Momelotinib: Unique polypharmacology and novel combination strategies for myelofibrosis and beyond

Momelotinib (Ojjaara / Omjjara) is a clinically differentiated JAK inhibitor that improves key manifestations of myelofibrosis (MF), including anemia, splenomegaly, and constitutional symptoms. Its efficacy stems from dual inhibition of JAK1/JAK2, addressing pro-inflammatory signaling, and targeting Activin A Receptor Type I (ACVR1/ALK2), which alleviates anemia by suppressing hepcidin expression, increasing iron bioavailability, and improving red blood cell production. Herein, we report comprehensive profiling of momelotinib's kinome selectivity revealing a distinctive polypharmacology beyond ACVR1 that includes inhibition of rho-associated kinases (ROCK1/ROCK2), inhibitor of NF-κB kinases (IKKs), and interleukin-1 receptor-associated kinase 1 (IRAK1). Cellular reporter assays demonstrated that this unique profile enables momelotinib to inhibit NF-kB activity stimulated by either canonical or non-canonical pro-inflammatory cytokines. These findings establish a strong rationale for momelotinib's therapeutic potential beyond MF in pro-inflammatory conditions, such as Vacuoles E1 X-chromosome Autoinflammatory Somatic (VEXAS) syndrome, low-risk myelodysplastic syndrome (LR-MDS), and graft-versus-host disease (GvHD), where these pathways are significantly dysregulated and medical need remains high. Additionally, recognizing momelotinib's differentiated clinical benefit and well-characterized safety profile, drug combination screening was performed to identify combination partners that cooperate with momelotinib to further improve MF patient outcomes. Specifically, two high-throughput drug screens targeting malignant cell viability in JAK2 V617F or MPL W515L MF models and hepcidin suppression in a BMP6-stimulated liver cell line were conducted with over 650 small molecules in late-stage clinical development. The viability screen identified inhibitors of signaling pathways that function in parallel to JAK-STAT as promising combination partners to reduce the viability of malignant MF cells. The hepcidin screen identified inhibitors that cooperated with momelotinib to additively suppress hepcidin expression. Notably, the XPO1 inhibitor selinexor emerged as a combination partner that both inhibited malignant cell growth and deepened hepcidin suppression. These discoveries highlight momelotinib's unique activity, both as a monotherapy for expanded indications and as an ideal combination partner to more effectively control anemia and halt disease progression in MF patients.