BMJ Open Gastroenterol. 2021 Aug;8(1):e000680. doi: 10.1136/bmjgast-2021-000680.

Kathy Weisel ¹, Nicola Scott ², Scott Berger ¹, Susanne Wang ¹, Kurt Brown ¹, Marcy Powell ³, Matthijs Broer ⁴, Clarissa Watts ⁵, Debra J Tompson ⁶, Susan W Burriss ⁷, Simon Hawkins ⁸, Kathy Abbott-Banner ⁹, Paul Peter Tak ¹⁰

Author information

• ¹Immunology and Inflammation, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
• ²Biostatistics, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK.
• ³Safety and Medical Governance, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
• ⁴Global Clinical Development, GlaxoSmithKline, Van Asch van Wijckstraat, LP Amersfoort, The Netherlands.
• ⁵Global Clinical Sciences and Delivery, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK.
• ⁶Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK.
• ⁷Global Clinical Sciences and Delivery, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
• ⁸Global Clinical Sciences and Delivery, GlaxoSmithKline, Brentford, Middlesex, UK.
• ⁹Discovery Medicine, GlaxoSmithKline, Brentford, Middlesex, UK kathy.x.abbott-banner@gsk.com.
• ¹⁰Pharmaceuticals Research and Development, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK.Abstract

Abstract

Tumour necrosis factor signalling via the receptor-interacting protein kinase 1 (RIPK1) pathway regulates colonic inflammation suggesting that RIPK1 inhibition may be a potential therapeutic target in ulcerative colitis (UC). This phase IIa, randomised, double-blind experimental medicine study investigated the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of the RIPK1 inhibitor GSK2982772 in patients with active UC.

Design: In part A, prior to a protocol amendment, one patient was randomised to receive GSK2982772 60 mg twice daily for 42 days. After the amendment, patients were randomised 2:1 to receive GSK2982772 60 mg or placebo three times daily for 42 days. In part B, all patients switched to open-label GSK2982772 60 mg three times daily for 42 days. Safety, PK, PD biomarkers, histological disease activity, clinical efficacy and quality of life were assessed at days 43 and 85.

Results: Thirty-six patients were randomised (n=12, placebo/open-label GSK2982772; n=24, GSK2982772/open-label GSK2982772). Most adverse events were mild, with headache reported the most frequently across groups (placebo/open-label GSK2982772, n=2 (17%); GSK2982772/open-label GSK2982772, n=8 (33%)). GSK2982772 was well distributed into colonic tissue, with generally higher concentrations in colonic biopsy samples versus plasma. No apparent differences between treatment groups were observed for PD, histological disease activity, clinical disease activity or quality-of-life measures. At screening, all patients had Mayo endoscopic scores of 2 or 3. At day 43, no patients in the placebo/open-label GSK2982772 group achieved Mayo endoscopic scores of 0 or 1 vs 3/24 (13%) for GSK2982772/open-label GSK2982772. At day 85, 1/9 (11%) achieved scores of 0 or one for placebo/open-label GSK2982772 vs 3/22 (14%) for GSK2982772/open-label GSK2982772.

Conclusion: GSK2982772 was generally well tolerated, with no treatment-related safety concerns identified. However, no significant differences in efficacy were observed between treatment groups, suggesting that GSK2982772 as monotherapy is not a promising treatment for patients with active UC.

Trial registration number: NCT02903966.