Thrombopoietin Targeting in Myeloproliferative Neoplasms

Project Summary/Abstract Treatment of patients with myeloproliferative neoplasms (MPNs) is limited to palliative and cytoreductive agents that mitigate proliferative blood counts and their effects. Small molecule selective tyrosine kinase (JAK1/JAK2) inhibitors were also shown to provide modest patient benefit, including reduced symptomatology and improved quality of life. Despite the available therapies, survival remains poor in patients with advanced forms of MPN, and some patients inevitably become refractory to all available therapies. Consequently, there is an unmet medical need for a new drug that can safely mitigate MPN symptoms and, ideally, also alter the long-term course of the disease. To address this important need, we propose to develop and investigate the therapeutic potential of Aronora’s proprietary drug candidate AB062, a thrombopoietin conjugate antisense oligonucleotide (THPO-ASO), to be used alone or in addition to other drugs, as a novel therapeutic for chronic myeloproliferative disorders. Our THPO-ASO inhibits hepatic thrombopoietin gene transcription in both murine and primate models, reduces serum thrombopoietin (TPO) levels, and results in dose- dependent reduction of TPO concentration-dependent downstream cellular effects. Work by our co- investigators and others has shown that TPO deprivation predominantly results in depletion of certain TPO-dependent mutant JAK2 carrier MPN stem cells while sparing healthy bone marrow progenitors. Targeting THPO/MPL/JAK2 axis also mitigates the MPN phenotype in murine MPN models, including reduction in proliferative blood counts and splenomegaly. These observations support our hypothesis that THPO-ASO could favorably alter the natural trajectory of certain MPNs. Our objective for Phase I of this SBIR Fast-Track project is to confirm that murine THPO-ASO treatment alone [or in combination with the JAK2 inhibitor, ruxolitinib,] can improve disease outcomes in a transgenic murine MPN model. Upon reaching this milestone, we will extend these studies into Phase II by: 1) evaluating murine THPO-ASO in a murine MPN transplant model that will allow us to assess the effects of THPO-ASO on the malignant clonal burden, 2) evaluating the reversibility of THPO-ASO and assess for synergy with the JAK inhibitor ruxolitnib, and 3) screen for and manufacture AB062, a drug-candidate ASO that targets human THPO. Positive results will justify further commercial development, and will help support an Investigational New Drug application for evaluating AB062 in patients with advanced myeloproliferative disorders who are in desperate need of new and innovative therapies.