E7820, an Anti-Cancer Sulfonamide, Degrades RBM39 in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial

Mutations in RNA splicing factor genes (SF3B1, SRSF2, and U2AF1) are common in AML and MDS and recent studies demonstrate pharmacologic degradation of the RNA splicing factor RBM39 results in preferential killing of splicing factor mutant cells. We therefore conducted a phase II clinical trial (NCT05024994) of the oral RBM39 degrader E7820 at the recommended phase II dose in patients with R/R MDS/AML and a splicing factor mutation. No patients met the primary endpoint of overall response rate in the first 12 patients enrolled, leading to study termination. However, E7820 was well-tolerated and achieved >50% RBM39 degradation in blood and disruption of splicing. At the same time, the degree of splicing disruption was far less than seen with in vitro doses exhibiting preclinical efficacy, providing potential explanation for limited clinical efficacy. Overall, this study demonstrates on-target safety and feasibility of RBM39 degradation in patients and supports future combination therapies with E7820. Differential RNA splicing analysis by RNA-sequencing on human K562 or NKM1 cell lines (comparing treatment with E7820 or DMSO vehicle control) or cells derived from splicing factor mutated patients (comparing prior to initiation of E7820 clinical trial or on-trial) using single-replicates.