Preliminary efficacy and safety data of RG6125 in RA patients with an inadequate response to TNF inhibitors

RG6125, an anti-cadherin-11 monoclonal antibody was well-tolerated with only mild to moderate adverse events. However, RG6125 in combination with TNF inhibitor (TNFi) therapy did not show a discernible treatment effect in rheumatoid arthritis (RA) patients compared with placebo.

The protein cadherin-11, found on stromal cells in the joint, has been identified as a new target for RA treatment. Cadherin-11 is expressed on fibroblasts in joints of RA patients and increases local fibroblast-mediated inflammation, pannus formation, and tissue invasion. RG6125 is a new human monoclonal antibody directed against cadherin-11, and is believed to disrupt immune cell adhesion in a non-immunosuppressive manner.

Junker et al. aimed to assess the safety, tolerability, and efficacy of RG6125 as adjunctive treatment in patients with moderately to severely active RA and unresponsive to TNFi treatment. In this phase 2, multicentre, randomised, double-blind placebo-controlled study, a total of 109 patients were randomised (2:1) to receive intravenous RG6125 810 mg or placebo, twice every 2 weeks and then monthly for a total of 4 dose administrations up to week 12. The majority of patients were female (71% in the csDMARDs group with a median age of approximately 55 years and median RA disease duration of 12.4 years). The primary endpoint was the proportion of patients with ACR50 response at week 12.

The results showed that there was little to no difference in efficacy between RG6125 and placebo. “It was quickly decided not to proceed with this project but hopefully RG6125 can be studied in other complex inflammatory diseases,” said Uwe Junker (Roche Innovation Center Basel, Switzerland). With regard to safety, musculoskeletal/connective tissue (14.3% vs. 8.1%) and gastrointestinal (12.9% vs. 8.1%) adverse events were noted on RG6125 compared with placebo. The pharmacokinetics of endpoints was not different across the exposure groups. There is an ongoing interest in synovial fibroblasts as key orchestrators of RA including therapy resistant disease and it will be interesting to see whether future fibroblast pathway targeting will find clinical utility.

1.  Junker U. et al. Abstract OP0224. EULAR 2019

Posted on 4 September 201916 February 2024