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

Key facts

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#

Jul 23Jan 24Jul 24Phase 222 Oct 2024 — phase change — MDD Phase 2b (NCT05712187, n=301) did NOT meet its primary endpoint; MDD development halted.2 Oct 2024 — phase change — Phase 2b adjunctive bipolar-depression trial (NCT06656416) initiated.25 Jul 2024 — Partnership — Wellcome Trust funding award to advance ALTO-100 in bipolar depression10 Jan 2023 — phase change — Positive MDD Phase 2a: biomarker-defined group showed 15.5-pt MADRS reduction vs 10.6 (p=0.001) at Week 6.
Phase change Readout Event UpcomingHover a marker for details.
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. PartnershipWellcome Trust funding award to advance ALTO-100 in bipolar depression↗
  4. 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

Sources#

  1. Alto Neuroscience Receives Funding Award from Wellcome Trust to Accelerate Development of ALTO-100 in Bipolar Depression — Business Wire / Alto Neuroscience, Inc.
  2. ALTO-100 in Bipolar Disorder With Depression (BD-D) — ClinicalTrials.gov
  3. ALTO-100 MDD Phase 2b topline (endpoint not met) — Alto Neuroscience
  4. Amdiglurax — Wikipedia
  5. investors.altoneuroscience.com — Reference