PMID- 32301501 OWN - NLM STAT- MEDLINE DCOM- 20210524 LR - 20240329 IS - 1532-6535 (Electronic) IS - 0009-9236 (Print) IS - 0009-9236 (Linking) VI - 108 IP - 4 DP - 2020 Oct TI - Response to Inhibition of Receptor-Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo-Controlled Study. PG - 808-816 LID - 10.1002/cpt.1852 [doi] AB - Receptor-interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune-mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug-related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs. CI - (c) 2020 GlaxoSmithKline. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Weisel, Kathleen AU - Weisel K AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Berger, Scott AU - Berger S AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Papp, Kim AU - Papp K AD - Probity Medical Research, Waterloo, Ontario, Canada. FAU - Maari, Catherine AU - Maari C AD - InnovaDerm Research, Montreal, Quebec, Canada. FAU - Krueger, James G AU - Krueger JG AD - The Rockefeller University, New York, New York, USA. FAU - Scott, Nicola AU - Scott N AD - GlaxoSmithKline, Stevenage, UK. FAU - Tompson, Debra AU - Tompson D AD - GlaxoSmithKline, Stevenage, UK. FAU - Wang, Susanne AU - Wang S AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Simeoni, Monica AU - Simeoni M AD - GlaxoSmithKline, Stockley Park, UK. FAU - Bertin, John AU - Bertin J AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Peter Tak, Paul AU - Peter Tak P AD - GlaxoSmithKline, Stevenage, UK. LA - eng SI - ClinicalTrials.gov/NCT02776033 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200707 PL - United States TA - Clin Pharmacol Ther JT - Clinical pharmacology and therapeutics JID - 0372741 RN - 0 (CD3 Complex) RN - 0 (GSK2982772) RN - 0 (Oxazepines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Triazoles) RN - EC 2.7.11.1 (RIPK1 protein, human) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) SB - IM MH - Adult MH - CD3 Complex/metabolism MH - Canada MH - Dermis/*drug effects/enzymology/immunology/pathology MH - Double-Blind Method MH - Female MH - Humans MH - Male MH - Middle Aged MH - Oxazepines/adverse effects/*therapeutic use MH - Protein Kinase Inhibitors/adverse effects/*therapeutic use MH - Psoriasis/diagnosis/*drug therapy/enzymology/immunology MH - Receptor-Interacting Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Remission Induction MH - Signal Transduction MH - T-Lymphocytes/drug effects/immunology/metabolism MH - Time Factors MH - Treatment Outcome MH - Triazoles/adverse effects/*therapeutic use PMC - PMC7540322 COIS- K.W., S.B., S.W., and P.P.T., are shareholders and were employees of GlaxoSmithKline (GSK) at the time of the study. K.P. reports grants and personal fees from AbbVie Inc., Akros Pharma Inc., Amgen, Boehringer Ingelheim, Celgene Corporation (Celgene), Coherus BioSciences, Eli Lilly and Company (Lilly), Galderma, Janssen Pharmaceutica (Janssen), Kyowa Hakko Kirin Co., Ltd., Merck (MSD), Merck-Serono, Novartis Pharmaceuticals Corporation (Novartis), Pfizer Inc. (Pfizer), Sanofi Genzyme, Takeda Pharmaceutical Company, UCB, Inc. (UCB), Bausch Health Companies Inc. (Bausch), and PRCL Research Inc.; grants from Anacor Pharmaceuticals Inc., Arcutis Biotherapeutics, Astellas Pharma, Baxalta, Bristol-Myers Squibb (BMS), Can-Fite Biopharma Ltd., Dermira, Inc., Dow Pharmaceutical Sciences, Inc., Genentech, GSK, LEO Pharma, Inc., MedImmune, LLC, Regeneron Pharmaceuticals, Inc., F. Hoffmann-La Roche Ltd (Roche), Gilead Sciences, Inc., InflaRx GmbH, Moberg Pharma AB, and Sun Pharmaceutical Industries Ltd. (Sun); and personal fees from Meiji Seika Pharma Co., Ltd., and Mitsubishi Tanabe Pharma. C.M. reports grants from GSK related to the submitted work and grants from Lilly, Asana, Bausch, AbbVie Inc., Dermavant Sciences Ltd., Janssen, Pfizer, and Boehringer Ingelheim. J.G.K., reports grants paid to his institution from Novartis, Pfizer, Amgen, Lilly, Boehringer Ingelheim, Innovaderm Research Inc., BMS, Janssen, AbbVie Inc., Parexel, LEO Pharma, Inc., Vitae Pharmaceuticals, Akros Pharma Inc., Regeneron Pharmaceuticals Inc., Allergan, Novan, Inc., Biogen MA Inc., Sienna Biopharmaceuticals, Inc. (Sienna), UCB, Celgene, Botanix Pharmaceuticals, Incyte Corporation, Avillion, LLP, and Exicure, Inc; he also reports personal fees from Novartis, Pfizer, Amgen, Lilly, Boehringer Ingelheim, BMS, Biogen Inc., Janssen, AbbVie Inc., LEO Pharma, Inc., Escalier Biosciences, Inc., Valeant Pharmaceuticals International, Inc., Aurigene Discovery Technologies Limited, Allergan plc, Sienna, UCB, Asana, Celgene, Nimbus Therapeutics, Menlo Therapeutics Inc., Aristea Therapeutics, Sanofi, Sun, Almirall SA, and Arena Pharmaceuticals, Inc. N.S., D.T., M.S., and J.B. are employees of and hold stock in GSK. EDAT- 2020/04/18 06:00 MHDA- 2021/05/25 06:00 PMCR- 2020/07/07 CRDT- 2020/04/18 06:00 PHST- 2019/10/28 00:00 [received] PHST- 2020/03/25 00:00 [accepted] PHST- 2020/04/18 06:00 [pubmed] PHST- 2021/05/25 06:00 [medline] PHST- 2020/04/18 06:00 [entrez] PHST- 2020/07/07 00:00 [pmc-release] AID - CPT1852 [pii] AID - 10.1002/cpt.1852 [doi] PST - ppublish SO - Clin Pharmacol Ther. 2020 Oct;108(4):808-816. doi: 10.1002/cpt.1852. Epub 2020 Jul 7.