Top-line results from COMFORT-I, the pivotal Phase III clinical trial of INCB18424, also known as INC424, currently being developed by Incyte Corporation in patients with myelofibrosis (MF) being conducted under the U.S. Food and Drug Administration (FDA) Special Protocol Assessment (SPA) Agreement shows that safety and tolerability of the drug are consistent with data from prior studies which also included reversible thrombocytopenia and anemia.

COMFORT-I (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Treatment) is a double-blind, placebo-controlled Phase III trial involving 309 patients. To be eligible for the study, patients had to have a palpated spleen length of 5 cm or greater and be classified as intermediate 2 or high risk according to the International Working Group (IWG) criteria [1]

Study results
The primary endpoint was the response rate defined as the percentage of patients achieving a 35% or greater reduction in spleen volume at 24 weeks as measured by magnetic resonance imaging, or computerized tomography, comparing the rates in patients receiving INCB18424 or placebo. The response rate was 42% in patients randomized to INCB18424 versus less than 1% of patients randomized to placebo; thus a high level of statistical significance (p < 0.0001) was achieved.

High levels of statistical significance were also achieved for the key secondary endpoints based on symptomatic improvement as measured by the modified Myelofibrosis Symptom Assessment FormDiary. Response rates among patients receiving INCB18424 were similar to those previously reported with INCB18424 in the Phase II trial while much lower response rates were reported for patients receiving placebo in COMFORT-I.

The company intends to submit the data from COMFORT-I for presentation during the upcoming 2011 American Society of Clinical Oncology Annual Meeting (ASCO) in Chicago from June 3-7, 2011.

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Paul Friedman, M.D., President and CEO of Incyte stated, “These highly significant results from COMFORT-I are similar to what was seen in the Phase II trial recently published in the New England Journal of Medicine. We look forward to continuing our work with the FDA and our investigators as we strive to make this new medicine available to patients with myelofibrosis as rapidly as possible. In this regard, we are proceeding with the preparation of a New Drug Application and believe INCB18424 has the potential to become the first FDA-approved treatment for this debilitating, life-threatening disease.”

“In addition to meeting the efficacy endpoints in this controlled trial, the safety and tolerability profile suggests that INCB18424 could become the first widely available medication to relieve the debilitating symptoms in patients with myelofibrosis,” added Richard Levy, M.D., Executive Vice President and Chief Drug Development and Medical Officer at Incyte.

Based on the SPA agreement, COMFORT-I is the only pivotal trial required for approval in the U.S. Data from a second Phase III trial, COMFORT-II, which is the pivotal trial for European Marketing Authorization, comparing INCB18424 to best available therapy, is being conducted by Novartis in Europe and is also expected to provide supportive data for approval and labeling in the U.S. Results of COMFORT-II are expected early next year. Incyte and Novartis announced a collaboration and license agreement in November 2009 in which Incyte retained exclusive rights to develop and commercialize INCB18424 in the U.S. and Novartis received exclusive rights to develop and commercialize INCB18424 for territories outside the U.S. Both the FDA and the European Medicines Agency have granted INCB18424 orphan drug status for myelofibrosis

Myeloproliferative neoplasms
Myelofibrosis or MF is an uncommon, life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms including fatigue, night sweats and pruritus, poor quality of life, and weight loss, as well as shortened survival [2]. MF is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) which also includes polycythemia vera and essential thrombocythemia. Of the JAK-associated MPNs, MF carries the greatest risk of a poor prognosis, including transformation to fatal acute myelogenous leukemia, and there are currently no approved treatments for MF in the U.S.[2,3]. Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and mortality and is usually appropriate only in younger patients [4].

JAK 1 and JAK2
INCB18424 is an orally available JAK1 and JAK2 inhibitor that entered Phase I clinical testing in May 2007. The JAK family of enzymes are key players in a number of important biologic processes, including the regulation of immune function and the formation and development of blood cells [5-10]. A strong association exists between abnormal JAK signaling and the development of myelofibrosis, polycythemia vera, and essential thrombocythemia [11 ? 15]. The discovery of JAK mutations common to myelofibrosis, polycythemia vera and essential thrombocythemia, has linked them on a molecular level [16]. This finding, together with the fact that these patients tend to have elevated inflammatory cytokines that signal through JAK1 and JAK2, led Incyte to the discovery and development of INCB18424, a potent, selective inhibitor of the JAK1 and JAK2 tyrosine kinases [17, 18]

References:
[1] Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006;108:1497-1503.
[2] Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of JAK1 & JAK2 Inhibitor, INCB018424, in Myelofibrosis. New Eng J Med. 2010 September 16;363:1117-1127.
[3] The Leukemia & Lymphoma Society. Idiopathic myelofibrosis Last accessed October 2010.
[4] Tefferi A. Allogeneic hematopoietic cell transplantation versus drugs in myelofibrosis: the risk-benefit balancing act. Bone Marrow Transplant. 2010;45(3):419-421.
[5] Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Curr Hematol Malig Rep. 2009 Jan;4(1):33-40.
[6] Huang HM, Lin YL, Chen CH, Chang TW. Simultaneous activation of JAK1 and JAK2 confers IL-3 independent growth on Ba/F3 pro-B cells. J Cell Biochem. 2005 Oct 1;96(2):361-75.
[7] Murray PJ. The JAK-STAT pathway: input and output integration. J Immunol. 2007;178:2623-2629.
[8] Sandberg EM, Wallace TA, Godeny MD, VonDerLinden D, Sayeski PP. Jak2 tyrosine kinase: a true Jak of all trades? Cell Biochem Biophys. 2004;41:207-231.
[9] Haan C, Kreis S, Margue C, Behrmann I. Jaks and cytokine receptors–an intimate relationship. Biochem Pharmacol. 2006;72:1538-1546.
[10]Ivashkiv LB, Hu X. The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arthritis Rheum. 2003;48(8):2092-2096.
[11] Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673-683.
[12] Kralovics R. Genetic complexity of myeloproliferative neoplasms. Leukemia. 2008;22:1841-1848.
[13] Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636-642.
[14] Fourouclas N, Li J, Gilby DC, et al. Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders. Haematologica. 2008;93:
1635-1644.
[15] Beer PA, Green AR. Pathogenesis and management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2009;621-628.
[16] Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233-245.
[17] Plo I, Vainchenker W. Molecular and genetic basis of myeloproliferative disorders: questions and perspectives. Clin Lymphoma Myeloma. 2009;9(Suppl 3):S329-S339.
[18] Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673-683

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