iclepertin (BI425809) / Boehringer Ingelheim - LARVOL DELTA

Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): results from three phase 3 randomised controlled trials. (PubMed, Lancet Psychiatry) - P3 | "Iclepertin was not associated with significant improvements in cognition in adults with schizophrenia, but it was well tolerated by patients. Findings from CONNEX provide insights into the challenges associated with studying new pharmacotherapies for CIAS."

Clinical • Journal • P3 data • CNS Disorders • Schizophrenia

Comment on "Assessing the Effect of Food on the Pharmacokinetics of Iclepertin in Healthy Volunteers: A Phase I, Open‑Label, Randomised, Cross‑Over Trial". (PubMed, Eur J Drug Metab Pharmacokinet) - No abstract available

Journal • PK/PD data

Pre-Emptive Drug Safety Evaluation of Iclepertin (BI-425809) Using Real-World Data and Virtual Addition of This Medication to the Actual Drug Regimen of Individuals from Large Populations. (PubMed, Pharmaceuticals (Basel)) - "The increase in MRS associated with the addition of iclepertin to the drug regimen of a large population was minimal and mostly driven by CYP3A4 interactions. Using this model, interactions can be identified a priori, making risk mitigable and preventable without exposing patients to toxicity."

Journal • Real-world evidence • Cardiovascular • CNS Disorders • Psychiatry • Schizophrenia • CYP3A4

The effects of iclepertin on QT/QTc interval following oral administration in healthy male and female volunteers (ECNP 2025) - "Iclepertin showed no clinically relevant QTcF interval prolongation at clinically relevant concentrations. Table. Iclepertin Predicted mean (90% CI) ΔΔQTcF, ms At predefined therapeutic iclepertin exposurea2.7 (0.0–5.4) At predefined supratherapeutic iclepertin exposurea4.8 (0.9–8.7)Slope estimate (90% CI), ms/(nmol/L)0.0027 (-0.0014–0.0069)Moxifloxacin Predicted mean (90% CI) ΔΔQTcF at gMean maximum plasma concentration after single dose, ms12.5 (9.8–15.3)Slope estimate (90% CI), ms/(nmol/L)0.0013 (0.0007–0.0018)aPredicted by population pharmacokinetics modelling and simulation.CI, confidence interval; gMean, geometric mean; ΔΔQTcF, placebo-corrected change from baseline in electrocardiogram QT interval corrected for heart rate using Fridericia method."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Augmentation of glutamatergic modulators for schizophrenia: A network meta-analysis. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Among add-on glutamatergic modulators with moderate to high certainty of benefit over placebo, piracetam 2400-4800 mg/day showed the greatest improvement in total psychopathology (standardized mean differences [SMD] -0.94, 95 % confidence interval [CI] -1.47 to -0.41), benzoate 1000-2000 mg/day was most effective for positive symptoms (SMD -0.43, 95 % CI -0.71 to -0.16), memantine 5-20 mg/day ranked highest for negative symptom reduction (SMD -0.64, 95 % CI -0.85 to -0.43), and the combination of sarcosine 2000 mg/day and benzoate 1000 mg/day showed the greatest enhancement in global cognitive function (SMD 1.08, 95 % CI 0.45 to 1.71). Other agents, including d-serine 2000-4000 mg/day, evenamide 30-60 mg/day, iclepertine 10-25 mg/day, lamotrigine, luvadaxistat 50 mg/day, minocycline 100-300 mg/day, N-acetylcysteine 2000 mg/day, sarcosine 2000 mg/day, and topiramate demonstrated benefits with moderate to high certainty in one or more domains. Notably, memantine,..."

Journal • Retrospective data • Review • CNS Disorders • Psychiatry • Schizophrenia

Pharmacological and Mechanistic Interventions for Cognitive Impairment Associated With Schizophrenia: A Review of Registered Clinical Trials. (PubMed, Acta Psychiatr Scand) - "In this comprehensive overview of clinical trials on pro-cognitive agents in schizophrenia, we identify emerging opportunities but also acknowledge a lack of replicated evidence. Despite extensive attempts to address CIAS, it remains an undertreated domain, and future trials should explore better ways to treat this important condition."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

The Effect of Multiple Oral Doses of a Glycine Transporter 1 Inhibitor, Iclepertin (BI 425809), on the Steady-state Pharmacokinetics of a Combined Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel: a Phase I Clinical Trial in Healthy Females. (PubMed, Clin Drug Investig) - P1 | "Iclepertin 10 mg had no meaningful effect on the pharmacokinetics of ethinylestradiol and levonorgestrel, suggesting that these drugs can be administered concomitantly."

Journal • P1 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Assessing the Effect of Food on the Pharmacokinetics of Iclepertin in Healthy Volunteers: A Phase I, Open-Label, Randomised, Cross-over Trial. (PubMed, Eur J Drug Metab Pharmacokinet) - P1 | "Iclepertin exposure was higher in fed versus fasted conditions, but the increase was minor, suggesting food has no meaningful effect on the pharmacokinetics of iclepertin 10 mg."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Evaluation of the Drug-Drug Interaction Potential of the GlyT1 Inhibitor Iclepertin (BI 425809): A Physiologically Based Pharmacokinetic (PBPK) Modeling Approach. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The iclepertin PBPK model was further qualified using clinical data of DDIs with a strong CYP3A4 inducer (rifampicin) and a strong CYP3A4 inhibitor (itraconazole). Based on the thorough qualification with clinical DDI data, the model was deemed qualified to predict new, untested clinical scenarios such as alternative drug doses, coadministration of different CYP3A4 substrates, coadministration of weak-moderate inducers and inhibitors of CYP3A4, and in the setting of polymedication in vivo. The model allows detailed analyses of DDI behaviors to inform appropriate prescribing of concomitant medications in patients treated with iclepertin."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Novel role of serum albumin imidase activity in the formation of BI 761036 (M232), a major metabolite of iclepertin. (PubMed, Drug Metab Dispos) - "SIGNIFICANCE STATEMENT: Human serum albumin exclusively hydrolyzed the intermediate metabolite of iclepertin, M526, leading to the formation of M232, a major metabolite of iclepertin. This discovery marks the first evidence of human serum albumin's direct involvement in the formation of a major human drug metabolite, underscoring the significant and previously unrecognized metabolic role of human serum albumin."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Unlocking the potential of lumateperone and novel anti-psychotics for schizophrenia. (PubMed, Bioimpacts) - "This review also focuses on a few more emerging antipsychotics like brexpiprazole, brilaroxazine, roluperidone, F17464, pimavanserin (ACP-103), xanomeline, BI 409306, BI 425809 and MK-8189 which are under different phase of clinical trials and might get approved soon. All the antipsychotic drugs covered did not show any other severe adverse effects except gastrointestinal issues and cardiometabolic risk factors. However, still rigorous clinical trials and modifications are needed to manage adverse effects, and we can expect a few antipsychotics to be on the market soon."

Journal • Review • Anesthesia • CNS Disorders • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Psychiatry • Schizophrenia

CONNEX-X: A Study to Test Long-term Safety of Iclepertin in People With Schizophrenia Who Took Part in a Previous CONNEX Study (clinicaltrials.gov) - P3 | N=1362 | Terminated | Sponsor: Boehringer Ingelheim | Completed ➔ Terminated; Sponsor decision, project discontinued

Trial termination • CNS Disorders • Psychiatry • Schizophrenia

CONNEX-X: A Study to Test Long-term Safety of Iclepertin in People With Schizophrenia Who Took Part in a Previous CONNEX Study (clinicaltrials.gov) - P3 | N=1362 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Modulation of the human GlyT1 by clinical drugs and cholesterol. (PubMed, Nat Commun) - "Here, we determine cryo-EM structures of GlyT1 in its apo state and in complex with clinical trial drugs iclepertin and sarcosine...Transport kinetics studies reveal that a delicate binding equilibrium for cholesterol is crucial for the conformational transition of GlyT1. This study significantly enhances our understanding of the physiological and pharmacological aspects of GlyT1."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

CONNEX-X: A Study to Test Long-term Safety of Iclepertin in People With Schizophrenia Who Took Part in a Previous CONNEX Study (clinicaltrials.gov) - P3 | N=1361 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Terminated ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Psychiatry • Schizophrenia

CONNEX-X: A Study to Test Long-term Safety of Iclepertin in People With Schizophrenia Who Took Part in a Previous CONNEX Study (clinicaltrials.gov) - P3 | N=1361 | Terminated | Sponsor: Boehringer Ingelheim | Trial completion date: Dec 2025 ➔ Jan 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Jan 2025; Sponsor decision

Trial completion date • Trial primary completion date • Trial termination • CNS Disorders • Psychiatry • Schizophrenia

Boehringer provides update on iclepertin Phase III program in schizophrenia (GlobeNewswire) - P3 | N=620 | CONNEX-1 (NCT04846868) | Sponsor: Boehringer Ingelheim | P3 | N=611 | CONNEX-2 (NCT04846881) | Sponsor: Boehringer Ingelheim | P3 | N=609 | CONNEX-3 (NCT04860830) | Sponsor: Boehringer Ingelheim | "Boehringer Ingelheim today announced top-line results from the Phase III CONNEX clinical program in cognitive impairment in adults with schizophrenia, showing primary and key secondary endpoints were not met....Overall, no statistically significant effects on cognition or functioning were observed in patients treated with iclepertin versus placebo at six months. All three trials demonstrated that iclepertin, a glycine transporter 1 (GlyT1) inhibitor, was generally well tolerated, with a safety profile that remains consistent with previous studies....Full efficacy and safety data will be submitted for presentation at an upcoming medical meeting."

P3 data • P3 data: top line • Schizophrenia

CONNEX-X: A Study to Test Long-term Safety of Iclepertin in People With Schizophrenia Who Took Part in a Previous CONNEX Study (clinicaltrials.gov) - P3 | N=1356 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Psychiatry • Schizophrenia

CONNEX-3: A Study to Test Whether Iclepertin Improves Learning and Memory in People With Schizophrenia (clinicaltrials.gov) - P3 | N=609 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-2) (clinicaltrials.gov) - P3 | N=611 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Health-Related Quality-of-Life (HRQoL) Assessment for Japanese Cognitive Impairment Associated With Schizophrenia (CIAS) (ISPOR-EU 2024) - " This study utilizes blinded baseline data of the Japanese subgroup in the Phase III randomized placebo-controlled trials of CONNEX-1 and CONNEX-2, which investigate the efficacy, safety, and tolerability of Iclepertin in adult patients with schizophrenia currently stable with antipsychotic treatment... This study is the first study to evaluate the QoL scores of Japanese patients with CIAS. HUI3 could contribute to appropriate assessment of QoL scores in Japanese patient with CIAS, as a cognitive attribute of HUI3 was demonstrated to be able to capture the effects of cognitive function."

Clinical • HEOR • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1) (clinicaltrials.gov) - P3 | N=620 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Effects of fluconazole, a moderate CYP3A4 inhibitor, and bosentan, a moderate CYP3A4 inducer on the pharmacokinetics of iclepertin (BI 425809) (ECNP 2024) - P1 | "Systemic exposure of iclepertin was altered in the presence of fluconazole and bosentan, confirming that iclepertin is a sensitive CYP3A4 substrate. Iclepertin was well tolerated when administered alone and in combination with fluconazole or bosentan. In real-world clinical settings, these DDIs should be considered when using concomitant medications which modulate the CYP3A4 pathway."

PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Pharmacokinetics, safety and tolerability of a single oral dose of iclepertin (BI 425809) in participants with and without renal impairment (ECNP 2024) - P1 | "A single oral dose of iclepertin 10mg resulted in minimal PK changes except for a 27–48% increase in overall exposure in participants with severe renal impairment and an 18% increase in peak plasma concentrations in participants with moderate renal impairment compared with controls. Iclepertin was well tolerated in all participants. Results indicate iclepertin 10mg may be given to participants independent of severity of renal impairment."

Clinical • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • CYP3A4

Pharmacokinetics, safety and tolerability of a single oral dose of BI 425809 in participants with and without hepatic impairment (ECNP 2024) - P1 | "A single oral dose of iclepertin 10mg resulted in minimal PK changes in patients with mild hepatic impairment, however, an 18% reduction in peak plasma concentration and 29% increase in overall exposure in patients with moderate hepatic impairment compared with controls was reported. Iclepertin was well tolerated in all participants. Results indicate iclepertin 10mg may be given to mild and moderate hepatic impaired patients without dose adaptation."

Clinical • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • CYP3A4