Georgios Filippou (1,2), Silvia Sirotti (1), Carlo Scirè (3), Lene Terslev (4)
Affiliation(s):
1. IRCCS Ospedale Galeazzi - Sant'Ambrogio, Rheumatology Unit, Milan - Italy
2. Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
3. School of Medicine and Surgery, University of Milano-Bicocca, Milan
4. Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
Background: Calcium Pyrophosphate Deposition (CPPD) is a prevalent condition, particularly among the elderly. Individuals affected by CPPD may develop arthritis, which can affect a single joint or multiple joints, including small, large, and/or axial joints. However, there is currently no specific treatment for this condition, and patients are often managed using off-label drugs to alleviate symptoms. The absence of experimental or animal models poses a significant hurdle in the development and testing of novel drugs, contributing to a comparatively slow pace of research in this domain, especially when contrasted with advancements in other rheumatic diseases. Consequently, clinical pharmacological trials emerge as the only alternative for evaluating potential treatments in CPPD disease.
Objective: This abstract outlines the challenges encountered and overcome during the initiation of a pharmacological trial for CPPD disease.
Methodology and Results: In 2023, the IRCCS Galeazzi – Sant’Ambrogio Hospital successfully secured funding from Eli Lilly for a pivotal pharmacological trial investigating the efficacy of baricitinib in treating CPPD disease. Given the unclear pathogenesis of crystal deposition and the absence of known deposition-reducing drugs, a promising treatment for CPPD disease should focus on reducing inflammation, subsequently alleviating pain and minimizing joint damage.
According to available data on the pathogenesis of arthritis in CPPD, baricitininb appears to be promising in reducing inflammation as it interacts with the pathways of some of the most overexpressed cytokines in CPPD disease. The efforts leading to the agreement for this pharmacological trial, commenced in 2018, taking five years to finalize. Despite facing setbacks due to the pandemic, various obstacles, both bureaucratic (such as new European trial regulations and intellectual property issues) and scientific (classification criteria for CPPD disease – they were developed after the submission of the protocol, patient classification based on disease phenotype, defining outcomes, determining the standard of care, justifying off-label use of drugs for the control group, etc.), had to be addressed. Finally, according to the new European regulation, a Contract Research Organization (CRO) had to be engaged in order to guarantee data quality and submission of the trial in the relevant organisms for approval, with a remarkable impact on the total budget of the trial. Despite addressing all the challenges diligently with the best scientific and legal knowledge available, the potential for substantial modifications to the protocol by the ethics committee remains a major concern.
Conclusions: Although CPPD is a prevalent condition, it remains largely neglected. Limited awareness within the scientific community and the general population contributes to CPPD being both underdiagnosed and underestimated. This inevitably impacts the development of clinical trial protocols, both formally and scientifically. Successful collaboration among different stakeholders (scientific, administrative, and legal) is crucial to overcoming the challenges encountered during the development of pharmacological trials for CPPD disease. All the challenges outlined form a comprehensive research agenda on CPPD, requiring resolution to facilitate a quicker and more effective development of clinical trials for this condition.