Small Molecule · ALTO-203

ALTO-203

Phase 2Alto Neuroscience, Inc. (ANRO)

Novel oral histamine H3 receptor inverse agonist from Alto Neuroscience for MDD with elevated anhedonia. H3 blockade disinhibits histamine/dopamine/norepinephrine/acetylcholine signaling (arousal, mood, cognition).

Also known as: ALTO-203

Data current as of

Key facts

Modality
Small molecule
Mechanism
H3 receptor Inverse agonist
Highest phase
Phase 2
Lead indication
Major depressive disorder
Developer
Alto Neuroscience, Inc. (ANRO)
Trials
1 tracked · 15 sites

Mechanism of action#

Histamine H3 receptor inverse agonist; H3 (auto/heteroreceptor) blockade increases dopamine in reward circuitry and enhances arousal/attention/mood — the rationale for targeting anhedonia in MDD.

TargetActionAffinity
H3 receptorprimaryHRH3Inverse agonist—ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
ALTO-203 oral
25 mcg or 75 mcg once daily (QD); evaluated in a single-dose crossover period plus a 28-day multi-dose once-daily period in the Phase 2 MDD proof-of-concept trial (NCT06391593)
OralOnce daily—

Development timeline#

2022202320242025Phase 226 Jun 2025 — phase change — Phase 2 POC completed; missed single-dose primary efficacy endpoint amid high placebo response, but PD-positive and identified an EEG patient-selection biomarker.11 Apr 2024 — phase change — Phase 2 study of ALTO-203 in MDD with anhedonia initiated (NCT06391593).4 Oct 2021 — Licensing deal — Alto acquires histamine H3 inverse agonist (ALTO-203) from Teva / Cephalon
Phase change Readout Event UpcomingHover a marker for details.
Phase 2Oct 2021 – Jun 2025
  1. Phase 2 POC completed; missed single-dose primary efficacy endpoint amid high placebo response, but PD-positive and identified an EEG patient-selection biomarker.↗
  2. Phase 2 study of ALTO-203 in MDD with anhedonia initiated (NCT06391593).↗
  3. Licensing dealAlto acquires histamine H3 inverse agonist (ALTO-203) from Teva / Cephalon↗

ALTO-203 for Major depressive disorder#

Phase 2CompletedMajor depressive disorder indication →

Phase 2 exploratory POC (NCT06391593) in MDD with elevated anhedonia. The single-dose primary efficacy endpoint (Bond-Lader VAS) was NOT met (high placebo response), but positive pharmacodynamics were reported: EEG theta/beta ratio identified as a patient-selection biomarker (p<0.05 at 25 µg), plus improvements in sustained attention and objective sleep. Next steps TBD.

Clinical trials#

NCT06391593Phase 2Completedn=69

Phase 2 PD/PK/Safety Study of ALTO-203 in Major Depressive Disorder

Started Mar 2024· Primary completion Apr 2025· 15 sites across 1 country

United States

missedprimaryBond-Lader VAS (positive emotion) — single dose

Primary efficacy endpoint not met (high placebo response). PD-positive: EEG theta/beta ratio reduced (p<0.05 at 25 µg); sustained-attention and objective-sleep improvements; ~2-pt MADRS improvement at Week 3 (25 µg).

Conference coverage#

ALTO-203 appears in 3 CNS Pulse conference abstracts:

Sources#

  1. Alto Neuroscience Identifies Biomarker and Reports Positive Pharmacodynamic Results from Exploratory Phase 2 Proof-of-Concept Trial of ALTO-203 — Alto Neuroscience
  2. Alto Neuroscience Reports Positive Pharmacodynamic Results from Exploratory Phase 2 Trial of ALTO-203 — Business Wire / Alto Neuroscience, Inc.
  3. investors.altoneuroscience.com — Reference
  4. PD, PK, and Safety of ALTO-203 in Patients With MDD — ClinicalTrials.gov