Fevipiprant Shows Promise for Severe, Refractory Asthma

Bridget M. Kuehn

August 11, 2016

Patients with moderate-to-severe asthma and sputum eosinophilia benefited from fevipiprant in a single-center, randomized trial published online August 5 in Lancet Respiratory Medicine.

The results are the latest to suggest targeted therapies may be useful in treating select subgroups of patients with asthma. In this case, fevipiprant is an antagonist of the prostaglandin D2 receptor, which is found in increased numbers in patients with severe asthma, explain lead author Sherif Gonem, PhD, from the University of Leicester, United Kingdom, and colleagues. The receptor modulates the immune response and may boost airway inflammation.

To test whether targeting this receptor would benefit patients with severe asthma, the researchers recruited 61 participants with persistent, moderate to severe asthma and a sputum eosinophil count greater than or equal to 2%. All patients, who continued inhaled steroids, received a single-blind placebo for 2 weeks before being randomly assigned to the twice-daily oral drug or a placebo. Participants received the fevipiprant or placebo for 12 weeks, followed by a 6-week washout period with a single-blind placebo.

The sputum eosinophil percentage decreased by 4.5 times from an average of 5.4% (95% confidence interval [CI], 3.1% - 9.6%) to 1.1% (95% CI, 0.7% - 1.9%) in the group that received fevipiprant and decreased by 1.3 times from 4.6% (95% CI, 2.5% - 8.7%) to 3.9% (95% CI, 2.3% - 6.7%) in the placebo group. No deaths or serious adverse events were reported in the fevipiprant group.

"Fevipiprant reduces eosinophilic airway inflammation and is well tolerated in patients with persistent, moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment," the authors write.

Fevipiprant-treated patients also had reduced eosinophilic inflammation in the bronchial submucosa, better asthma control and asthma-related quality of life, and improved postinhaler forced expiratory volume in 1 second scores compared with patients in the placebo group, the authors report.

The effect on eosinophilic inflammation was similar in magnitude to that seen with mepolizumab, a monoclonal antibody that targets interleukin 5, the authors write. But unlike mepolizumab and other biologics, fevipiprant did not change the blood eosinophil count.

In an accompanying comment, Guy G. Brusselle, MD, PhD, head of the respiratory medicine clinic at Ghent University Hospital in Belgium, and colleagues describe the results as a "proof-of-concept" study for a "promising new compound" that could fill an unmet need for a subgroup of patients who have uncontrolled severe asthma that is partly resistant to corticosteroid treatment.

"There is an unmet need for effective therapies that can be delivered orally or that target specific corticosteroid-resistant pathogenic pathways," write Dr Brusselle and colleagues.

One advantage of this approach might be that fevipiprant also has effects on inflammatory cells other than eosinophils, noted Thomas B. Casale, MD, executive vice president of the American Academy of Allergy Asthma and Immunology and a professor of medicine at the University of South Florida in Tampa. For example, the authors note, the DP2 receptor has effects on T-helper-2 cells and type 2 innate lymphoid cells, which release inflammatory cytokines.

"If this turns out to be effective therapy, it could be a way to decrease airway inflammation that's not just specific to eosinophils, but [targets] these other key inflammatory cells as well," Dr Casale said.

However, Dr Bruselle and colleagues note the trial's small size, single-center design, and short duration make it impossible to draw conclusions about the long-term safety and efficacy of the fevipiprant or whether the drug will prevent exacerbations over time.

"Therefore, large, long-term, multicenter studies are needed to investigate whether fevipiprant improves clinical outcomes and reduces asthma exacerbations in patients with uncontrolled asthma," Dr Brusselle and colleagues write.

Dr Casale agreed that larger, longer-term studies are needed to confirm the efficacy and better assess the drug's safety profile.

The AirPROM project and the UK National Institute for Health provided funding for the study. Several of the authors report employment by Novartis, which also funded the study. The remaining authors report a variety of relationships with pharmaceutical companies and medical organizations including Novartis, Chiesi, GlaxoSmithKline, the European Respiratory Society, AstraZeneca, Almirall, Boehringer Ingelheim, Aerocrine, Genentec, Regeneron, Teva, Roche, Pulmacide, Pfizer, MedImmune, and Vectura. The editorialists have disclosed no relevant financial relationships. Dr Casale reports consulting for or receiving funding from Genetech, MedImmune/Astra Zeneca, Novartis, Teva, and Sanofi/Regeneron. Dr Casale's consulting honoraria are given to the University of South Florida.

Lancet Respir Med. Published online August 5, 2016. Article abstract, Comment extract

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