Treating Non-cystic Fibrosis Bronchiectasis with CFTR modulators: Early Case Reports

Non-cystic fibrosis bronchiectasis (NCFB) afflicts millions of patients worldwide, with few drug therapies that address underlying pathogenic mechanism. Despite the time-honoured view that NCFB is unrelated to cystic fibrosis (CF), growing evidence indicates many patients with NCFB exhibit functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR). We investigated whether modulator compounds that activate both wild-type and mutant CFTR could improve clinical status in certain patients with NCFB, and explored the relationship(s) between CFTR and NCFB. High cost of CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI; ~$300,000/year) largely precludes "off label" prescribing, making a test of CFTR activation in patients with NCFB problematic. Special efforts were therefore made to administer ETI in three patients with severe NCFB. Marked improvements in clinical status (pulmonary function, symptom scores, chest imaging) were observed. These patients were representative of individuals with NCFB followed in general practice and/or pulmonary clinics and are among the first reported with NCFB to be treated successfully with CFTR modulators. ETI would not have been considered part of standard care, even in the setting of severe clinical disease. CF genotype, in vivo CFTR activity (sweat chloride analysis), and in vitro (cellbased) CFTR functional reserve were also assessed in the context of non-CF and CF-related bronchiectasis. Available literature and present findings support a need for future studies to examine and validate clinically meaningful association(s) between NCFB and CFTR. Investigations of this sort are expected to have important mechanistic, diagnostic, and therapeutic implications for many patients with non-CF bronchiectasis.