Tag: KDC-MN-313

NSI-189 (amdiglurax; ALTO-100) is a benzylpiperazine-aminopyridine small molecule identified through a phenotypic screen of approximately 10,000 compounds against human hippocampal neural stem cells and advanced as a first-in-class hippocampal neurogenesis stimulator for the treatment of major depressive disorder (MDD). The compound was discovered by Karl Johe and colleagues at Neuralstem, Inc. (Germantown, Maryland) and is now under development by Alto Neuroscience (Mountain View, California) under the designation ALTO-100. NSI-189 is mechanistically distinct from all marketed antidepressants: it has no detectable activity at serotonin, norepinephrine, or dopamine transporters, no binding at 52 standard neurotransmitter receptor and ion channel targets, and no activity across a panel of 900 kinases. Instead, the compound stimulates proliferation and neurogenic differentiation of hippocampal neural stem cells in vitro with low-micromolar potency and, on oral administration to rodents at 10 to 30 mg/kg/day, produces dose-dependent increases in hippocampal volume (up to 66 percent at 30 mg/kg in mice), upregulation of brain-derived neurotrophic factor (BDNF), stem cell factor (SCF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF), and activation of the TrkB/Akt signaling pathway. The morphological effects are confined to the dentate gyrus of the hippocampus and the subventricular zone; no structural changes have been observed elsewhere in the brain. A bell-shaped dose-response relationship is observed in preclinical hippocampal volume endpoints, with 100 mg/kg producing less effect than 30 mg/kg, suggesting an optimal range for neurogenic stimulation.

Clinical development has proceeded through Phase 1 (41 healthy volunteers, 2011), Phase 1b (24 MDD patients, Fava et al. 2016, published in Molecular Psychiatry), and Phase 2 (220 MDD outpatients, Papakostas et al. 2020, published in Molecular Psychiatry). The Phase 1b trial demonstrated safety and tolerability at 40, 80, and 120 mg daily for 28 days, with medium-to-large effect sizes on the Symptoms of Depression Questionnaire (SDQ) and the Cognitive and Physical Functioning Questionnaire (CPFQ). The Phase 2 trial, conducted using a sequential-parallel comparison design across 12 weeks, did not meet its primary endpoint (change from baseline on the Montgomery-Asberg Depression Rating Scale, MADRS) at either 40 mg or 80 mg daily. However, 40 mg daily produced statistically significant improvements on the SDQ (pooled mean difference -8.2; Cohen’s d = -0.64 in Stage 2; p = 0.04), the CPFQ (pooled mean difference -1.9; p = 0.03), and several objective cognitive measures on the CogScreen battery (Cohen’s d ranging from 0.12 to 1.12 for significant measures). Hippocampal volume was not significantly changed in MDD patients at the studied doses and duration, despite the robust preclinical volumetric signal.

Alto Neuroscience acquired the NSI-189 program in October 2021 and redesignated the compound ALTO-100. A Phase 2b trial (301 adults with MDD, 34 U.S. sites, 6 weeks, biomarker-enriched design using a cognitive memory test) reported topline results in 2024: ALTO-100 did not demonstrate statistically significant improvement in MADRS versus placebo in the biomarker-defined population and did not meet secondary endpoints. The compound was well tolerated, with headache, nausea, and abnormal dreams as the most common adverse events at rates similar to placebo. A Phase 2b trial in bipolar depression is expected to report in 2026, and the compound remains under investigation for post-traumatic stress disorder.

Preclinical pharmacology extends beyond depression. NSI-189 reverses cognitive and motor deficits in a rat model of ischemic stroke (30 mg/kg oral), ameliorates central and peripheral neuropathy in mouse models of type 1 and type 2 diabetes (10 to 30 mg/kg oral), enhances synaptic plasticity and reverses motor and cognitive impairments in a mouse model of Angelman syndrome through TrkB/Akt pathway activation, and enhances long-term potentiation in hippocampal slice preparations in vitro. The compound has linear pharmacokinetics across the 40 to 120 mg/day clinical dose range, an oral Tmax of 1 to 2 hours, a plasma elimination half-life of 17.4 to 20.5 hours supporting once-daily dosing, and achieves steady state within 4 to 5 days.

This monograph reviews the chemical identity and synthesis of NSI-189; the discovery through phenotypic screening; the molecular pharmacology and neurotrophic factor cascade; the comprehensive pharmacokinetic profile; the preclinical evidence base across depression, stroke, neuropathy, and Angelman syndrome models; the clinical evidence base from Phase 1 through Phase 2b; sourcing, reconstitution, and handling considerations; stack interactions; the adverse-event and safety signal; and a structured comparative assessment of five neurogenesis-associated compounds (fluoxetine, ketamine, agomelatine, psilocybin, and 7,8-dihydroxyflavone) against NSI-189 on five competency standards. The compound is not approved by any regulatory authority for any indication. It is sold as a research-grade preparation; investigators should obtain analytical confirmation of identity and purity on every lot.