Improving Drug Trial Success Rates in Systemic Lupus Erythematosus: Endotyping-based Patient Stratification Could Be the Way Forward

Abstract

Abstract Systemic lupus erythematosus (SLE) is a complex heterogeneous autoimmune disease with protean clinical manifestations and phenotypes. As a result, any candidate molecule aiming to modulate a particular pathobiological pathway would likely fail to demonstrate efficacy in patients with mixed phenotypes. The success of the belimumab trial and the recent anifrolumab trial in SLE has provided evidence that stratifying patients based on their underlying pathobiological mechanism (e.g., endotype) can improve the chances of success in drug trials. Various approaches to endotyping have been proposed to stratify SLE patients, such as biomarker profiling, gene expression signature fingerprinting, utilizing transcriptomics and other “omics” techniques for patient stratification, and molecular characterization in both human subjects and animal models of SLE. Besides stratification of SLE patients based on endotyping, incorporating “theratyping” (which refers to outliers in any failed drug trial who exhibit a positive response) would further “fine-tune” the subgrouping with uniform underlying pathobiology. Using a 2-pronged approach of defining theratypes of preendotyped patients could fast-track drug discovery of drugs for SLE treatment. Considering the success of recent trials, there is compelling evidence that this approach can significantly increase the likelihood of success in drug trials and pave the way for more effective treatments for SLE.