S2044 Safety, Tolerability, and Efficacy of PL8177 in Adults With Active Ulcerative Colitis: Results From a Phase 2a, Randomized, Placebo-Controlled Study

Introduction: PL8177 is a synthetic, selective melanocortin receptor 1 (MC1R) agonist. The oral formulation contains polymers to inhibit degradation in the upper gastrointestinal (GI) tract and optimize lower GI release. In a rat model of ulcerative colitis (UC), PL8177 reduced colonic macroscopic damage, fecal occult blood, and colon weight and improved stool consistency. Here, we present clinical results from a phase 2a, double-blind, randomized, placebo-controlled, parallel group study of the safety, tolerability, and efficacy of PL8177 in adults with UC. Methods: Participants aged 18-75 years with active, mild-to-moderate UC received PL8177 (20 mg) or placebo (randomized 3:1) once daily for 56 days. Endoscopic examination of the colon with biopsy was performed at baseline and at day 56. Blood and/or fecal samples were collected on days 1, 15, 29, and 56. Clinical response, clinical remission, and symptomatic remission were determined using the modified Mayo score (endoscopy, rectal bleeding, stool frequency). The primary endpoint was an endoscopic subscore of 0 or 1 (modified to exclude friability). Adverse events (AEs) were collected. Results: A total of 64 participants were screened and 12 participants (PL8177, n = 9; placebo, n = 3) were randomized. Mean age was 47.1 years (range, 24-75) and 50.0% were women. A total of 12 AEs in 4 participants and 6 AEs in 1 participant were reported in PL8177 and placebo groups, respectively. All AEs were deemed not related or unlikely related to treatment. A clinical response was achieved in 7 of 9 participants (78%) in the PL8177 group compared with 1 of 3 (33%) in the placebo group. Clinical remission was achieved by 3 of 9 participants (33%) in the PL8177 group (vs none with placebo), while symptomatic remission was achieved by 5 of 9 (56%) with PL8177 (vs 1 of 3 [33%] with placebo). The planned primary endpoint was achieved by 3 of 9 participants (33%) with PL8177 and 1 of 3 (33%) with placebo. Conclusion: There is an unmet need for pharmacologic treatments that target novel, pathologic mechanisms of UC and/or inflammatory bowel disease. In this proof-of-principle phase 2a study, PL8177 provides broad efficacy at 8 weeks across key endpoints defined by the FDA (clinical remission and response) and also in symptomatic remission. The efficacy and excellent tolerability represent a highly differentiated profile and potential alternative to current immunosuppressive and steroid treatments.