molecules of the year

The H3 Biomedicine RNA splicing modulator, H3B-8800, targets the spliceosome SF3b complex containing either wild-type (WT) or mutant SF3B1. Splicesome inhibition can induce synthetic lethality since cancer cells bearing spliceosome mutations are more dependent on WT spliceosome function. The compound is derived from the natural product, pladienolide B, optimizing for preferential cytotoxicity in spliceosome-mutant cells. H3B-8800 completed a Ph. I study in myeloid neoplasias (MDS, CMML, AML) where it was given once-daily in cycles (e.g. 7-20 mg, 21d on, 7d off). Mostly low-grade treatment-related adverse events (TAEs) were seen but no objective responses were observed, though patients with a TMEM14C biomarker were more likely to become transfusion independent. The rest cycles in the study design suggest some on-target toxicity was probably anticipated, drug activity was not…