iclepertin (BI425809) / Boehringer Ingelheim - LARVOL DELTA

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

Efficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme (ECNP 2024) - P2, P3 | "Demonstration of efficacy of iclepertin in improving cognition in this Phase III programme would provide important insight into the role of glutamate in cognitive symptoms, that may also have relevance for other cognitive disorders. Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia."

Clinical • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

The effect of iclepertin on hematology parameters in phase II trials (ECNP 2024) - P2 | "Phase II data showed a progressive, dose dependent decrease of Hb, MCV, MCH in both CIAS and AD study population. Changes in reticulocytes/erythrocytes ratio were present across studies and different doses. The Hb drop in the Phase II studies was generally mild, of limited clinical significance and recovered after treatment discontinuation."

P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Population pharmacokinetic-pharmacodynamic modelling of the iclepertin drug effect on hemoglobin levels (ECNP 2024) - P2 | " The model was developed based on data from 3 clinical iclepertin studies (n=25 healthy volunteers, n=599 Alzheimer's Disease Dementia patients, n=492 Schizophrenia patients, EudraCT Numbers: 2014-005652-26, 2015-005438-24, 2016-000285-28), and a literature model describing the effect of the discontinued Roche GlyT1 inhibitor bitopertin on hemoglobin levels [1]. The current model can describe the effects of chronic iclepertin administration on patient hemoglobin levels. The model serves as a platform to assess the risk of anaemia in patients and vulnerable patient subpopulations, during untested administration scenarios, and to inform the need for monitoring."

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

Effect of multiple oral doses of iclepertin (BI 425809) on metabolism of the CYP3A4 probe drug midazolam in healthy males (ECNP 2024) - P1 | "When midazolam was administered concomitantly with once-daily iclepertin 10 mg to participants, its AUC0–tz and Cmax were reduced by 11% and 13%, respectively, compared with midazolam alone. This suggests once-daily iclepertin at this dose has no clinically meaningful effect on the pharmacokinetics of sensitive CYP3A4 substrates. Treatment with iclepertin was well tolerated, with the observed AEs in line with previous findings."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • CYP3A4

Effect of multiple oral doses of BI 425809 on steady-state pharmacokinetics of a combined oral contraceptive in healthy females (ECNP 2024) - P1 | "Iclepertin did not affect the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy females. The combination of iclepertin and Microgynon® was well-tolerated."

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

CONNEX-X extension trial examining the long-term safety of iclepertin (BI 425809) in patients with schizophrenia from Phase III CONNEX trials (ECNP 2024) - P2, P3 | "Conclusions Patient enrolment rates from the CONNEX parent trials to the CONNEX-X open-label extension study are stable. CONNEX-X will allow the exploration of long-term safety, as well as descriptive analyses of cognitive and functional endpoints of iclepertin in the treatment of CIAS."

Clinical • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities. (PubMed, Med Res Rev) - "Notably, the sigma-2, 5-HT2A, and α1A receptor antagonist roluperidone, as well as a fixed-dose combination of the M1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5-HT1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small-molecule entities and fixed-dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Finding the right dose: NMDAR modulating treatments for cognitive and plasticity deficits in schizophrenia and the role of pharmacodynamic target engagement. (PubMed, Biol Psychiatry) - "A range of direct and indirect NMDAR modulators will be covered, including d-serine, d-cycloserine, memantine, glycine and "first generation" glycine transport inhibitors (GTI, e.g. sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel GTI and luvadaxistat, a D-amino acid oxidase inhibitor (DAAO-I) that increases brain d-serine levels and indirect non-invasive brain stimulation NMDAR modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery will be emphasized, including mismatch negativity (MMN), auditory steady state (ASSR) and time-frequency event-related potential (TF-ERP) approaches."

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

Pharmacological Treatment of Cognitive Impairment Associated With Schizophrenia: State of the Art and Future Perspectives. (PubMed, Schizophr Bull Open) - "In particular, the effects on CIAS of antipsychotic medications, anticholinergic medications, benzodiazepines, which are currently commonly used in the treatment of SSD, and of iclepertin, d-serine, luvadaxistat, xanomeline-trospium, ulotaront, anti-inflammatory molecules, and oxytocin, which are undergoing regulatory trials or can be considered as experimental agents, will be reported and discussed. Some molecules that are currently being investigated in Phase 2 and Phase 3 trials have provided very promising preliminary results, but more information is currently required to assess their effectiveness in real-world contexts and to provide clear recommendations regarding their use in clinical practice. The results of ongoing and future studies will reveal whether any of these molecules represents the awaited pharmacological game-changer in the treatment of CIAS."

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

A Study in Healthy People to Test Whether Iclepertin Has an Effect on Cardiac Safety (clinicaltrials.gov) - P1 | N=56 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion