New Anti-Chemokine Oral Drug XC8 in the Treatment of Asthma Patients with Poor Response to Corticosteroids: Results of a Phase 2A Randomized Controlled Clinical Trial

Abstract

Introduction: A significant number of patients with moderate asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS). These patients do not yet meet the criteria for oral corticosteroids (OCS) and monoclonal antibodies. The new anti-chemokine oral drug XC8 could represent an alternative treatment option for these patients. The objective of this trial was to evaluate the effect of different doses of the XC8 in patients with partly controlled asthma in a phase 2a clinical trial.

Methods: A double-blind, parallel-group, randomized, multicenter, phase 2a trial was conducted at 12 sites in Russia. Patients with asthma were randomized into four groups (n = 30 each) to receive XC8 at 2 mg, 10 mg, 100 mg or placebo once-daily for 12 weeks in addition to low-dose ICS with or without LABA. Efficacy and safety parameters were evaluated at weeks 0, 2, 6, and 12.

Results: No statistically significant difference between the treatment arms in the number of patients with adverse events was observed. The primary endpoint, improvement of forced expiratory volume in 1 s (FEV₁) % predicted over 12 weeks compared to placebo, was not statistically significant. The treatment of patients with XC8 (100 mg) resulted in statistically and clinically significant improvements in FEV₁ compared to baseline (7.40% predicted, p < 0.001). Patients with elevated peripheral blood eosinophil count (PBEC, > 300 cells/μl) or serum interferon-γ (IFN-γ) level (> 100 pg/mL) treated with XC8 (100 mg) achieved a statistically significant improvement in FEV₁ (11.33% predicted or 8.69% predicted, respectively, p < 0.05) as compared to the baseline versus the placebo. The strongest effect was observed in patients with both high PBEC and IFN-γ level. Pharmacodynamic engagement was demonstrated through the reduction of serum levels of C-C motif ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10). Treatment with XC8 (100 mg) alleviated resistance to maintenance ICS therapy in patients with elevated IFN-γ level.

Conclusions: Given the high safety, oral route of administration, and efficacy, XC8 may provide a promising treatment option for patients with mild-to-moderate asthma.

Trial registration: 795-30/12/2015 (Ministry of Health Russian Federation), NCT03450434 (ClinicalTrials.gov).

Keywords: Asthma; Chemokine; Corticosteroid resistance; Eosinophils; Interferon-gamma; XC8.