A systematic comparison of the profiles of inhaled ENaC blocker candidates on mucociliary clearance: are we under-dosing in clinical studies?
Henry Danahay1, Clive McCarthy1 and Martin Gosling1
1Enterprise Therapeutics, UK
Objectives: Recent clinical studies with ENaC modulator compounds have challenged the validity of the target for treating CF lung disease. Our aim was to establish retrospective human dose predictions for several of these compounds to understand whether this might be a factor in the failure of the clinical studies to show benefit.
Methods: ENaC modulators used in recent CF clinical studies were assessed in a sheep model of mucociliary clearance (MCC) and were compared with ETD001, a novel, non-amiloride based inhaled ENaC blocker (Enterprise Therapeutics), entering clinical development in 2019. Test compounds were administered directly into the sheep airways by aerosolization and MCC was measured by gamma-scintigraphy between 4-6h after the completion of dosing. Using the dose required to achieve a maximal increase in MCC in the sheep, an estimated ‘minimal effective clinical dose’ was calculated for each ENaC modulator.
Results: Each of the compounds studied induced a dose-dependent increase in MCC, typically reaching a maximum of between 20-25% clearance of the 99mTc-sulfur colloid tracer. Combining the predicted clinical dose (based on the sheep MCC model) with the actual dose/nebuliser used in the respective clinical study (www.clintrials.gov), suggests that all the ENaC modulators tested in the clinic to date have potentially been under-dosed by as much as 90%. This analysis further assumes that the healthy sheep airways in the MCC model predict for a clinical dose in a CF lung on a 1:1 basis. If a CF lung requires a higher dose than a sheep airway, the potential for under-dosing increases.
Conclusions: The pre-clinical safety profile of ETD001 currently enables doses of between 30-40x above the minimum predicted clinically efficacious dose to be tested in clinical studies. This profile provides a good opportunity to test the ENaC therapeutic hypothesis and ultimately provide a new therapy for CF patients.