Targeted release oral cyclosporine (ST-0529) as a potential new therapy for ulcerative colitis: Safety results from a phase IIA study

Abstract

Background/Aims: Ciclosporin (CsA) has similar efficacy to infliximab in patients with acute severe ulcerative colitis (UC) who have failed corticosteroids; however, long-term maintenance use of CsA is limited by nephrotoxic, hepatotoxic and immunologic side ef- fects. ST-0529 is a novel, oral, solubilized CsA formulation designed to optimise delivery to colonic tissue. ST-0529 achieves similar or higher colonic tissue concentrations of CsA compared to continuous intravenous CsA infusion, limiting systemic exposure. Materials and Methods: In a phase IIa double-blind, randomised study of patients with mild to moderate UC (Image 1), 53 subjects received 75 mg/day ST-0529 and 65 received placebo for 4 weeks and were followed for 4 weeks after completing the treatment period. At each study visit, subjects were evaluated for adverse events (AEs) and laboratory tests were performed. Results: Most subjects completed the study, including 81.1% in the ST-0529 group and 64.6% in the placebo group. A higher propor- tion of subjects receiving placebo compared to ST-0529 discontinued the study prematurely (35.4 vs 18.9%), mostly due to AEs (24.6 vs 11.3%), and lack of efficacy (7.7 vs 7.5%). The overall proportion of subjects with treatment-emergent AEs (TEAEs) were comparable between groups (Table 1). TEAEs that occurred more frequently in ST-0529 subjects included abdominal pain and distension, lower and upper respiratory tract infections, fatigue, headache, cough and oropharyngeal pain (Table 2). In general, these events were mild or moderate, were not serious, and resulted in relatively few treatment discontinuations. Serious AEs were balanced among study groups and ST-0529 reduced AEs leading to discontinuation. Common AEs associated with CsA were not seen with ST-0529. No subjects died, 1 ST-0259 patient had an abnormal liver function test, and no relevant changes from baseline in renal function (creatinine, 2.0 vs 0.8 μmol/L), nor blood pressure (2.0 vs 3.0 systolic; 0.4 vs 1.2 diastolic) were observed between placebo vs ST-0529. Conclusion: These phase IIa results demonstrated that ST-0529 was well tolerated and no safety concerns were identified. AEs commonly associated with CsA were not observed with ST-0529. These data suggest that 75 mg ST-0529 may offer a clinically meaningful contribution to the management of patients with UC and support further investigation of ST-0529 in UC patients with moderate disease, which will be the focus of the phase IIb trial.