Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes

Abstract

Abstract Momelotinib (Ojjaara / Omjjara) is a clinically differentiated JAK inhibitor that improves the key manifestations of myelofibrosis (MF) including anemia, splenomegaly, and constitutional symptoms. In addition to suppressing proinflammatory signaling via JAK1 and JAK2 inhibition, momelotinib also alleviates anemia via inhibition of the Activin A Receptor Type I (ACVR1/ALK2) kinase, suppression of hepcidin expression, increased iron bioavailability, and improved red blood cell production. Momelotinib's differentiated clinical benefit and well-characterized safety profile position it as an ideal drug combination partner for MF. The experiments described herein aim to identify potential combinations that enhance momelotinib's clinical benefit by: 1) reducing the viability of malignant cells responsible for driving and maintaining MF, and 2) deepening hepcidin suppression to further improve the anemia benefit of momelotinib monotherapy. Two parallel high-throughput drug screens were performed with >600 small molecules representing diverse mechanisms in combination with momelotinib in multiple isogenic cell line models harboring JAK-STAT pathway activating mutations (VAF screen) or a BMP6-stimulated liver cell line expressing a hepcidin HiBiT transgene (hepcidin screen). The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis.