BI 443651 / Boehringer Ingelheim - LARVOL DELTA

The inhaled ENaC inhibitor BI 443651 does not affect response to methacholine but induces post-inhalation airway obstruction and cough in mild asthmatics (ECFS 2019) - "BI 443651 did not significantly change MCh responsiveness in mild asthmatics but did induce post-dose airway obstruction and coughing."

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

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."

The inhaled epithelial sodium channel (ENaC) inhibitor BI 443651 is safe and well tolerated in adult patients with cystic fibrosis (ECFS 2019) - "BI 443651 has an overall good safety and tolerability profile in moderate CF patients following 14 days' bid administration."

Clinical

Both BI 443651 and BI 1265162 show inhibition of ENaC-mediated in vitro water resorption (ECFS 2019) - "Both BI ENaC inhibitors are able to inhibit the liquid transport across a M1 cell layer in a transwell system and qualify for in vivo testing."

Preclinical

Both BI 443651 and BI 1265162 demonstrate inhibition of the liquid absorption from the rat airway epithelium in vivo (ECFS 2019) - "For comparison, with 3mg/kg amiloride, a mean of only 15% inhibition was achieved. Both BI 443651 and BI 1265162 showed inhibition of fluid absorption from rat lungs. Therefore, ENaC inhibition might be a good target for clinical studies in CF."

Preclinical

Single and multiple doses of the inhaled ENaC inhibitor BI 443651 are well tolerated in healthy males (ECFS 2019) - "After single doses up to 3600µg and multiple dosing up to 1800µg over 1 week, BI 443651 was well tolerated in HV. Only cough and throat irritation were observed after high doses."

Clinical