Barriers and Opportunities in Therapeutic Development for Early-Onset Preeclampsia

Early-onset preeclampsia (EOPE) remains a major contributor to maternal and fetal/neonatal morbidity and mortality worldwide, with delivery, frequently at early preterm gestations, remaining the only effective way to halt disease progression. Therapeutic development has been limited by disease heterogeneity, unpredictable conditions, a progressive course, ethical and safety concerns in pregnancy, and uncertainty over trial design and regulatory pathways. This document summarizes an international multidisciplinary convening of clinicians, trialists, pharmacologists, regulators, and global health experts who met to explore key challenges and emerging strategies for therapeutic development in EOPE. Discussion centered on EOPE, marked by abnormal placentation, pronounced angiogenic imbalance, and high maternal-fetal risk, viewed as a potentially tractable target for disease-modifying interventions. Key themes included trial eligibility and enrollment, use of angiogenic biomarkers for enrichment and monitoring, defining meaningful maternal and fetal end points, safety oversight in the dual-patient context, and the potential of adaptive trial designs. Participants also considered translational tools such as pharmacokinetic (physiologically based pharmacokinetic) modeling and placental transfer studies. Participants identified both areas of alignment and continued uncertainty. Biologically informed strategies, such as biomarker-supported enrollment and carefully designed early-phase studies were seen as helpful in reducing uncertainty, especially alongside early regulatory engagement. Although many developers are pursuing soluble fms-like tyrosine kinase-1 as a therapeutic target for EOPE, participants stressed the need for further biomarker validation, careful maternal-fetal risk-benefit assessment, and globally feasible approaches. Though focused on EOPE, these discussions may inform future research on late-onset disease, given its distinct underlying biology.