It’s time for a more personalized approach to clinical trials in rheumatoid arthritis (RA), according to Costantino Pitzalis, MD, PhD, FRCP. Dr. Pitzalis discussed his work on identifying predictive molecular biomarkers to inform the design of biomarker-driven trials during Precision Clinical Trial Design in Rheumatoid Arthritis.
The session is available for on-demand viewing for registered ACR Convergence participants through October 31, 2024, on the meeting website.
“If we continue to do the same thing, we will get the same results,” said Dr. Pitzalis, Versus Arthritis Professor of Rheumatology, Queen Mary University of London, United Kingdom. “It’s time to change the way we do clinical trials, moving away from a one-size-fits-all approach, and select patients based on their likelihood of response.”
Though conventional randomized controlled trials have been instrumental in the development of dozens of effective therapies that have transformed the experience of patients with RA, Dr. Pitzalis stressed that several unmet needs remain. Approximately 5–20% of patients are refractory to current agents. In addition, available agents, regardless of mechanism of action, exhibit a ceiling effect in terms of the number of responders.
To identify molecular markers of treatment response, Dr. Pitzalis turned to the synovial fluid.
“Thirty years of studying peripheral biomarkers have not yielded anything that can predict response,” he said. “The blood is not a faithful window of what is happening in the diseased tissue.”
Using ultrasound-guided synovial biopsies of small and large joints, Dr. Pitzalis’ group has characterized the synovial tissue to an unprecedented level. This has defined three disease pathotypes based on transcriptomic signatures that exhibit different response rates to different RA therapies.
The work has led to two biomarker-driven clinical trials led by the Taxonomy, Treatments, Targets and Remission (3TR) project to investigate whether transcriptomic-based signatures can predict response to current therapies. The first study, 3TR Molecular Pathobiology-Driven Precision Therapy in Early RA (3TR PARTNER-RA), will investigate response to abatacept in patients with early RA. The second study, the 3TR Molecular Pathobiology-Driven Precision Therapy in RA (3TR Precis-The-RA), will investigate response to sarilumab and etanercept.
Dr. Pitzalis is hopeful that these studies will demonstrate the utility of synovial biopsy. He is optimistic that such biopsies can become incorporated into routine care if it leads to higher response rates.
“The road to precision medicine is long and winding,” he said. “There is no doubt it will be difficult. We have made a start on this journey. I hope that these new trials will help us give the right drug to the right patient on the first try.”