Dual JAK and ROCK inhibition with CPL'116 in patients with rheumatoid arthritis with inadequate response to methotrexate: a randomised, double-blind, placebo-controlled, phase 2 trial.

Abstract

Background: Janus kinase (JAK) inhibitors are an effective treatment option in rheumatoid arthritis and other autoimmune diseases. However, the use of JAK inhibitors is associated with increased total cholesterol, LDL cholesterol, triglycerides, and creatinine kinase, reducing the net clinical benefit of using them. Adding Rho-associated protein kinase (ROCK) inhibition to JAK inhibition might provide cardioprotection as ROCK inhibitors have been shown to reduce vascular inflammation, improve endothelial function, and prevent cardiac remodelling in preclinical models. In this study we investigated CPL409116 (hereafter referred to as CPL'116), a novel dual JAK and ROCK inhibitor, in patients with rheumatoid arthritis with inadequate response to methotrexate, to assess dose-dependent effects on disease control, pharmacokinetics, and laboratory abnormalities among other safety events.

Methods: This phase 2, randomised, double-blind, dose-ranging, placebo-controlled, parallel group trial enrolled patients aged 18-75 years at nine hospitals or clinics in Poland and Ukraine. Main inclusion criteria were a documented diagnosis of adult-onset, moderate-to-severe rheumatoid arthritis for at least 6 months before screening, and inadequate response to current methotrexate treatment (oral or injected 15-25 mg once weekly, or ≥10 mg once weekly if reduced due to side-effects or intolerance). Participants were randomly assigned via an interactive web response system (1:1:1:1, block size of four, stratified by age) to oral CPL'116 (60 mg, 120 mg, or 240 mg) or placebo twice daily for 12 weeks, with continuation of background methotrexate. The primary endpoint of the study was the change from baseline in Disease Activity Score based on 28 joints and C-reactive protein (DAS28-CRP) at week 12, analysed with a mixed-effects repeated measures model by a modified intention-to-treat approach. p values were nominal. Safety parameters including adverse events, vital functions, and laboratory results were closely monitored and reported for the safety analysis population, comprising all participants who received at least one dose of CPL'116 or placebo. People with lived experience were not involved in the study. The trial was registered with ClinicalTrials.gov, NCT05374785, and is completed.

Findings: Between May 30, 2022, and Feb 7, 2024, 106 patients were randomly assigned (27 in the CPL'116 60 mg group, 25 in the 120 mg group, 26 in the 240 mg group, and 28 in the placebo group). Overall mean age was 54·4 years (SD 10·5); 79 (75%) of 106 participants were women and 27 (25%) were men, and all individuals self-reported as White. The least squares mean difference in the change from baseline in DAS28-CRP at 12 weeks with CPL'116 versus placebo was -0·15 (95% CI -0·81 to 0·52; p=0·67) for the 60 mg dose; -0·56 (-1·25 to 0·12; p=0·10) for the 120 mg dose; and -0·89 (-1·56 to -0·22; p=0·010) for the 240 mg dose. Thus the primary endpoint was met for the 240 mg dose only. Overall CPL'116 was well tolerated. Two participants had serious treatment-emergent adverse events (one in the 60 mg dose group [non-fatal non-ST-elevation myocardial infarction, deemed possibly related to CPL'116] and one in the 240 mg dose group [non-muscle invasive bladder cancer, deemed unrelated to CPL'116]); both events led to discontinuation of CPL'116. CPL'116 was also discontinued due to leukopenia which was deemed to be possibly related to CPL'116 in one participant who received the 240 mg dose. No severe adverse events or deaths were reported. No laboratory or haematology abnormalities were recorded at any CPL'116 dose.

Interpretation: The findings of this study suggest a dose-dependent response with CPL'116, with significant efficacy at the high dose of 240 mg twice daily. The drug was generally well tolerated and was not associated with lipid abnormalities or creatinine kinase increase. These findings warrant further investigation in larger studies and different clinical settings.

Funding: Celon Pharma and the National Centre for Research and Development (Poland).