A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Polycythemia Vera

More than 98% of patients with polycythemia vera (PV) carry the activating JAK2 mutation V617F, which may play a role in the pathogenesis of PV by promoting hematopoetic cell proliferation and survival. PV is characterized by an increased red blood cell mass and is generally accompanied by increased myeloid and megakaryocytic production. Current therapy consists of supportive care measures including aspirin, phlebotomy, interferon and hydroxyurea to reduce the risk of complications of the disease such as thrombotic events. Such palliative therapy is often unsatisfactory due to side effects and the persistent susceptibility of the patients to development of thrombosis, and the failure to prevent transformation to myelofibrosis or acute leukemia. XL019 potently and selectively inhibits JAK2 (K_i of 2 nM); relative to other JAK family kinases (JAK1 K_i of 134 nM, JAK3 K_i of 195 nM and TYK2 K_i of 344 nM). Cellular selectivity of XL019 was confirmed in primary human cell assays; while EPO-stimulated pSTAT5 in primary erythroid cells was quite sensitive to XL019 treatment (IC₅₀ of 64 nM), stimulation of T-cells with IL-2 or B-cells with IL-4 or IL-6 gave pSTAT IC₅₀s of >800 nM in each case. Potent effects on JAK2-STAT signaling were also demonstrated in single-dose pharmacodynamic studies in xenograft tumors, including HEL92.1.7, CFPAC-1 and DU 145. XL019 is being evaluated in a Phase 1 dose escalation study in subjects with PV who have failed or are intolerant of standard therapies defined as follows: symptomatic splenomegaly in spite of current therapy, thrombocytosis with a platelet count >450K/μl, or non-controlled constitutional symptoms such as pruritus, night sweats, or weight loss. The primary objectives of this study are to determine the safety and tolerability of XL019 when administered orally either once daily, or every Monday, Wednesday, and Friday in 28-day cycles (starting doses 10 mg QD and 25 mg QMWF). Secondary objectives include determination of the pharmacokinetics and pharmacodynamics of XL019, and to evaluate clinical response using the following endpoints:

• hematologic response;

• time to hematologic response;

• duration of hematologic response;

• phlebotomy independence;

• change in spleen and/or liver size;

• change in bone marrow morphology;

• impact on quality of life (QOL); and

• impact on functional exercise capacity.

Pharmacodynamic assessments for this study include JAK2 V617F allele burden, erythropoietin-independent colony formation, changes in cytokine levels and JAK2 signaling pathways in peripheral blood mononuclear cells, and changes in bone marrow histology. Our initial findings regarding the tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of XL019 in PV patients will be presented.