CFTR MODULATOR DRUG DISCOVERY AND TRANSLATION INTO THE CLINIC

CFTR modulators, small molecules that directly target the primary disease defect, are derived from large-scale drug library screens. Since their introduction in the clinic in 2012, they have changed the lives of many people with CF (pwCF) worldwide. Currently four modulator combinations are registered for people with a F508del mutation or a gating mutation, covering up to 80% of the population. Modulators have failed to show efficacy for pwCF who carry nonsense mutations. Importantly, high prices limit the use of effective modulators in pwCF living in less-affluent countries. Market approval for pwCF carrying rare and uncharacterized genetic variants is limited because low patient numbers hamper classical clinical trial designs with widely accepted endpoints (i.e., pulmonary function and sweat chloride improvement). There are several potential biomarkers that could help to target the right CFTR modulator to pwCF who are not eligible by the current labels of these drugs. One of the biomarkers of interest is the Forskolin-Induced Swelling (FIS) assay in organoids cultured from patient-derived adult stem cells. CFTR function is measured by the amount of swelling that occurs without (residual function) or with addition of modulators (drug response). Multiple studies have shown a clear correlation between FIS and disease severity and between FIS and clinical modulator response. The European HIT-CF project uses the FIS assay to preselect patients with ultrarare CFTR variants to enter clinical trials. In coming years, initiatives like HIT-CF can help to build further knowledge on the most effective ways to speed up CFTR modulator discovery and to translate them into the clinic.