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

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.

What's in the pipeline? Prospects for monoclonal antibodies (mAbs) as therapies for lung diseases.

The striking clinical results from recent studies with Remicade (infliximab, a monoclonal anti-TNFalpha antibody) in rheumatoid arthritis, Crohn's disease and psoriasis demonstrate the disease-altering potential of monoclonal antibodies (mAbs) in chronic inflammation. Chronic obstructive pulmonary disease (COPD) and asthma represent two major chronic pulmonary inflammatory diseases with substantial unmet medical needs. Most of the cells and mediators implicated in the pathophysiology of COPD and asthma are excellent targets for mAb intervention. Indeed, clinical trials with mAbs directed against IL-5, IgE, and CD4 yielded results that are critical in dissecting the pathophysiology of asthma, and reinforce the potential for mAbs as therapeutic agents in treating pulmonary diseases. Furthermore, fundamental advances in the discovery, manufacture and safety of mAbs underscore the enormous therapeutic value of these agents for chronic pulmonary diseases. Indeed, a large number of mAbs are in pre-clinical and clinical development for treating these conditions. In this review, we discuss the scientific rationale for generating mAb therapies directed specifically toward COPD and asthma. We believe that as a therapeutic class, mAbs offer the opportunity to alter symptoms, progression and outcome of chronic pulmonary diseases.

Coming of age: anti-cytokine therapies.

Although cytokines are critical in maintaining normal physiology, excessive production of these proteins can lead to pathological consequences. Inhibitors of cytokine production or action are therefore widely investigated as potential therapeutic agents in a variety of immune and inflammatory diseases. Indeed, the successful application of inhibitors of tumor necrosis factor-alpha in rheumatoid arthritis and Crohn's disease heralds the great therapeutic potential of biopharmaceutical agents to counteract cytokine activities. Emerging opportunities for new therapeutics, as well as the challenges we face in their use and development, are described in this review.