazine-aminopyridine derivative investigated as a neurogenic/neuroplasticity-modulating agent for major depressive disorder. It stimulates hippocampal neural progenitor proliferation and differentiation in vitro and neurogenesis in vivo (mouse), acting independently of monoamine reuptake pathways. NSI-189 has never been FDA-approved; Phase 2 monotherapy trials in MDD (220 patients, 2020) and a Phase 2b trial under Alto Neuroscience (~300 patients, 2024) both failed to meet primary MADRS endpoints, and it remains investigational only.

Mechanism of Action

NSI-189 stimulates proliferation and differentiation of human hippocampal neural progenitor cells in vitro and increases hippocampal neurogenesis in vivo in mice. Clinical papers frame its antidepressant hypothesis as acting independently of monoamine (serotonin/dopamine/norepinephrine) reuptake pathways, with proposed downstream involvement of neuroplasticity and BDNF signaling. The compound was originally identified through phenotypic screening in a human hippocampal progenitor cell line.

Research Summary

Human data exist from three registered trials: a Phase 1 single-dose PK study in healthy volunteers (NCT01310881), a Phase 1B multiple-dose-escalation study in 24 MDD patients (28-day inpatient dosing at 40 mg once/twice/thrice daily; half-life ~17.4–20.5 hours; no serious adverse events; no significant hippocampal volume change at day 28 or 84), and a Phase 2 double-blind, placebo-controlled trial in 220 MDD outpatients (12 weeks at 40 mg or 80 mg daily) that missed its primary MADRS endpoint at both doses (p=0.22 and p=0.34, respectively), with some significant secondary/patient-reported benefits at 40 mg. A Phase 2b trial under the ALTO-100 designation (~300 adults, 34 US sites, 6-week double-blind) also failed to meet its primary MADRS endpoint (topline October 2024). Preclinical findings include improved motor/neurological deficits sustained to 24 weeks in a rat stroke model (oral dosing starting 6 hours post-MCAO; increased hippocampal/cortical MAP2 neurite outgrowth; in vitro OGD/R assays showed reduced cell death and upregulated BDNF/SCF), reversal of motor and cognitive impairments in an Angelman syndrome mouse model (with mild performance enhancement in wild-type mice), improved Barnes maze memory retention in a 5xFAD Alzheimer's mouse model (conference abstract), and prevention of peripheral neuropathy indices with increased hippocampal neurogenesis/synaptic markers/volume and protected long-term memory in mouse and rat models of type 1 and type 2 diabetes, alongside enhanced mitochondrial function in a type 2 diabetic rat model.

Reported Side Effects

• Headache (~50% in Phase 1B)
• Dizziness (~27.8% in Phase 1B)
• Somnolence (~27.8% in Phase 1B)
• No serious adverse events reported in Phase 1B or Phase 2 trials
• Long-term safety outside controlled trials not established

Compare NSI-189 with Others

Research References

• NSI-189 — PubChem Compound Summary (CID 50922681).
• NSI-189 phosphate — PubChem Compound Summary (CID 50922680).
• A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients. 2016. PMID 27528461.
• A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder. 2020.

Frequently asked questions

How does NSI-189 work?

NSI-189 stimulates proliferation and differentiation of human hippocampal neural progenitor cells in vitro and increases hippocampal neurogenesis in vivo in mice. Clinical papers frame its antidepressant hypothesis as acting independently of monoamine (serotonin/dopamine/norepinephrine) reuptake pathways, with proposed downstream involvement of neuroplasticity and BDNF signaling. The compound was originally identified through phenotypic screening in a human hippocampal progenitor cell line.

What does the research say about NSI-189?

Human data exist from three registered trials: a Phase 1 single-dose PK study in healthy volunteers (NCT01310881), a Phase 1B multiple-dose-escalation study in 24 MDD patients (28-day inpatient dosing at 40 mg once/twice/thrice daily; half-life ~17.4–20.5 hours; no serious adverse events; no significant hippocampal volume change at day 28 or 84), and a Phase 2 double-blind, placebo-controlled trial in 220 MDD outpatients (12 weeks at 40 mg or 80 mg daily) that missed its primary MADRS endpoint at both doses (p=0.22 and p=0.34, respectively), with some significant secondary/patient-reported benefits at 40 mg. A Phase 2b trial under the ALTO-100 designation (~300 adults, 34 US sites, 6-week double-blind) also failed to meet its primary MADRS endpoint (topline October 2024). Preclinical findings include improved motor/neurological deficits sustained to 24 weeks in a rat stroke model (oral dosing starting 6 hours post-MCAO; increased hippocampal/cortical MAP2 neurite outgrowth; in vitro OGD/R assays showed reduced cell death and upregulated BDNF/SCF), reversal of motor and cognitive impairments in an Angelman syndrome mouse model (with mild performance enhancement in wild-type mice), improved Barnes maze memory retention in a 5xFAD Alzheimer's mouse model (conference abstract), and prevention of peripheral neuropathy indices with increased hippocampal neurogenesis/synaptic markers/volume and protected long-term memory in mouse and rat models of type 1 and type 2 diabetes, alongside enhanced mitochondrial function in a type 2 diabetic rat model.