OP024 A randomized, double-blind, placebo-controlled induction trial of an oral S1P receptor modulator (RPC1063) in moderate to severe Ulcerative Colitis: Results of the TOUCHSTONE study
W. Sandborn*1, B. Feagan2, D. Wolf3, G. D'Haens4, S. Vermeire5, S. Hanauer6, S. Ghosh7, H. Smith8, M. Cravets8, P. Frohna8, S. Gujrathi8, A. Olson8
1University of California San Diego, Division of Gastroenterology, La Jolla, United States, 2University of Western Ontario, Department of Gastroenterology, London, Canada, 3Atlanta Gastroenterology Associates, Emory Saint Joseph's, Atlanta, United States, 4Academic Medical Centre, Inflammatory Bowel Disease Centre, Amsterdam, Netherlands, 5University Hospital Leuven, Department of Gastroenterology, Leuven, Belgium, 6Northwestern University Feinberg School of Medicine, Digestive Health Center, Chicago, United States, 7University of Calgary, Department of Gastroenterology, Alberta, Canada, 8Receptos, Inc., Clinical Development, San Diego, United States
RPC1063 is an oral, selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator in clinical development for the treatment of ulcerative colitis (UC) and relapsing multiple sclerosis. The objective of this study was to evaluate the efficacy of 0.5 mg (low dose, LD) and 1.0 mg (high dose, HD) RPC1063 in comparison to placebo (PBO), and characterize the safety of RPC1063 in patients with moderate to severe UC.
This was an international, 8-week induction trial in UC, with a continuing maintenance period for responders. 197 patients were randomized (1:1:1) and treated once daily with PBO (n=65), LD (n=65) or HD (n=67). The primary endpoint was the proportion of subjects in remission (Mayo score ≤ 2, no subscore >1) at Wk 8. Secondary endpoints were the proportion of patients in response (reduction in Mayo score of ≥ 3 and ≥ 30 % with a decrease in the rectal bleeding score of ≥1 or a rectal bleeding score ≤1), proportion of patients with mucosal improvement (endoscopy score ≤1), and the change in Mayo score. Safety assessments included ECG, Holter monitoring, pulmonary function testing, optical coherence tomography and adverse events (AEs).
95% of patients completed the induction portion of the study. The proportion of patients achieving clinical remission was 16.4% for HD (p=0.0482 vs. PBO), 13.8% for LD (p=0.1422), and 6.2% for PBO. The proportion of patients with clinical response was 58.2% for HD (p=0.0140), 53.8% for LD (p=0.0648), and 36.9% for PBO. The proportion of patients with mucosal improvement was 34.3% for HD (p=0.0023), 27.7% for LD (p=0.0348), and 12.3% for PBO. The improvement in Mayo score from baseline was 3.3 points for HD (p=0.0035), 2.6 points for LD (p=0.0986), and 1.9 for PBO.
The AE profiles were comparable between groups, with approximately 31% of patients experiencing a treatment emergent AE (TEAE) across all groups. The most common TEAEs in the study were worsening of ulcerative colitis (HD 1 [1.5%], LD 2 [3.1%], PBO 3 [4.6%]) and anemia/decreased Hgb (HD 0, LD 3 [4.6%], PBO 3 [4.6%]). Only modest effects on heart rate were seen with no notable cardiac, pulmonary, ophthalmologic or malignancy AEs observed. Transient ALT ≥3x ULN occurred in 3 patients (HD 1 [1.5%], LD 2 [3.1%]) and decreased with continued treatment.
Modulation of S1P receptors in patients with moderate to severe UC with RPC1063 1 mg induced clinical remission, clinical response, and mucosal improvement, validating a novel therapeutic approach for the treatment of UC. The positive efficacy and the safety/tolerability results from this study suggest a favorable risk-benefit profile of RPC1063 that supports a Phase 3 UC program.