BI-474121 / Boehringer Ingelheim - LARVOL DELTA

Safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121: An overview of phase I randomized trials in healthy volunteers. (PubMed, J Psychopharmacol) - "Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone. BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development."

Journal • P1 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • CYP3A4

Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies. (PubMed, Br J Clin Pharmacol) - P1 | "BI 474121 crosses the blood-brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121."

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

PDE2 and PDE9 Inhibition Improves Cognitive Flexibility in a Rat Model Related to Schizophrenia (SIRS 2023) - "The aim of the present study was to assess functional target engagement with a PDE2 inhibitor, BI 474121 and the PDE9 inhibitor, Bay 73-6691 on cGMP increase in the brain...The aim of the present study was to assess functional target engagement with a PDE2 inhibitor, BI 474121 and the PDE9 inhibitor, Bay 73-6691 on cGMP increase in the brain...Keyword Keywords PDE2 PDE9 cognitive flexibility animal model Poster Award No Please list all co-authors for this poster submission. * Presenting Author First Name Last Name Affiliation Holger * Rosenbrock * CNS Discovery Research, Boehringer Ingelheim GmbH & Co KG Ben Grayson University of Manchester Giovanni Podda University of Manchester Nagi Idris University of Manchester 2Joanna Neill University of Manchester Scott Hobson CNS Discovery Research, Boehringer Ingelheim Pharma GmbH & Co KG Consent of Release of Rights I have read and agree to the above terms and conditions."

Preclinical • CNS Disorders • Schizophrenia

Effects of the novel phosphodiesterase-2 inhibitor BI 474121 on rodent auditory event-related potentials biomarkers and cognition tasks related to schizophrenia (ECNP 2022) - "After systemic administration, BI 474121 showed robust efficacy in reversing MK-801 induced deficits of various AERP readouts related to sensory processing integrity of neural networks believed to be important for cognitive function, e.g. excitatory/inhibitory balance as determined by evoked gamma and 40 Hz ASSR recordings. In addition, confirming previous findings of other PDE2 inhibitors, BI 474121 showed memory enhancing effects in rodent cognition tasks further demonstrating that PDE2 inhibition may be a potential approach to pharmacologically improve cognition in psychiatric disorders such as schizophrenia."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanylyl monophosphate concentrations in rats and humans (ECNP 2022) - P1 | "As previously reported, BI 474121 was generally well tolerated. Overall, these data indicate that BI 474121 crosses the human blood-brain barrier and inhibits PDE2 in the brain, supporting further clinical development of the compound."

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

Safety, tolerability, pharmacokinetics and relative bioavailability of BI 474121 in healthy males – a Phase I study (ECNP 2022) - P1 | "BI 474121 was safe and well tolerated across dose groups. Absorption was slower and Cmax was lower for TF versus OS. Dose-proportionality was observed for AUC0–tz with either formulation, but only with TF for Cmax."

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

A Study in Healthy Men to Test Whether BI 474121 Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Boehringer Ingelheim | Trial primary completion date: Feb 2023 ➔ Jun 2023

Trial primary completion date • Cognitive Disorders

A Study in Healthy Men to Test Whether BI 474121 Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Boehringer Ingelheim | Not yet recruiting ➔ Withdrawn | N=48 ➔ 0

Enrollment change • Trial withdrawal • Cognitive Disorders

A Study in Healthy Men to Test Whether BI 474121 Can Reverse the Memory Problems Caused by Ketamine (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: Boehringer Ingelheim

New P1 trial • Cognitive Disorders

A Study in Healthy Men to Test How BI 474121 is Tolerated (clinicaltrials.gov) - P1; N=32; Completed; Sponsor: Boehringer Ingelheim; Recruiting ➔ Completed

Clinical • Trial completion

A Study in Healthy Men and Women Who Are Either Between 18 - 45 Years or Between 65 - 80 Years to Test How Different Doses of BI 474121 Are Tolerated (clinicaltrials.gov) - P1; N=60; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Clinical • Trial completion

A Study in Healthy Men and Women Who Are Either Between 18 - 45 Years or Between 65 - 80 Years to Test How Different Doses of BI 474121 Are Tolerated (clinicaltrials.gov) - P1; N=60; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

BI 474121 - PDE2 Inhibitor - P1 Alzheimer's Disease (clinicaltrials.gov) - P1; N=32; Recruiting; Sponsor: Boehringer Ingelheim; Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders

BI 474121 - PDE2 Inhibitor - P1 Alzheimer's Disease (clinicaltrials.gov) - P1; N=32; Not yet recruiting; Sponsor: Boehringer Ingelheim

Clinical • New P1 trial • Alzheimer's Disease • CNS Disorders

A Study in Healthy Men to Test How Different Doses of BI 474121 Are Taken up and How They Influence the Amount of a Molecular Messenger (cGMP) in the Spinal Fluid (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Clinical • Trial completion

A Study in Healthy Men to Test How Different Doses of BI 474121 Are Taken up and How They Influence the Amount of a Molecular Messenger (cGMP) in the Spinal Fluid (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Boehringer Ingelheim; Completed ➔ Active, not recruiting; N=16 ➔ 24

Enrollment change • Enrollment closed

A Study in Healthy Men to Test How Different Doses of BI 474121 Are Taken up and How They Influence the Amount of a Molecular Messenger (cGMP) in the Spinal Fluid (clinicaltrials.gov) - P1; N=16; Completed; Sponsor: Boehringer Ingelheim; Recruiting ➔ Completed; N=24 ➔ 16

Clinical • Enrollment change • Trial completion

A Study in Healthy Men and Women Who Are Either Between 18 - 45 Years or Between 65 - 80 Years to Test How Different Doses of BI 474121 Are Tolerated (clinicaltrials.gov) - P1; N=60; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: May 2021 ➔ Oct 2021; Trial primary completion date: May 2021 ➔ Oct 2021

Clinical • Trial completion date • Trial primary completion date

A Study in Healthy Men to Test How the Body Takes up and Tolerates Different Doses of BI 474121, and Whether it Makes a Difference if BI 474121 is Taken as a Tablet or a Drink. (clinicaltrials.gov) - P1; N=66; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Trial completion

A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 474121 in the Blood (clinicaltrials.gov) - P1; N=14; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Trial completion

A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 474121 in the Blood (clinicaltrials.gov) - P1; N=14; Active, not recruiting; Sponsor: Boehringer Ingelheim; N=28 ➔ 14

Clinical • Enrollment change

A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 474121 in the Blood (clinicaltrials.gov) - P1; N=28; Active, not recruiting; Sponsor: Boehringer Ingelheim; N=14 ➔ 28

Clinical • Enrollment change

A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 474121 in the Blood (clinicaltrials.gov) - P1; N=14; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study in Healthy Men to Test How the Body Takes up and Tolerates Different Doses of BI 474121, and Whether it Makes a Difference if BI 474121 is Taken as a Tablet or a Drink. (clinicaltrials.gov) - P1; N=54; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 474121 in the Blood (clinicaltrials.gov) - P1; N=14; Recruiting; Sponsor: Boehringer Ingelheim; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open