Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review.

Renée Dagenais,Bradley Quon,Victoria Su

doi:10.3390/jcm10010023

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and are generally well-tolerated; however, real-world studies indicate the frequency of discontinuation and adverse events (AEs) may be higher than what was observed in clinical trials. The objectives of this systematic review were to summarize real-world AEs reported for market-available CFTR modulators (i.e., ivacaftor (IVA), lumacaftor/ivacaftor (LUM/IVA), tezacaftor/ivacaftor (TEZ/IVA), and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA)), and to identify ways in which the pharmacist on CF healthcare teams may contribute to mitigating and managing these AEs. The MEDLINE, EMBASE, CINAHL, and Web of Science Core Collection online databases were searched from 2012 to 1 Aug 2020. Full manuscripts or conference abstracts of observational studies, case series, and case reports were eligible for inclusion. The included full manuscripts and conference abstracts comprised of 54 observational studies, 5 case series, and 9 case reports. The types of AEs reported generally aligned with what have been observed in clinical trials. LUM/IVA was associated with a higher frequency of respiratory-related AE and discontinuation in real-world studies. A signal for mental health and neurocognitive AEs was identified with all 4 CFTR modulators. A systematic approach to monitoring for AEs in people with CF on CFTR modulators in the real-world setting is necessary to help better understand potential AEs, as well as patient characteristics that may be associated with higher risk of certain AEs. Pharmacists play a key role in the safe initiation and monitoring of people with CF on CFTR modulator therapies.

Highlights

Cystic fibrosis (CF) is an autosomal recessive disorder affecting the CF transmembrane conductance regulator (CFTR) gene, resulting in alteration of CFTR protein synthesis, processing, or function
Two observational cohort studies included control subjects as comparison for non-safety outcomes related to LUM/IVA therapy [25,26], but only data regarding the participants on LUM/IVA was extracted and included in the descriptive analysis of this review
As a growing number of people with CF gain access to CFTR modulators, it is prudent for healthcare providers to be aware of potential adverse events (AEs) as well as approaches for prevention and/or management to optimize patient safety

Summary

Introduction

Cystic fibrosis (CF) is an autosomal recessive disorder affecting the CF transmembrane conductance regulator (CFTR) gene, resulting in alteration of CFTR protein synthesis, processing, or function. The CFTR protein is a channel that transports chloride and bicarbonate across cell membranes, regulating fluid and electrolyte balance in several organs throughout the body; dysfunctional CFTR protein results in viscous mucus and secretions [1]. In the lungs, this viscous mucus causes impaired mucociliary clearance as well as chronic infection and inflammation, which, over time, leads to irreversible airway damage and progressive lung function decline [1]. Pharmacists have been identified as integral members of multidisciplinary teams providing care to people with CF, with essential roles such as: optimizing the effectiveness of medication regimens and tailoring to each individuals’ needs; providing medication education and counselling; promoting adherence to therapies; as well as monitoring and managing drug-related adverse events (AE) and interactions [3,4,5,6]

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