Small Molecule · ALTO-100

ALTO-100 (amdiglurax)

Phase 2Alto Neuroscience, Inc. (ANRO)

Oral pro-neurogenesis/pro-plasticity small molecule (formerly NSI-189), reported as a TLX (NR2E1) nuclear-receptor agonist that enhances hippocampal neurogenesis (indirect BDNF signaling). Alto Neuroscience uses a verbal-memory cognitive biomarker to enrich responders. A biomarker-defined MDD Phase 2b missed its primary endpoint (Oct 2024); now in a Phase 2b adjunctive bipolar-depression trial.

Also known as: ALTO-100, NSI-189, amdiglurax

Data current as of

Modality
Small molecule
Chemical class
benzylpiperazine, aminopyridine
Chemistry
Achiral
Mechanism
TLX agonist
Highest phase
Phase 2
Lead indication
Bipolar depression
Developer
Alto Neuroscience, Inc. (ANRO)
Trials
1 tracked · 1 recruiting · 27 sites

Mechanism of action

Reported as a potent agonist of the orphan nuclear receptor TLX (NR2E1), which regulates neural stem-cell proliferation; thought to indirectly enhance BDNF and hippocampal neuroplasticity. Mechanism historically described as incompletely defined.

TargetActionAffinity
TLXprimaryNR2E1AgonistEC50 36.1 pMⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
ALTO-100 oral tablettablet
40 mg tablet twice daily (Phase 2b bipolar depression, adjunctive to a mood stabilizer and/or atypical antipsychotic); dosing range studied 40-150 mg/day
OralTwice dailyt½ 18.95 h · Tmax 1.5 h

Development timeline

Phase 2Jan 2023 – Oct 2024
  1. MDD Phase 2b (NCT05712187, n=301) did NOT meet its primary endpoint; MDD development halted.↗
  2. Phase 2b adjunctive bipolar-depression trial (NCT06656416) initiated.
  3. Positive MDD Phase 2a: biomarker-defined group showed 15.5-pt MADRS reduction vs 10.6 (p=0.001) at Week 6.↗

ALTO-100 (amdiglurax) for Bipolar depression

Phase 2RecruitingBipolar depression indication →

ALTO-100 adjunctive Phase 2b in bipolar I/II depression (NCT06656416, recruiting; supported in part by a Wellcome Trust award) — the current lead mood program after the biomarker-defined MDD Phase 2b (NCT05712187, n=301) missed its primary endpoint in Oct 2024.

Clinical trials

NCT06656416Phase 2Recruitingn=200

ALTO-100 Adjunctive in Bipolar Disorder With Depression

Started Oct 2024· Primary completion Aug 2026· 📍 27 sites across 1 country (United States)

Related compounds

More from Alto Neuroscience, Inc.

Identifiers

Sources

  1. ALTO-100 in Bipolar Disorder With Depression (BD-D) — ClinicalTrials.gov
  2. ALTO-100 MDD Phase 2b topline (endpoint not met) — Alto Neuroscience
  3. Amdiglurax — Wikipedia
  4. investors.altoneuroscience.com — Reference