Designing Clinical Trials for Anti-Inflammatory Therapies in Cystic Fibrosis

Abstract

The inflammatory response in the CF airway begins early in the disease process and becomes persistent through life in most patients. Inflammation, which is predominantly neutrophilic, worsens airway obstruction and plays a critical role in the development of structural lung damage. While cystic fibrosis transmembrane regulator modulators will likely have a dramatic impact on the trajectory of CF lung disease over the coming years, addressing other important aspects of lung disease such as inflammation will nevertheless remain a priority. Considering the central role of neutrophils and their products in the inflammatory response, potential therapies should ultimately affect neutrophils and their products. The ideal anti-inflammatory therapy would exert a dual effect on the proinflammatory and pro-resolution arms of the inflammatory cascade, both of which contribute to dysregulated inflammation in CF. This review outlines the key factors to be considered in the design of clinical trials evaluating anti-inflammatory therapies in CF. Important lessons have been learned from previous clinical trials in this area and choosing the right efficacy endpoints is key to the success of any anti-inflammatory drug development program. Identifying and validating non-invasive biomarkers, novel imaging techniques and sensitive lung function tests capable of monitoring disease activity and therapeutic response are important areas of research and will be useful for the design of future anti-inflammatory drug trials.

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators

“…It is noteworthy that additional ion channels are functionally relevant and are being evaluated to improve the hydration of mucus [207]. To date, the effects of HEMT on inflammatory responses in clinical studies are still variable, likely due to differences in the pre-existing disease severity e.g., irreversible bronchiectasis, with some of the patient groups studied having ongoing infection [208] and because of the limited consensus on the clinical parameters to reliably assess the effectiveness of drugs on CF lung inflammation [209].…”

Advances in the Cystic Fibrosis Drug Development Pipeline

“…Furthermore, as part of the innate immune response, chemokines and chemoattractant molecules in the airways attract large quantities of neutrophils to clear the site of infection; however, neutrophilic phagocytosis is inefficient, particularly in excessive mucoid airways [ 100 , 101 ]. Neutrophils also release proteases, pro-inflammatory cytokines, reactive oxygen species, and neutrophil extracellular traps, thereby fueling further neutrophil influx and inflammation and ultimately causing lung damage [ 97 , 100 , 101 ]. Throughout time, clinical trials have been conducted to examine different therapies aimed at reducing inflammation in CF.…”

Future therapies for cystic fibrosis

“…Despite decades of research, drugs that specifically target CF inflammation remain elusive. The inflammatory process in CF is complicated 43 , characterised by early and sustained neutrophil influx and high levels of elastase which correlate with structural damage on imaging even in early life. There is some evidence that normal resolution mechanisms are impaired 44 , so that inflammation can persist even if an infective insult is cleared 45 .…”