Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation causing increased red cell mass, blood hyperviscosity, significant morbidity, shortened lifespan and possible evolution to acute myeloid leukemia. Splenomegaly, debilitating symptoms, leukocytosis, and thrombocytosis are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers and other side effects. Control of hematocrit is not always achieved with HU and many patients are either intolerant of or become resistant to HU; second line therapeutic options are limited with no drugs approved in this setting. Janus kinase (JAK) 2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F gain-of-function mutation or a JAK2 exon 12 mutation. In a phase II study in HU-resistant or -intolerant PV patients, INC424, a potent and selective inhibitor of JAK1 and JAK2, was well tolerated and achieved rapid and durable clinical responses including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell counts, platelet counts, and disease-related symptoms (Verstovsek S, et al. at 52nd ASH Annual Meeting; December 4–7, 2010. #313). Methods: RESPONSE, a global, open-label phase III trial (NCT01243944), is designed to compare the efficacy and safety of INC424 to Best Available Therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (by ELN criteria), require phlebotomy due to inadequate hematocrit control, and exhibit palpable splenomegaly ≥ 5 cm below the costal margin with either leukocytosis > 15 x 10⁹/L and/or thrombocytosis > 600 x 10⁹/L. The primary efficacy endpoint, assessed after 32 weeks of treatment, is based on achieving both phlebotomy independence and a ≥ 35% reduction in spleen volume as measured by imaging. All patients will be treated for 80 weeks to assess safety and response durability. Patients randomized to BAT may be eligible to cross over to receive INC424 after week 32. Enrollment is now open globally with a target of 300 patients to be randomized 1:1 to INC424 or BAT.