Background: Despite the availability of various treatments, the first line approach for rheumatoid arthritis remains unchallenged for years, and relays on disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX), often accompanied with glucocorticoids. Still, many patients fail to achieve satisfactory responses to available therapies. Alternative therapies must not only ensure effectiveness in controlling the primary symptoms of RA but also address the safety concerns arising from the additional health issues associated with the disease, particularly an elevated risk of cardiovascular disease, which further complicates its management. To address this issue, we propose a novel therapeutics approach, CPL’116, a dual kinase inhibitor, with enhanced selectivity towards both: Janus family kinases (JAKs) and Rho- associated kinases (ROCK). Blocking JAK signaling which plays a crucial role in immune response regulation, while providing overall cardioprotective and antifibrotic effects of ROCK inhibition make it a compelling candidate for treating autoimmune diseases like RA.

Objectives: We aimed to determine the safety and efficacy of CPL’116 in patients suffering from RA who have had inadequate response to MTX.

Methods: This was a 12-week, phase II, randomized, double blind, placebo-controlled, parallel group study evaluating the safety and efficacy of CPL’116 in patients with moderate-to-severe RA with inadequate response to MTX. After completing all screening evaluations, eligible patients were randomly assigned (1:1:1:1) to one of four treatment groups: CPL’116 60 mg, 120 mg, 240 mg, or placebo. All treatments were administered orally twice daily.

Results: 106 enrolled patients were randomized to either placebo or active CPL’116 arm. Majority or the subjects were women (75%) and the mean age of the participants was 54.4 years (± 10.5). Among the study population, 99 patients completed the treatment period (placebo group: 27/28 [96%]; CPL’116 60 mg group: 24/27 [89%]; CPL’116 120 mg group: 25/25 [100%]; and CPL’116 240 mg group: 23/26 [89%]). The drug was well tolerated. A total of 170 adverse events, mild or moderate, were recorded during the study. Treatment-related AEs accounted for 92 cases (54%). There were two serious AEs (1.2%), and three participants (2.8%) discontinued the study medication permanently due to adverse events. There were no AEs leading to dose reduction or death. CPL’116 improved patients’ condition measured with Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) in a dose-dependent manner. Decrease from baseline in the DAS28-CRP score at week 12 compared to placebo (LS MD) was 0.145 (p=0.67); 0.564 (p=0.10), and 0.887 (p=0.01) for doses of 60, 120 and 240 mg, respectively. Moreover, the fast statistically significant benefit over placebo was observed as early as week 4 of treatment. Noteworthy was also the remission rate (defined as DAS28-CRP<2.6) observed for the dose CPL’116 240 mg that exceeded 45% throughout the study. During treatment period Tender Joint Count (TJC) and Swollen Joint Count (SJC) significantly decreased when compared to baseline. Changes from baseline at week 12 on both scales were statistically significant for two highest CPL’116 doses, dropping 10.76 points (p=0.017) for TJC and 7.92 points (p=0.032) for SJC in the 120 mg cohort and 8.88 points (p=0.037) for TJC and 7.92 points (p=0.029) for SJC in the 240 mg cohort. Physician’s Global Assessment of Arthritis (PhGA) showed a decreasing trend throughout the study for all the CPL’116 doses, reaching the significance at 120 mg dose at Weeks 8 and 12, and minimally missing the significance for the highest dose. Patients Reported Outcomes - Patient’s Assessment of Arthritis Pain (PAAP) and Patient’s Global Assessment of Arthritis (PtGA) - also showed a general downward trend over the course of the study. The mean PAAP score started at 61.72 (± 17.41) on Day 1, decreased to 33.56 (± 23.13) on Day 85. Similarly, the mean PtGA score on Day 1 was 63.82 (17.22) that further declined to reach its lowest mean on Day 85 at 34.48 (± 23.16). Most vital signs and ECG findings remained stable, with values consistently falling within normal limits. It is worth to notice that blood parameters such as lipid profile, ALT, AST, CK, red blood cell and platelet count, hematocrit, and hemoglobin did not deteriorate significantly under the influence of CPL409116, which represents a superior outcome within the JAK inhibitor group.

Conclusion: To the best of our knowledge, we present the first dual JAK/ROCK inhibitor as a possible therapeutic option for patients suffering from RA. In the phase II clinical trial, CPL’116 demonstrated dose-dependent response and was effective in alleviating RA symptoms, reaching the statistical significance at the highest dose (240 mg). Moreover, the studied drug was well tolerated and escaped the burden of the undesired side effects of JAK inhibitors. Taken together, the dual nature and the favorable safety profile of CPL’116, position this molecule as a promising treatment for RA patients and other autoimmune diseases especially with fibrotic components, like RA-ILD or IPF.

REFERENCES: NIL.

Acknowledgements: Celon Pharma would like to thank the patients who participated in the study and all the sites’ personnel for their contribution. We want to acknowledge our vendors, CROS CRO for the engagement in monitoring the study and BioStat for providing statistical advice and final analysis. Authors want to express their gratitude to present and past co-workers Angelika Judycka-Giedronowicz, Agnieszka Gierczak-Pachulska, and Piotr Rudzki for their assistance and advice during the course of this clinical trial. The study was funded by Celon Pharma and European funds by the National Centre for Research of Development (Poland) under Smart Growth Operational Programme 2014-2020, project JAKSON – Selective JAK/ROCK kinases inhibitor in treatment of immune-mediated diseases, POIR.01.01.01-00-0382/16.

Disclosure of Interests: Maciej Wieczorek holds stocks of Celon Pharma S.A., Bartłomiej Kisiel: None declared, Dorota Włodarczyk previously employed by Celon Pharma S.A., Piotr Leszczynski: None declared, Iryna Kurylchyk: None declared, Ivan Vyshnyvetskyy: None declared, Izabela Kierzkowska: None declared, Piotr Pankiewicz previously employed by Celon Pharma S.A., Michał Kaza employed by Celon Pharma S.A., Martyna Banach employed by Celon Pharma S.A., Joanna Kogut employed by Celon Pharma S.A.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.