Efficacy and Safety Study Comparing CPL409116 to Placebo in Participants With Active Rheumatoid Arthritis

The purpose of the following phase II clinical trial is to determine safety and effectiveness of Janus kinases and Rho-kinases inhibitor (JAK/ROCKi) in patients with Rheumatoid arthritis after oral administration of investigational medicinal product (IMP) called CPL409116. JAK inhibitors are a new class of small molecule drugs that modulate inflammatory pathways by blocking one or more JAK receptors. In recent years, JAK inhibitors have emerged as a new option for the treatment of various inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, skin disorders and others. CPL409116 inhibits JAK1 and JAK3 with less inhibitory activity against JAK2 and Tyk2. Inhibition of these kinases decreases inflammatory cytokine release which in turn decreases lymphocyte activation and proliferation. Moreover, CPL409116 blocks Rho-kinases (ROCKs), which are involved in diverse cellular processes including actin cytoskeleton organization, cell adhesion and motility, proliferation, apoptosis as well as smooth muscle contraction. ROCKs signalling is one of the major pathways implicated in the pathogenesis of cardiovascular, renal as well as fibrotic diseases. However recent data indicate their role in immune cell regulation and inflammatory disease development. CPL409116 was designed predominantly for the therapy of immune-related diseases: rheumatoid arthritis (RA) or psoriasis but the unique mode of action of this compound may be beneficial for patients suffering from fibrotic complications developing on the basis of autoimmune diseases. RA is a chronic systemic autoimmune disease characterised by persistent joint inflammation leading to loss of joint function as well as cartilage and bone damage. Chronic, progressive course of the disease results in disability, reduced quality of life, as well as higher comorbidity and mortality rates. It is well documented that JAK kinases play a pivotal role in cytokine receptor signalling to phosphorylate and activate signal transducer and activator of transcription (STAT) proteins. Several of these JAK-controlled cytokine receptor pathways are immediately involved in the initiation and progression of RA pathogenesis. After preclinical studies conducted by Celon Pharma, CPL409116 could have been classified as a good clinical candidate for the treatment of patients with RA and next, results obtained after the phase I clinical trial in healthy volunteers confirmed its safety and a good pharmacokinetic profile.

This is to be a 12-week, phase II, multicentre, randomised, double blind, efficacy and safety study of CPL409116 in participants with active rheumatoid arthritis who are taking methotrexate but have an inadequate response to this drug. Eligible subjects are to be randomised into one of the 4 treatment arms (60 mg BID, 120 mg BID, 240 mg BID of CPL409116 or palcebo) and approximately 100 male and female subjects are to be enrolled in the study (25 patients per arm). The study is to include the screening period, the treatment period and the follow-up period. In all treatment arms the investigated product/ placebo is to be administered orally for 12 weeks in a blinded fashion. In order to maintain the blind and minimize bias, all subjects will receive the same number and types of tablets each day of treatment. In the screening period, patients are to undergo screening assessments from Day -28 to Day 0. Rolling admission is to be employed in this study. Patients that fulfil all the inclusion criteria and none of the exclusion criteria will be considered eligible for this study. During the treatment period, patients are to be dosed with 60, 120, 240 mg CPL409116 administered twice a day or placebo administered twice a day for 85 consecutive days (Day 1 to Day 85). The MTX dosage which should be orally or parenterally administered by participants during the study and before the start of the study should be in the range of 15-25 mg/ week, which is typical of current clinical practice. MTX must be applied for at least 12 weeks prior to Screening, and with no change in dosage and route of administration for at least 8 weeks prior to Day 1/ baseline. Within the follow-up period patients are to undergo safety assessment for 4 weeks after the last dose of IMP.