A new dual inhibitor targeting both Janus kinase (JAK) and Rho-associated protein kinase (ROCK) has shown encouraging results in patients with rheumatoid arthritis (RA) who failed to respond adequately to methotrexate. Findings from the phase 2 trial of CPL409116 (CPL’116) were published in The Lancet Rheumatology.
The randomized, double-blind, dose-ranging, placebo-controlled trial enrolled 106 adults aged 18 to 75 years across nine hospitals and clinics in Poland and Ukraine. All participants had moderate-to-severe RA for at least six months and continued background methotrexate while being randomly assigned to receive oral CPL’116 at 60 mg, 120 mg, or 240 mg, or placebo, twice daily for 12 weeks. Results revealed a clear dose-dependent response. At 12 weeks, the least squares mean difference in DAS28-CRP change versus placebo was –0.15 for the 60 mg dose (p=0.67), –0.56 for 120 mg (p=0.10), and –0.89 for 240 mg (p=0.010). Only the highest dose met statistical significance, achieving the trial’s primary endpoint.
CPL’116 was generally well tolerated. Two participants experienced serious treatment-emergent adverse events: one non-fatal heart attack in the 60 mg group, considered possibly related to the drug, and one case of bladder cancer in the 240 mg group, deemed unrelated. Both led to treatment discontinuation. Another participant in the 240 mg group stopped treatment due to leukopenia possibly linked to CPL’116. Importantly, no deaths occurred, and unlike conventional JAK inhibitors, CPL’116 was not associated with lipid abnormalities, creatinine kinase elevations, or other concerning laboratory findings. JAK inhibitors are widely used in RA but their clinical benefit is often offset by metabolic side effects, including increased cholesterol and triglycerides. ROCK inhibition, by contrast, has shown cardioprotective effects in preclinical research, reducing vascular inflammation and improving endothelial function. CPL’116 combines these mechanisms, preferentially targeting JAK1 and JAK3 in addition to ROCK.
Preclinical studies supported its therapeutic potential, demonstrating kidney protection in lupus-prone mice, anti-inflammatory effects in models of arthritis and psoriasis, and possible applications for pulmonary delivery. According to the study authors, the findings suggest that CPL’116 at 240 mg twice daily provides meaningful disease control while potentially avoiding the metabolic complications that limit traditional JAK inhibitor use. Larger phase 3 trials will be needed to confirm these benefits and establish its place in RA treatment.
References
- Wieczorek M, Kisiel B, Włodarczyk D, Leszczyński P, Kurylchyk IV, Vyshnyvetskyy I, Kierzkowska I, Pankiewicz P, Kaza M, Banach M, Kogut J. 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. Lancet Rheumatol. 2025 Sep;7(9):e629-e641.
- Rudzki PJ, Jarus-Dziedzic K, Włodarczyk D, Kaza M, Pankiewicz P, Gierczak-Pachulska A, Banach M, Zygmunt B, Piwowarczyk C, Żero P, Rabczenko D, Segiet-Święcicka A, Wieczorek M. First-in-human study of CPL’116 – a dual JAK/ROCK inhibitor – in healthy subjects. Front Pharmacol. 2025 Apr 1;16:1583723.