ARRY–502 – CRTh2 Program for Asthma
ARRY-502 is an oral, potent, and highly selective CRTh2 antagonist designed to treat patients with allergic asthma. Despite the range of available treatments, there remains a significant need for a convenient, safe and effective therapy for patients with persistent allergic asthma. In particular, lack of adherence with currently approved inhaled medications is a significant challenge to disease control. Allergic asthma, which is characterized by a Th2 gene signature, is associated with elevated IgE, mast cell degranulation, and activation of Th2 T-cells and eosinophils. The CRTh2 receptor is expressed on Th2 T cells and eosinophils, and its ligand, prostaglandin D2, is released by mast cells. CRTh2 is a key mediator of the migration and activation of inflammatory cells leading to many symptoms of asthma including coughing, difficulty breathing, and possibly exacerbations. Because current asthma therapies do not fully target this pathway, antagonists of CRTh2 represent an exciting new approach to enhanced disease control, and the Th2 gene signature may be used to guide treatment for CRTh2 antagonists. ARRY-502 may provide the most patient benefit in a Th2 gene signature-enriched population. Ultimately, the Th2 gene signature which is present in approximately 50% of the asthma population, spans mild, moderate and severe disease. This suggests broad applicability for ARRY-502 in these populations, as well as in other Th2-driven diseases.
In July 2013, we announced positive results from a placebo-controlled, randomized, double-blind Phase 2 trial of ARRY-502 in mild to moderate persistent allergic asthma. ARRY-502 achieved the primary endpoint of significant improvement in pre-bronchodilator FEV1. ARRY-502 was well tolerated with fewer adverse events compared to placebo.
This proof-of-concept study enrolled 184 patients in the U.S. with mild-to-moderate persistent allergic asthma, a population which represents more than 12 million patients in the U.S. ARRY-502, dosed at 200 mg twice daily (N = 93) for 4 weeks, improved FEV1 by 3.9% versus placebo (N = 91), achieving statistical significance (P = 0.02). A predefined endpoint using the median baseline value of a Th2 associated biomarker was also evaluated. Patients in this population achieved enhanced improvement in FEV1 (6.8 % versus placebo, P = 0.008).
Secondary efficacy endpoints also achieved statistical significance, including:
- Reduced short-acting beta agonist, or SABA, use
- Asthma control as measured by the Asthma Control Questionnaire, or ACQ
- Forced Vital Capacity, or FVC, improvement
- Symptom-free days during treatment
- Improvement in Rhinasthma and Asthma Quality of Life questionnaires, or AQLQ
The overall frequency of adverse events was lower in the ARRY-502 group, including fewer asthma exacerbations, versus the placebo group. There were no treatment-emergent serious adverse events in patients receiving ARRY-502; all treatment-related adverse events were either mild or moderate in severity. A total of 15 (11 in the placebo group, four in the ARRY-502 group) out of 184 patients discontinued the study early, primarily due to exacerbations of asthma (five in the placebo group, one in the ARRY-502 group).
Development Plan: Based on the promising results of the proof-of-concept study in persistent asthma and our decision to focus on our hematology/oncology programs, Array is seeking a partner for further development of ARRY-502 in this large market disease indication.