Asthma Treatment Shows Promise in Mid-Stage Trial
CRTh2 antagonist improves lung function versus placebo
Positive results have been reported from a phase II trial of ARRY-502 (Array BioPharma) in patients with mild-to-moderate asthma driven by T helper type 2 (Th2) cells. The findings were announced at the 2014 American Academy of Allergy, Asthma & Immunology annual meeting, held February 28 to March 4 in San Diego.
ARRY-502, an oral antagonist of the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2), was studied in 184 patients with mild-to-moderate persistent allergic asthma in a placebo-controlled, randomized, double blind, phase II study. ARRY-502 improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) — the trial’s primary endpoint — by 3.9% compared with placebo (P = 0.02). FEV1 responses for the total cohort were statistically significant on a week-by-week basis.
A predefined endpoint using the median baseline value of fractional exhaled nitric oxide (FENO), a Th2-associated biomarker, was also evaluated. The measurement of FENO is an office-based, noninvasive method for evaluating pulmonary inflammation. ARRY-502–treated patients with elevated baseline FENO demonstrated enhanced activity, with a median FEV1 improvement of 6.8% compared with placebo, at week 4 (P = 0.008). This is the first published report demonstrating that CRTh2 antagonism provides meaningful clinical benefit in patients with high FENO.
Overall, ARRY-502 was well tolerated, with fewer adverse events in the ARRY-502 group compared with the placebo group, including fewer asthma exacerbations (ARRY-502, n = 4; placebo, n = 9). There were no treatment-emergent serious adverse events in patients receiving ARRY-502, and all treatment-related adverse events were mild or moderate in severity. In addition, no significant changes were observed in safety signals, heart-rated corrected QT interval (QTc), hematology, or vital signs in patients treated with ARRY-502. Fifteen of the 184 patients discontinued the study early, with fewer discontinuations occurring in the ARRY-502 arm than in the placebo arm (n = 4 and n = 11, respectively). Six of these discontinuations were due to asthma exacerbations (ARRY-502, n = 1; placebo, n = 5).
ARRY-502 is an oral, highly selective CRTh2 antagonist designed to treat patients with allergic asthma. The CRTh2 receptor is expressed on Th2 T cells (basophils and eosinophils), and its ligand, prostaglandin D2 (PGD2), is released by mast cells. The results of this study demonstrate that the PGD2/CRTh2 axis plays a key role in the migration and activation of inflammatory cells leading to many symptoms of asthma, including coughing, difficulty breathing, and exacerbations. Because current asthma therapies do not fully target the Th2 pathway, antagonism of CRTh2 may represent an important new approach to enhancing disease control.
Based on its mechanism of action, ARRY-502 may provide the most patient benefit in a Th2 gene signature-enriched population. Several baseline Th2-related biomarkers were evaluated in the phase II study. The Th2 gene signature, which is present in about 50% of the asthma population, spans mild, moderate, and severe disease and suggests broad applicability for ARRY-502 in asthma as well as in other Th2-driven diseases, such as allergic rhinitis and atopic dermatitis.
Source: Array BioPharma; March 3, 2014.