An update on new and emerging therapies for cystic fibrosis

Abstract

Cystic fibrosis (CF) is a genetic disorder that results in a multi-organ disease with progressive respiratory decline that ultimately leads to premature death. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for the CFTR anion channel. Established CF treatments target downstream manifestations of the primary genetic defect, including pulmonary and nutritional interventions. Areas covered: CFTR modulators are novel therapies that improve the function of CFTR, and have been approved in the past five years to mitigate the effects of several CF-disease causing mutations. This review summarizes currently approved CFTR modulators and discusses emerging modulator therapies in phase II and III clinical trials described on clinical trials.gov as of April, 2017. Results of relevant trials reported in peer-reviewed journals in Pubmed, scientific conference abstracts and sponsor press releases available as of November, 2017 are included. Expert opinion: The current scope of CF therapeutic development is robust and CFTR modulators have demonstrated significant benefit to patients with specific CFTR mutations. We anticipate that in the future healthcare providers will be faced with a different treatment paradigm, initiating CFTR-directed therapies well before the onset of progressive lung disease.

Rapid therapeutic advances in CFTR modulator science

“…This singular fact provides a clear need to develop more effective therapies for CF. There continues to be a great deal of effort directed towards new drug development that targets symptomatic aspects of CF, with numerous drugs in the therapeutic pipeline . These include strategies to normalize epithelial sodium transport (eg, inhibitors of the epithelial sodium channel), agents which reduce or help to resolve inflammation, muco‐active compounds, novel anti‐infective therapies, and treatments that address nutritional and GI aspects of CF disease .…”

“…There continues to be a great deal of effort directed towards new drug development that targets symptomatic aspects of CF, with numerous drugs in the therapeutic pipeline . These include strategies to normalize epithelial sodium transport (eg, inhibitors of the epithelial sodium channel), agents which reduce or help to resolve inflammation, muco‐active compounds, novel anti‐infective therapies, and treatments that address nutritional and GI aspects of CF disease . In addition to these more traditional targets, clinical trials testing highly novel strategies are underway, such as allogenic human mesenchymal stem cells (NCT02866721), iron chelators to disrupt microbial biofilms (NCT02354859), and inhaled nitric oxide that target difficult to treat CF infections (NCT02498535, NCT01958944).…”

“…There has been a great deal of interest and excitement in the CF care and research community recently regarding a new class of drugs termed CFTR modulators . These drugs differ fundamentally from established CF therapeutics in that they aim to increase or potentially restore the function of disease‐causing CFTR variant protein.…”

“…A new approach that has the potential to impact many disease‐causing CFTR variants is co‐treatment with a CFTR amplifier. This concept increases the amount of translated CFTR protein substrate, and therefore, could be readily applicable to CF subjects with a variety of CFTR variants . These include subjects with reduced levels of functional CFTR at the plasma membrane, or subjects primarily treated with potentiators and/or correctors.…”

“…sodium transport (eg, inhibitors of the epithelial sodium channel), agents which reduce or help to resolve inflammation, muco-active compounds, novel anti-infective therapies, and treatments that address nutritional and GI aspects of CF disease. [12][13][14][15][16][17][18][19] In addition to these more traditional targets, clinical trials testing highly novel strategies are underway, such as allogenic human mesenchymal stem cells (NCT02866721), iron chelators to disrupt microbial biofilms (NCT02354859), and inhaled nitric oxide that target difficult to treat CF infections (NCT02498535, NCT01958944). These approaches focus on important disease pathologies downstream of the genetic defect causing CF and can be applied to CF patients independent of their background genotype.…”