BI 1265162 / Boehringer Ingelheim - LARVOL DELTA

ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo. (PubMed, J Cyst Fibros) - "These data support that the ENaC blocker hypothesis is yet to be appropriately tested in pwCF. ETD001 has a profile that enables dosing at a level sufficient to provide a long duration of action in a Phase 2 clinical study in pwCF scheduled for 2024."

Journal • Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Discovery and development of BI 1265162, an ENaC inhibitor for the treatment of cystic fibrosis. (PubMed, Eur J Med Chem) - "We describe the discovery and development of BI 1265162, the first ENaC inhibitor devoid of the amiloride structural motif that entered clinical trials. A phase 2 study with BI 1265162 did not provide a clear sign of clinical benefit. Whether ENaC inhibition will be able to hold its promise for CF patients remains an open question."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Phosphine oxides from a medicinal chemist's perspective (ACS-Fall 2023) - "Phosphine oxides and related phosphorus-containing functional groups such as phosphonates and phosphinates are established structural motifs that are still underrepresented in today's drug discovery projects.In this lecture, the physicochemical and in vitro properties of phosphine oxides and related functional groups are presented and compared to more commonly used structural motifs in drug discovery. Furthermore, the properties of the phosphine oxide containing epithelial sodium channel (ENaC) inhibitor BI 1265162 for the inhalative treatment of cystic fibrosis will be discussed.We conclude that phosphine oxides and related phosphorus-containing functional groups are valuable polar structural elements and that they deserve to be considered as a routine part of every medicinal chemist's toolbox."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE-CF™ 1 - a randomised, Phase II study. (PubMed, Eur Respir J) - "BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated."

Clinical • Journal • P2 data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Study in Healthy Men to Test How BI 1265162 is Taken up and Processed by the Body (clinicaltrials.gov) - P1; N=7; Terminated; Sponsor: Boehringer Ingelheim; Trial completion date: Dec 2020 ➔ Apr 2020; Trial primary completion date: Dec 2020 ➔ Apr 2020

Clinical • Trial completion date • Trial primary completion date

A Study in Healthy Men to Test How BI 1265162 is Taken up and Processed by the Body (clinicaltrials.gov) - P1; N=7; Terminated; Sponsor: Boehringer Ingelheim; N=16 ➔ 7; Trial completion date: Jun 2021 ➔ Dec 2020; Suspended ➔ Terminated; Trial primary completion date: Jun 2021 ➔ Dec 2020; Due to the current COVID-19 pandemic, the recruitment of new subjects is temporarily discontinued. Ongoing, randomised patients are managed per Trial Protocol.

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination

First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers. (PubMed, ERJ Open Res) - P1 | "Accumulation was minimal. Twice-daily dosing is supported for future development."

Clinical • Journal • Cystic Fibrosis • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Respiratory Diseases

Preclinical evaluation of the epithelial sodium channel inhibitor BI 1265162 for treatment of cystic fibrosis. (PubMed, ERJ Open Res) - "BI 1265162 alone and in combination with CF transmembrane conductance regulator (CFTR) modulators decreased water transport and increased MCC in both normal and CF airway human epithelial models and also increased the effects of CFTR modulators in CF epithelium to reach the effect size seen in healthy epithelium with ivacaftor/lumacaftor alone. These results demonstrate the potential of BI 1265162 as a mutation agnostic, ENaC-inhibitor-based therapy for CF."

Journal • Preclinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

An innovative phase II trial to establish proof of efficacy and optimal dose of a new inhaled epithelial sodium channel inhibitor BI 1265162 in adults and adolescents with cystic fibrosis: BALANCE-CF 1. (PubMed, ERJ Open Res) - P2 | "The design ensures that potential for effect is assessed ahead of wider enrolment, allowing investigation of a dose-response effect with minimal patient numbers. The results will increase understanding of efficacy, safety and optimal dosing of the inhaled ENaC inhibitor BI 1265162 in adults and adolescents with CF."

Clinical • Journal • P2 data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

A Study in Healthy Men to Test How BI 1265162 is Taken up and Processed by the Body (clinicaltrials.gov) - P1; N=16; Suspended; Sponsor: Boehringer Ingelheim; Trial completion date: Jan 2021 ➔ Jun 2021; Trial primary completion date: Jan 2021 ➔ Jun 2021

Clinical • Trial completion date • Trial primary completion date

An update on BALANCE-CF™ 1: a Phase II trial of the inhaled ENaC inhibitor BI 1265162 in adults and adolescents with cystic fibrosis (ECFS 2020) - P2 | "BALANCE-CF™ 1 will increase understanding of efficacy, safety and optimal dosing of BI 1265162 in patients with CFaged≥12 years."

Clinical • P2 data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

A Study in Healthy Men to Test How BI 1265162 is Taken up and Processed by the Body (clinicaltrials.gov) - P1; N=16; Suspended; Sponsor: Boehringer Ingelheim; Trial completion date: Jul 2020 ➔ Dec 2020; Trial primary completion date: Jul 2020 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date

A 4-week Study to Test Different Doses of BI 1265162 in Adolescents and Adults With Cystic Fibrosis Using the Respimat® Inhaler - BALANCE - CF™1 (clinicaltrials.gov) - P2; N=52; Terminated; Sponsor: Boehringer Ingelheim; N=98 ➔ 52; Trial completion date: Sep 2020 ➔ Apr 2020; Suspended ➔ Terminated; Trial primary completion date: Sep 2020 ➔ Apr 2020; Not due to safety reasons

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

A Study in Healthy Men to Test How BI 1265162 is Taken up and Processed by the Body (clinicaltrials.gov) - P1; N=16; Suspended; Sponsor: Boehringer Ingelheim; Trial completion date: Apr 2020 ➔ Jul 2020; Recruiting ➔ Suspended; Trial primary completion date: Apr 2020 ➔ Jul 2020

Clinical • Trial completion date • Trial primary completion date • Trial suspension

A 4-week Study to Test Different Doses of BI 1265162 in Adolescents and Adults With Cystic Fibrosis Using the Respimat® Inhaler - BALANCE - CF™1 (clinicaltrials.gov) - P2; N=98; Suspended; Sponsor: Boehringer Ingelheim; Recruiting ➔ Suspended

Clinical • Trial suspension

A Study in Healthy Men to Test How BI 1265162 is Taken up and Processed by the Body (clinicaltrials.gov) - P1; N=16; Recruiting; Sponsor: Boehringer Ingelheim; Not yet recruiting ➔ Recruiting

Enrollment open

A Study in Healthy Men to Test How BI 1265162 is Taken up and Processed by the Body (clinicaltrials.gov) - P1; N=16; Not yet recruiting; Sponsor: Boehringer Ingelheim

Clinical • New P1 trial

A Study in Healthy Men That Tests if Taking BI 1265162 by Mouth, Intravenously, or Inhaled Influences the Amount of BI 1265162 in the Blood (clinicaltrials.gov) - P1; N=12; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Clinical • Trial completion

A Study in Healthy Men That Tests if Taking BI 1265162 by Mouth, Intravenously, or Inhaled Influences the Amount of BI 1265162 in the Blood (clinicaltrials.gov) - P1; N=12; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A 4-week Study to Test Different Doses of BI 1265162 in Adolescents and Adults With Cystic Fibrosis Using the Respimat® Inhaler (clinicaltrials.gov) - P2; N=98; Recruiting; Sponsor: Boehringer Ingelheim; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A 4-week Study to Test Different Doses of BI 1265162 in Adolescents and Adults With Cystic Fibrosis Using the Respimat® Inhaler (clinicaltrials.gov) - P2; N=98; Not yet recruiting; Sponsor: Boehringer Ingelheim

Clinical • New P2 trial

A 4-week study to test different doses of BI 1265162 in adolescents and adults with cystic fibrosis using the Respimat® inhaler (clinicaltrialsregister.eu) - P2; N=98; Sponsor: Boehringer Ingelheim

Clinical • New P2 trial

Both epithelial sodium channel (ENaC) inhibitors BI 443651 and BI 1265162 increase mucociliary clearance in sheep (ECFS 2019) - "Both ENaC inhibitors BI 443651 and BI 1265162 after aerosol inhalation resulted in an acceleration of mucociliary clearance in sheep without changing plasma electrolytes. Therefore, ENaC inhibition might be a good target for clinical studies in CF."

BI 443651 and BI 1265162 demonstrate in vitro inhibition of epithelial sodium channel (ENaC) in the Ussing chamber (ECFS 2019) - " A human bronchial epithelial cell line (NCI H441) or a mouse kidney collecting duct cell line (M1) were grown on transwell filters with dexamethasone to upregulate ENaC expression and to achieve sufficient short circuit currents (ISC). These data indicate that both BI 443651 and BI 1265162 are potent inhibitors of the ENaC and superior to the standard ENaC inhibitor amiloride (in-house Ussing chamber IC 50 s 210 nM [M1] and 238 nM [H441]). BI 1265162 proved to be more potent than BI 443651."

Preclinical

A single application of the epithelial sodium channel inhibitor BI 1265162 significantly improves water transport and mucociliary clearance of cystic fibrosis epithelial tissue, alone or combined with lumacaftor/ivacaftor or isoproterenol (ECFS 2019) - "A single application of BI 1265162 dose-dependently increases water transport and MCC in normal and CF epithelial tissue, alone, or when associated with ISO or IVA/LUM, or both, indicating a synergistic effect between ENaC inhibition and CFTR modulation."