A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis

Kathleen Weisel, Scott Berger, Katie Thorn, Peter C Taylor, Charles Peterfy, Hilary Siddall, Debra Tompson, Susanne Wang, Emilia Quattrocchi, Susan W Burriss, Jochen Walter, Paul Peter Tak, Kathleen Weisel, Scott Berger, Katie Thorn, Peter C Taylor, Charles Peterfy, Hilary Siddall, Debra Tompson, Susanne Wang, Emilia Quattrocchi, Susan W Burriss, Jochen Walter, Paul Peter Tak

Abstract

Background: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA).

Methods: Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85.

Results: A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms.

Conclusions: These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA.

Trial registration: ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.

Keywords: Pharmacodynamics; Pharmacokinetics; RIPK1; Receptor-interacting protein kinase 1; Rheumatoid arthritis.

Conflict of interest statement

KW, SB, EQ, SW, and PPT are former employees of and stockholders in GlaxoSmithKline (GSK).

KT is an employee of GSK.

PCT reports personal consultant fees from GSK and grants from Celgene, Galapagos, and Eli Lilly. He also reports personal fees from AbbVie, Galapagos, Gilead, GSK, Eli Lilly, and Pfizer.

CP received nonfinancial support from GSK. He is an employee of and stockholder in Spire Sciences Inc. which received research funding from GSK to conduct the study. He reports consulting or personal fees from AbbVie, Acerta Therapeutics, Five Prime, Genentech, Modern Bioscience, Myriad, Novartis, Roche, Set Point, and Vorso and speakers fees from Amgen and Bristol Myers Squibb.

HS, DT, and SWB are employees of and hold stock options in GSK.

JW reports personal fees and nonfinancial support from AbbVie, Medac, and Pfizer, and personal fees from Fraunhofer Institute, Gilead, GSK, Janssen-Cilag, Medac, Novartis, and Pfizer.

Figures

Fig. 1
Fig. 1
Patient disposition. AE, adverse event; b.i.d., twice daily; t.i.d., three times daily
Fig. 2
Fig. 2
DAS28-CRP. a DAS28-CRP adjusted mean change from baseline and unadjusted box and whisker plot of unadjusted change from baseline by treatment over time (combined b.i.d. and t.i.d. dosing). b DAS28-CRP adjusted mean change from baseline by dosing regimen. b.i.d., twice daily; CRP, C-reactive protein; DAS28-CRP, disease activity score for 28 joints using CRP value; t.i.d., three times daily
Fig. 3
Fig. 3
Clinical efficacy parameters (combined b.i.d. and t.i.d. dosing). Adjusted mean change from baseline and unadjusted box and whisker plot of unadjusted change from baseline by treatment over time. a C-reactive protein. b Swollen joint count (28). c Tender joint count (28). d Patient assessment of joint pain. b.i.d., twice daily; CRP, C-reactive protein; t.i.d., three times daily
Fig. 4
Fig. 4
Health outcomes measures (combined b.i.d. and t.i.d. dosing). Adjusted mean change from baseline and unadjusted box and whisker plot of unadjusted change from baseline by treatment over time. a HAQ-DI. b FACIT fatigue. c Clinical disease activity index (CDAI). d Simple disease activity index (SDAI). b.i.d., twice daily; FACIT, Functional Assessment of Chronic Illness Therapy; HAQ-DI, Health Assessment Questionnaire-Disability Index; t.i.d., three times daily
Fig. 5
Fig. 5
RAMRIS parameters. Adjusted mean change from baseline and unadjusted box and whisker plot of unadjusted change from baseline by treatment over time. a Synovitis. b Bone erosion. c Osteitis (combined b.i.d. and t.i.d. dosing). d Cumulative plot probability of change from baseline in bone erosion total score on day 85. b.i.d., twice daily; RAMRIS, Rheumatoid Arthritis MRI Scoring System; t.i.d., three times daily

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