Considerations for the Conduct of Clinical Trials with Antiinflammatory Agents in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

Abstract

Inflammation leads to lung destruction and loss of pulmonary function in patients with cystic fibrosis (CF). Drugs that modulate the cystic fibrosis transmembrane conductance regulator (CFTR) have recently been approved. Although the impact of CFTR modulators on sweat chloride and lung function are exciting, they have not yet demonstrated an effect on inflammation. Therefore, CF antiinflammatory drug development must continue. Unfortunately, the lack of clarity with this process has left investigators and industry sponsors frustrated. The Cystic Fibrosis Foundation established a working group in early 2014 to address this issue. There are many inflammatory processes disrupted in CF, and, therefore, there are many potential targets amenable to antiinflammatory therapy. Regardless of a drug's specific mechanism of action, it must ultimately affect the neutrophil or its products to impact CF. The working group concluded that before bringing new antiinflammatory drugs to clinical trial, preclinical safety studies must be conducted in disease-relevant models to assuage safety concerns. Furthermore, although studies of antiinflammatory therapies must first establish safety in adults, subsequent studies must involve children, as they are most likely to reap the most benefit. The working group also recommended that pharmacokinetic-pharmacodynamic studies and early-phase safety studies be performed before proceeding to larger studies of longer duration. In addition, innovative study designs may improve the likelihood of adequately assessing treatment response and mitigating risk before conducting multiyear studies. Learning from past experiences and incorporating this knowledge into new drug development programs will be instrumental in bringing new antiinflammatory therapies to patients.

Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

“…While several excellent reviews provide deeper insight into this field, here, only the main approaches will be mentioned [195,196,197,198]. Inhibition of NE represents a rather classical approach to diminish PMN-mediated lung damage in CF [199,200,201].…”

“…Inhibition of NE represents a rather classical approach to diminish PMN-mediated lung damage in CF [199,200,201]. Phosphodiesterase (PDE4) inhibitors reduce cAMP synthesis and thereby have direct inhibitory action on inflammatory cell signaling and PMN recruitment [195]. Attractive lipid mediator targets are lipoxins, mainly LXA4, that are generated from arachidonic acid and have a general suppressive role on inflammation, including PMN effector mechanisms [195].…”

“…Phosphodiesterase (PDE4) inhibitors reduce cAMP synthesis and thereby have direct inhibitory action on inflammatory cell signaling and PMN recruitment [195]. Attractive lipid mediator targets are lipoxins, mainly LXA4, that are generated from arachidonic acid and have a general suppressive role on inflammation, including PMN effector mechanisms [195]. Resolvins are other lipid mediators of interest because they also have general anti-inflammatory, pro-resolution effects, including inhibition of PMN respiratory burst, chemotaxis and attachment [195].…”

“…Attractive lipid mediator targets are lipoxins, mainly LXA4, that are generated from arachidonic acid and have a general suppressive role on inflammation, including PMN effector mechanisms [195]. Resolvins are other lipid mediators of interest because they also have general anti-inflammatory, pro-resolution effects, including inhibition of PMN respiratory burst, chemotaxis and attachment [195]. The cannabinoid receptor CB2 is highly expressed on immune cells, and its activation promotes anti-inflammatory effects, including reduced proinflammatory cytokine production and leukocyte migration [195].…”

“…Resolvins are other lipid mediators of interest because they also have general anti-inflammatory, pro-resolution effects, including inhibition of PMN respiratory burst, chemotaxis and attachment [195]. The cannabinoid receptor CB2 is highly expressed on immune cells, and its activation promotes anti-inflammatory effects, including reduced proinflammatory cytokine production and leukocyte migration [195]. Leukotriene modulators target two enzymes, 5-lipoxygenase and leukotriene A4 hydrolase, in the hope of significantly reducing LTB4 levels and preventing PMN recruitment [195].…”