iclepertin (BI425809) / Boehringer Ingelheim - LARVOL DELTA

Derivation of score interpretation thresholds in clinical outcome assessments measuring cognitive impairment associated with schizophrenia. (PubMed, Schizophr Res) - "The proposed score interpretation thresholds may be valuable for assessing improvement in CIAS in future clinical research. Anchor-based analyses may be limited in this patient population as patient, caregiver and clinician-based global ratings of severity tend to have low correlations with multi-item COA scores, particularly with performance-based measures."

Clinical data • Journal • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Pharmacokinetic/pharmacodynamic analysis to characterize the effect of long-term GlyT1 inhibitor iclepertin exposure on hemoglobin levels. (PubMed, Front Pharmacol) - "The results of this analysis suggest that iclepertin drug effects on patient hemoglobin levels are small, reversible, and of limited significance, even under long-term treatment. This is the first model of the relationship between iclepertin exposure and hemoglobin levels, and, to our best knowledge, the first model to characterize a drug effect on hemoglobin levels over time that has been validated with clinical data that extend beyond the erythrocyte life span of ∼126 days."

Journal • PK/PD data • CNS Disorders • Hematological Disorders • Psychiatry • Schizophrenia

Advances in schizophrenia research and treatment: exploring neurotransmitter imbalances, genetics, and innovative therapies. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Recently, the antipsychotics lumateperone and xanomeline-trospium were approved. Iclepertin, ralmitaront, roluperidone, and brilaroxazine are molecules in Phase 2 or 3 clinical trials...Adjuvant treatments aimed at mitigating neuroinflammation and oxidative stress; microbiome-targeted interventions, neuroprotective and metabolic agents are being explored. Current research efforts aim to improve treatment outcomes by addressing gaps in antipsychotic therapy and mitigating its adverse effects."

Journal • Review • CNS Disorders • Cognitive Disorders • Inflammation • Mental Retardation • Psychiatry • Schizophrenia

The Effect of Iclepertin on Hematological Parameters: An Overview of Nonclinical Studies and Clinical Trials in Healthy Volunteers and Patients with Cognitive Impairment Associated with Schizophrenia. (PubMed, J Clin Pharmacol) - "As the primary and secondary CIAS efficacy endpoints were not met, the CONNEX trial program was terminated. Findings from these nonclinical studies and clinical trials suggest reversible mean hemoglobin reductions were of limited significance and iclepertin was well-tolerated with a consistent safety profile."

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

Structural and construct validity assessment of the schizophrenia cognition rating scale (SCoRS) using data from three international phase 3 randomized controlled trials (CONNEX programme). (PubMed, Schizophr Res) - "Using data from a clinical trial of iclepertin in adult patients with schizophrenia, we explored the dimensionality of the SCoRS using various CFA models including single factor, four correlated factor, and bifactor models. Three external reference anchors were used to assess known-groups validity, based on clinician and study partner ratings of disease severity over time. We found that the models support the essential unidimensionality of the SCoRS, while the known-group validity analysis showed that the SCoRS interviewer total score was able to discriminate between severity groups, which supports its use for measuring CIAS in both clinical research and real-world clinical practice."

Journal • P3 data • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

GlyT1 (SLC6A9) inhibition in neurological and psychiatric disorders. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "We further synthesize pharmacological advances in GlyT1 inhibition, evaluating both sarcosine-derived and non-sarcosine inhibitors, such as NFPS (ALX-5407), bitopertin, and iclepertin. The clinical and preclinical evidence for GlyT1 as a therapeutic target in psychiatric, neurological, and neurodegenerative disorders is critically assessed. Finally, we address key translational challenges, including dosing constraints, compensatory mechanisms, and SLC6 family selectivity, while highlighting the potential of structure-guided design to refine GlyT1-targeted therapies."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Mental Retardation • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Iclepertin (BI 425809): Results from Two Phase I Open-Label, Non-randomised, Single Dose, Parallel Design Studies. (PubMed, Drugs R D) - P1 | "These findings indicate that although some increased exposure to iclepertin is expected in patients with severe renal impairment or moderate hepatic impairment, iclepertin 10 mg demonstrated a favourable safety profile, was well-tolerated, and can be administered in patients with varying degrees of renal or hepatic impairment without dose modification."

Journal • P1 data • PK/PD data • Hepatology • Pain • Renal Disease • CYP3A4

New Pharmacological Treatment Approaches for Schizophrenia: Navigating the Post-iclepertin Landscape. (PubMed, CNS Drugs) - "The most compelling therapeutic approaches continue to be serotonin-dopamine activity modulators (brilaroxazine) and emerging M4 selective agonists (NBI-1117568). While iclepertin's discontinuation represents a significant setback for GlyT1 inhibition strategies, the approval of KarXT and advancing pipeline candidates offer potential for therapeutic advances. Critical challenges include escalating placebo responses that compromise trial assay sensitivity, underscoring the need for improved patient stratification, refined trial methodology, and outcome measures that accurately capture real-world benefit."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia • DRD2

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