Small Molecule · BI 425809
Iclepertin (BI 425809)
Oral, once-daily (10 mg) potent and highly selective glycine transporter-1 (GlyT1 / SLC6A9) inhibitor. By blocking glycine reuptake it raises synaptic glycine, the obligatory NMDA-receptor co-agonist, to enhance glutamatergic/NMDA signaling. Developed by Boehringer Ingelheim as adjunctive therapy for cognitive impairment associated with schizophrenia (CIAS); inactive at GlyT2. The Phase 3 CONNEX program missed its primary and key secondary endpoints and development for schizophrenia was discontinued in January 2025.
Also known as: BI 425809, BI-425809, iclepertin, 1421936-85-7
Key facts
- Modality
- Small molecule
- Chemical class
- isoxazole, azabicyclo[3.1.0]hexane, benzamide
- Chemistry
- Single enantiomer
- Mechanism
- GlyT1 inhibitor
- Highest phase
- Discontinued
- Lead indication
- Schizophrenia
- Developer
- Boehringer Ingelheim
- Trials
- 4 tracked · 656 sites
Mechanism of action#
Potent, selective, oral inhibitor of glycine transporter-1 (GlyT1 / SLC6A9). GlyT1 blockade raises extracellular/synaptic glycine, the obligatory co-agonist at the NMDA receptor glycine-B site, thereby augmenting NMDA-receptor-mediated glutamatergic neurotransmission hypothesized to be deficient in schizophrenia and to underlie cognitive impairment (CIAS). In vitro GlyT1 inhibition IC50 ~5.0 nM in human SK-N-MC cells (~5.2 nM in rat primary neurons), with no measurable activity at the related transporter GlyT2 (SLC6A5).
| Target | Action | Affinity |
|---|---|---|
| GlyT1primarySLC6A9 | Inhibitor | IC50 5 nMⓘ |
Formulations#
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Iclepertin oral tablet 10 mg once daily (Phase III dose; Phase II tested 10 mg and 25 mg) | Oral | Once daily | t½ 37 h · Tmax 4 h |
Development timeline#
- Phase 3 CONNEX program initiated (CONNEX-1/-2/-3 plus the CONNEX-X open-label extension); iclepertin 10 mg once daily over 26 weeks adjunctive to stable antipsychotic treatment.
- Phase 2 proof-of-concept (NCT02832037, n=509, 12 weeks) reported: iclepertin was well tolerated and significantly improved cognition (MCCB) vs placebo in CIAS, supporting Phase 3.↗
Iclepertin (BI 425809) for Schizophrenia#
DiscontinuedDiscontinuedSchizophrenia indication →
Phase 3 CONNEX program for cognitive impairment associated with schizophrenia (CIAS): three replicate randomized, double-blind, placebo-controlled trials of iclepertin 10 mg once daily over 26 weeks adjunctive to stable antipsychotic therapy (CONNEX-1 NCT04846868, CONNEX-2 NCT04846881, CONNEX-3 NCT04860830; ~1,840 patients across 41 countries) plus an open-label long-term-safety extension (CONNEX-X, NCT05211947). On 16 January 2025 Boehringer Ingelheim announced all three trials missed the primary endpoint (change from baseline in MCCB overall composite T-score at week 26) and the key secondary functioning endpoint, with no statistically significant effect on cognition or functioning vs placebo at six months; iclepertin was generally well tolerated. Boehringer discontinued the CONNEX-X extension effective immediately, ending iclepertin development in schizophrenia. Pooled results were published in The Lancet Psychiatry in December 2025 (MCCB adjusted mean difference 0.127, 95% CI -0.396 to 0.650, p=0.63).
Readouts
- 2025-12-01ReportedFull resultsmissedNCT04860830
Pooled CONNEX Phase 3 results published in The Lancet Psychiatry: iclepertin no better than placebo on MCCB (p=0.63). ↗
- 2025-01-16ReportedTopline datamissedNCT04860830
Phase 3 CONNEX (CONNEX-1/-2/-3) missed primary (MCCB) and key secondary endpoints; iclepertin development in schizophrenia discontinued. ↗
Clinical trials#
NCT052119471346-0014Phase 3Discontinuedn=1356
An Open Label, Single Arm, Extension Trial to Examine Long-term Safety of Iclepertin Once Daily in Patients With Schizophrenia Who Have Completed Previous Iclepertin Phase III Trials (CONNEX-X)
JapanUnited StatesChinaArgentina
terminatedprimaryLong-term safety of iclepertin 10 mg once daily (open-label extension)
Open-label long-term safety extension discontinued effective immediately after the parent CONNEX trials missed their endpoints; trial status TERMINATED on ClinicalTrials.gov.
NCT048468681346-0011Phase 3Completedn=620
A Phase III Randomized, Double-blind, Placebo-controlled Parallel Group Trial to Examine the Efficacy and Safety of Iclepertin Once Daily Over 26 Week Treatment Period in Patients With Schizophrenia (CONNEX-1)
JapanUnited StatesChinaGreece
missedprimaryChange from baseline in MCCB overall composite T-score at Week 26
Primary cognition endpoint not met; no statistically significant effect on cognition vs placebo at 26 weeks (reported in the pooled CONNEX topline announcement, 16 Jan 2025).
NCT048468811346-0012Phase 3Completedn=611
A Phase III Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Examine the Efficacy and Safety of Iclepertin Once Daily Over 26 Week Treatment Period in Patients With Schizophrenia (CONNEX-2)
JapanUnited StatesSpainFrance
missedprimaryChange from baseline in MCCB overall composite T-score at Week 26
Primary cognition endpoint not met; no statistically significant effect on cognition vs placebo at 26 weeks (reported in the pooled CONNEX topline announcement, 16 Jan 2025).
NCT048608301346-0013Phase 3Completedn=609
A Phase III Randomized, Double-blind, Placebo-controlled Parallel Group Trial to Examine the Efficacy and Safety of Iclepertin Once Daily Over 26 Week Treatment Period in Patients With Schizophrenia (CONNEX-3)
United StatesChinaArgentinaUnited Kingdom
missedprimaryChange from baseline in MCCB overall composite T-score at Week 26 (pooled CONNEX-1/-2/-3) — adjusted mean difference 0.127 (95% CI -0.396 to 0.650) (0.63)
Primary cognition endpoint not met in any CONNEX trial; pooled adjusted mean difference vs placebo 0.127 (p=0.63). Key secondary functioning endpoint (VRFCAT) also not met. Iclepertin generally well tolerated. Pooled results published in The Lancet Psychiatry, Dec 2025.
Sources#
- Boehringer provides update on iclepertin Phase III program in schizophrenia (16 Jan 2025) — CONNEX endpoints not met; CONNEX-X discontinued — Boehringer Ingelheim (press release via BioSpace)
- CONNEX-1: Phase 3 iclepertin vs placebo over 26 weeks in schizophrenia (NCT04846868) — ClinicalTrials.gov
- CONNEX-2: Phase 3 iclepertin vs placebo over 26 weeks in schizophrenia (NCT04846881) — ClinicalTrials.gov
- CONNEX-3: Phase 3 iclepertin vs placebo over 26 weeks in schizophrenia (NCT04860830) — ClinicalTrials.gov
- CONNEX-X: open-label long-term safety extension of iclepertin (NCT05211947) — TERMINATED — ClinicalTrials.gov
- Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia — Eur Arch Psychiatry Clin Neurosci (Rosenbrock et al., PMC)
- Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): results from three phase 3 randomised controlled trials — The Lancet Psychiatry