osoresnontrine (BI 409306) / 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

AI-based medication adherence prediction in patients with schizophrenia and attenuated psychotic disorders. (PubMed, Schizophr Res) - P2 | "Adherence data with longer monitoring durations (14 days), lower adherence cut-offs (0.6), and later timepoints (Trial-End) produced most accurate adherence predictions. Accurate adherence prediction provides insights about medication adherence patterns that may help clinicians improve individual adherence."

Adherence • Journal • CNS Disorders • Psychiatry • Schizophrenia

BI 409306 Cardiac Safety Trial in Healthy Volunteers (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Boehringer Ingelheim | N=12 ➔ 20

Enrollment change

Effects of Lamotrigine, the PDE9 Inhibitor BI 409306, and GlyT1 Inhibitor BI 425809 on Attenuation of Ketamine-Induced Memory Impairment: An Exploratory Study in Healthy Subjects (SIRS 2024) - P1 | "Of 40 randomized subjects, 35 completed the trial. Across treatment sequences, n=33 treatments for placebo, n=21 for BI 425809, n=21 for BI 409306 and n=24 for lamotrigine were used for analysis. Ketamine elicited consistent worsening of cognitive performance assessed with all 3 tasks in placebo-treated subjects: PAL (+10.3 errors, standard deviation (SD) 14.8), SWM (+5.9 errors, SD 9.2) and RVP (-0.047, SD 0.052)."

Clinical • CNS Disorders • Schizophrenia

Effects of the phosphodiesterase 9 inhibitor BI 409306 on mouse electroencephalography and auditory event-related potential biomarkers related to schizophrenia (ECNP 2023) - "There is growing evidence that these deficits are related to N-methyl-D-aspartate (NMDA) receptors hypofunction as part of schizophrenia pathophysiology, and hence NMDA receptor antagonists such as MK-801 or ketamine induce symptoms in animals and humans that closely resemble those of schizophrenia patients. Our study in mice demonstrates that PDE9 inhibition by BI 409306 to improve NMDA receptor signalling in glutamatergic neurons is sufficient to attenuate MK-801 induced deficits in translatable EEG/AERP readouts with relevance to schizophrenia. Thus, PDE9 inhibition might be a therapeutic approach to address cortical network dysfunction in patients with schizophrenia."

Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Pooling trial data to identify heterogeneity and characteristics of patients most likely to respond to treatment: a causal forest approach (AAIC 2023) - " We requested data from fifteen completed phase I–III trials investigating several compounds in AD individuals and were granted access to six trial datasets using compounds LY450139 (semagacestat), GSK933776, and BI409306 (with donepezil) with 2,397 participants (73.3±7.8 years old, 55% female, Table 1), through the Vivli platform. We took an innovative approach and provided a methodological basis to examine heterogeneity in treatment effects by pooling existing trial datasets. Our results imply that responsiveness to treatment may not be well-explained by the patient characteristics to our disposal, or that different compounds should be investigated. More research into other factors possibly related to treatment response is needed, e.g., fluid biomarkers and genetics."

Clinical • Heterogeneity • Alzheimer's Disease • CNS Disorders

A Study in Healthy Men to Test Whether BI 409306, BI 425809 or Lamotrigine Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1 | N=39 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion • Cognitive Disorders

Combined ligand-based and structure-based design of PDE 9A inhibitors against Alzheimer's disease. (PubMed, Mol Divers) - "PF-04447943 and BI-409306 targeting PDE9 are undergoing clinical trials (Phase II). The hits were subjected to molecular dynamics (MD) studies, wherein they formed stable complexes with PDE9 protein and had ligand RMSDs within acceptable limits. The processes involved in the combined ligand and structure-based strategies."

Journal • Alzheimer's Disease • CNS Disorders • Pain

A Study in Healthy Men to Test Whether BI 409306, BI 425809 or Lamotrigine Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1 | N=39 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Enrollment closed • Cognitive Disorders

A Study in Healthy Men to Test Whether BI 409306, BI 425809 or Lamotrigine Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Apr 2022 ➔ Jul 2022 | Trial primary completion date: Mar 2022 ➔ Jul 2022

Trial completion date • Trial primary completion date • Cognitive Disorders

The effect of BI 409306 on heart rate in healthy volunteers: a randomised, double-blind, placebo-controlled, crossover study. (PubMed, Eur J Clin Pharmacol) - "Observed hemodynamic effects following BI 409306 administration were of low amplitude, transient, and followed the pharmacokinetic profile of BI 409306."

Journal • Cardiovascular • CNS Disorders • Psychiatry • Schizophrenia

New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics. (PubMed, Neurosci Biobehav Rev) - "Cariprazine, brexpiprazole and brilaroxazine are partial dopamine agonists effective in acute relapse. Lumateperone (serotonin and dopamine receptor antagonist) additionally benefits asocial and depressive symptoms. F17464 (D3 antagonist and 5-HT1A partial agonist) has one positive phase II study. Lu AF35700 (dopamine and serotonin receptor antagonist) was tested in treatment-resistance with no positive results. Pimavanserin, roluperidone, ulotaront and xanomeline do not act directly on the D2 receptor at clinical doses...BI 409306, BI 425809 and MK-8189 target glutamatergic dysfunction in schizophrenia, though of these only BI 425809 showed efficacy. These medications largely have favourable cardiometabolic side-effect profiles. Overall, the novel pharmacology, clinical trial and tolerability data indicate these compounds are promising new additions to the therapeutic arsenal."

Adverse events • Clinical • Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

This Study Tests Whether BI 409306 Prevents Patients With Schizophrenia From Becoming Worse. This Study Looks at How Well Patients Tolerate BI 409306 and How Effective it is Over 6 Months (clinicaltrials.gov) - P2; N=264; Terminated; Sponsor: Boehringer Ingelheim; Completed ➔ Terminated; disruption due to COVID-19

Clinical • Trial termination • CNS Disorders • Psychiatry • Schizophrenia

This Study Tests Whether BI 409306 Prevents Patients With a Specific Type of Mental Illness (Attenuated Psychosis Syndrome) From Becoming Worse. This Study Looks at How Well Patients Tolerate the Medicine and How Effective it is Over 1 Year (clinicaltrials.gov) - P2; N=50; Terminated; Sponsor: Boehringer Ingelheim; Completed ➔ Terminated; disruption due to COVID-19

Clinical • Trial termination • CNS Disorders • Psychiatry

A Study in Healthy Men to Test Whether BI 409306, BI 425809 or Lamotrigine Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: Oct 2021 ➔ Apr 2022; Trial primary completion date: Sep 2021 ➔ Mar 2022

Clinical • Trial completion date • Trial primary completion date • Cognitive Disorders

Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders. (PubMed, Neuropsychopharmacology) - "Furthermore, BI 409306 1 mg/kg alone or in combination with risperidone 0.025 mg/kg significantly reversed social interaction deficits and attenuated amphetamine-induced hyperlocomotion in MIA offspring (Study 2). Taken together, our findings suggest that symptomatic treatment with BI 409306 can restore social interaction deficits and dopaminergic dysfunctions in a MIA model of neurodevelopmental disruption, lending preclinical support to current clinical trials of BI 409306 in patients with schizophrenia. Moreover, BI 409306 given during adolescence has preventive effects on adult social interaction deficits in this model, supporting its use in people with APS."

Journal • CNS Disorders • Developmental Disorders • Psychiatry • Schizophrenia

This Study Tests Whether BI 409306 Prevents Patients With a Specific Type of Mental Illness (Attenuated Psychosis Syndrome) From Becoming Worse. This Study Looks at How Well Patients Tolerate the Medicine and How Effective it is Over 1 Year (clinicaltrials.gov) - P2; N=50; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Clinical • Trial completion • CNS Disorders • Psychiatry

This Study Tests Whether BI 409306 Prevents Patients With a Specific Type of Mental Illness (Attenuated Psychosis Syndrome) From Becoming Worse. This Study Looks at How Well Patients Tolerate the Medicine and How Effective it is Over 1 Year (clinicaltrials.gov) - P2; N=50; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting; N=300 ➔ 50

Clinical • Enrollment change • Enrollment closed • CNS Disorders • Psychiatry

This Study Tests Whether BI 409306 Prevents Patients With Schizophrenia From Becoming Worse. This Study Looks at How Well Patients Tolerate BI 409306 and How Effective it is Over 6 Months (clinicaltrials.gov) - P2; N=264; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

[VIRTUAL] Efficacy and Safety of Osoresnontrine (BI 409306) Once Daily for Prevention of Relapse in Patients with Schizophrenia: Phase II Trial Methodology (SIRS 2021) - P2 | "Final results are expected in Q2 2021 and will be disclosed. Discussion his will be the first public release of top-line Phase II data that will determine whether osoresnontrine as add-on to antipsychotic treatment is superior to placebo for the prevention of relapse and is well tolerated in patients with schizophrenia."

Clinical • P2 data • CNS Disorders • Schizophrenia

[VIRTUAL] Efficacy and Safety of Osoresnontrine (BI 409306) Once Daily for Prevention of Relapse in Patients with Schizophrenia: Phase II Trial Methodology (SIRS 2021) - P2 | "Final results are expected in Q2 2021 and will be disclosed. Discussion his will be the first public release of top-line Phase II data that will determine whether osoresnontrine as add-on to antipsychotic treatment is superior to placebo for the prevention of relapse and is well tolerated in patients with schizophrenia."

Clinical • P2 data • CNS Disorders • Schizophrenia

[VIRTUAL] Efficacy and Safety of Osoresnontrine (BI 409306) Once Daily for Prevention of Relapse in Patients with Schizophrenia: Phase II Trial Methodology (SIRS 2021) - P2 | "Final results are expected in Q2 2021 and will be disclosed. Discussion his will be the first public release of top-line Phase II data that will determine whether osoresnontrine as add-on to antipsychotic treatment is superior to placebo for the prevention of relapse and is well tolerated in patients with schizophrenia."

Clinical • P2 data • CNS Disorders • Schizophrenia

A Study in Healthy Men to Test Whether BI 409306, BI 425809 or Lamotrigine Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: Jun 2021 ➔ Sep 2021; Trial primary completion date: May 2021 ➔ Aug 2021

Clinical • Trial completion date • Trial primary completion date • Cognitive Disorders

This Study Tests Whether BI 409306 Prevents Patients With Schizophrenia From Becoming Worse. This Study Looks at How Well Patients Tolerate BI 409306 and How Effective it is Over 6 Months (clinicaltrials.gov) - P2; N=264; Active, not recruiting; Sponsor: Boehringer Ingelheim; N=387 ➔ 264

Clinical • Enrollment change • CNS Disorders • Psychiatry • Schizophrenia

This Study Tests Whether BI 409306 Prevents Patients With a Specific Type of Mental Illness (Attenuated Psychosis Syndrome) From Becoming Worse. This Study Looks at How Well Patients Tolerate the Medicine and How Effective it is Over 1 Year (clinicaltrials.gov) - P2; N=300; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: May 2022 ➔ Apr 2021; Trial primary completion date: Apr 2022 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry