A Phase 1b trial of AVID200, a TGFβ 1/3 trap, in patients with myelofibrosis

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGF-β, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, down-regulates anti-tumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGF-β 1/3 trap, reduced TGF-β1 induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with wild-type JAK2 rather than JAK2V617F. We conducted an investigator-initiated, multicenter, phase 1b trial of AVID200 monotherapy in 21 advanced MF patients. No dose limiting toxicity was identified at the three dose levels tested and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGF-β1 levels, and pSMAD2 in MF cells. AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of MF patients and should be evaluated further in thrombocytopenic MF patients in combination with agents that target aberrant MF intracellular signaling pathways.