CFTR Modulator Therapy and Its Impact on Lung Transplantation in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian people and is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein. It is a multisystem disorder; however, CF lung disease causes most of its morbidity and mortality. Although survival for CF has improved over time due to a multifaceted symptomatic management approach, CF remains a life-limiting disease. For individuals with progressive advanced CF lung disease (ACFLD), lung transplantation is considered the ultimate treatment option if compatible with goals of care. Since 2012, newer drugs, called CFTR modulators, have gradually become available, revolutionizing CF care, as these small-molecule drugs target the underlying defect in CF that causes decreased CFTR protein synthesis, function, or stability. Because of their extremely high efficacy and overall respectable tolerability, CFTR modulator drugs have already proven to have a substantial

Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis

“…Importantly, there is some evidence of clinical benefit in people with advanced lung disease, a cohort of patients who have not been included in clinical trials yet there is an urgent need for effective treatments. 70 A case series of patients with advanced lung disease receiving elexacaftor/tezacaftor/ivacaftor as part of a managed access programme in Ireland showed significant improvements in ppFEV 1 , BMI and CFRD. 71 Careful consideration is required of clinically significant drug interactions, especially following transplantation, for example, with calcineurin inhibitors or azole antifungals.…”

“…71 Careful consideration is required of clinically significant drug interactions, especially following transplantation, for example, with calcineurin inhibitors or azole antifungals. 70 Post-licensing studies also suggest that there is a higher frequency of reported adverse events with lumacaftor/ ivacaftor compared with other modulators, which are more pronounced in those with severe lung disease. These are predominantly respiratory in nature and include symptoms of dyspnoea and chest tightness, often occurring at treatment initiation but have led to discontinuation in up to 30% of the patients.…”

“…These are predominantly respiratory in nature and include symptoms of dyspnoea and chest tightness, often occurring at treatment initiation but have led to discontinuation in up to 30% of the patients. 69,70,72…”

“…Several strategies have been used to minimise these effects including reducing the starting dose and co-administration with an inhaled bronchodilator in patients with severe disease. 70 Elevated blood pressure has been reported in clinical trials for lumacaftor/ivacaftor and elexacaftor/tezacaftor/ ivacaftor. 72 Other reported adverse events include liver enzyme derangement, which is typically transient, headache and fatigue specifically reported with lumacaftor/ivacaftor and rash with all available modulator combinations, but these effects are seldom associated with cessation of treatment.…”

The changing landscape of pediatric lung transplantation

“…It is possible that this is due to the sicker ILD population aforementioned. In recent years, post‐transplant survival has reached a median of more than 9 years for adults with CF according to ISHLT Registry data, 48 with comparable outcomes in children with CF 3,26 …”