Positive long-term clinical results today from an ongoing open-label Phase II trial for INCB18424 (also known as INC424), a selective, oral JAK1 and JAK2 inhibitor developed by Incyte Corporation , in patients with advanced polycythemia vera (PV) and essential thrombocythemia (ET) provide evidence of potential broad clinical utility of this drug candidate.

With a median duration of 21 months of follow-up, clinical responses observed in 34 patients enrolled with PV included durable improvements in splenomegaly (spleen enlargement), hematocrit control and symptomatic burden including pruritus, night sweats and bone pain. Clinical responses seen in 39 patients enrolled with ET included long-term reductions in elevated platelet and white blood cell counts, and, when present, splenomegaly and constitutional symptoms.

“It is encouraging to see that treatment with INCB18424 provided long-term clinical benefit in this Phase II trial, with ongoing responses observed in patients who now have up to 27 months of follow-up,” said Srdan Verstovsek, M.D., Ph.D., Associate Professor, Leukemia Department, Myeloproliferative Disorders Program Leader, University of Texas M.D. Anderson Cancer Center, and INCB18424 principal investigator. “This is particularly notable given the fact that the enrolled patient populations were refractory to, or intolerant of, hydroxyurea, our current standard of care for these chronic and under-served disorders. Importantly, INCB18424 has been well tolerated in these advanced patients, with mechanism-based hematologic changes effectively managed with individualized dose titration.”

Study 18424-256 is an ongoing, multi-center, single-arm, open-label Phase II study being conducted in the United States and Italy. An initial 8-week run-in evaluation established 10 mg and 25 mg twice daily as starting doses for expansion cohorts in PV and ET, respectively; dose adjustments for safety and efficacy were allowed so that each patient could be titrated to his or her most appropriate dose.

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Key Efficacy Findings
In polycythemia vera patients: After a median follow-up of 21 months, 97% of enrolled patients (n=34) achieved hematocrit control to less-than or equal to 45% in the absence of phlebotomy. All patients continued to maintain phlebotomy-independence at the time of their last follow-up visit. Splenomegaly was present in 74% of patients at entry; 80% of patients achieved a greater-than or equal to 50% reduction in palpable spleen length and 68% have achieved complete resolution. Leukocytosis (white blood cell count elevation > 15×109/L) was present in 44% of patients at baseline, and counts normalized in 73%. Thrombocytosis (platelet count elevation > 600×109/L) was present in 38% of subjects at baseline, and counts normalized in 69%. Improvements in patient reported symptoms of pruritus, bone pain, and night sweats have been observed in the majority of patients as of the last follow-up visit.

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In essential thrombocythemia patients: After a median follow-up of 21 months, 49% of enrolled patients (n=39) normalized platelet counts, and 79% achieved platelet counts < 600×109/L or a greater-than or equal to 50% reduction from baseline. Of the 14 patients with extreme thrombocytosis > 1000×109/L at baseline, 13 (93%) experienced > 50% reduction. WBC counts for patients with baseline counts > 10×109/L normalized within the first month and were maintained for a median duration of 14 months. Palpablespleens completely resolved in 3 of 4 patients with baseline splenomegaly; 1 reduced >50% from baseline.

Safety
The adverse events associated with INCB18424 in this study were consistent with the safety profile established by previous trials with INCB18424 in MPNs. Drug-related adverse events were generally mild-to-moderate in intensity and manageable with dose adjustments.

In polycythemia vera patients:Six patients (18%) discontinued therapy (2 for adverse events (AEs), 2 withdrew consent, 1 for no response and 1 for disease progression). Grade 3 AEs potentially related to study medication included thrombocytopenia (2), neutropenia (1), renal tumor (1), asthenia (1), viral infection (1), and atrial flutter (1). No Grade 4 drug-related AEs have occurred.

In essential thrombocythemia patients: Eleven patients (28%) discontinued therapy (4 for AEs, 2 withdrew consent, 5 for no response). Grade 3 AEs potentially related to study medication included leukopenia (2 patients), GI disorder (1), and peripheral neuropathy (1). No Grade 4 drug-related AEs have occurred.

Dysfunction of the bone marrow
Myeloproliferative Neoplasms or MPNs are a related group of hematological neoplasms characterized by dysfunction of the bone marrow resulting in either over production of blood cells or ineffective hematopoiesis. The three main Philadelphia-negative MPNs are myelofibrosis, polycythemia vera and essential thrombocythemia.

Myelofibrosis is associated with bone marrow failure, splenomegaly and debilitating symptoms, transformation to acute myelogenous leukemia and shortened survival. MF occurs as primary or secondary MF. Primary MF presents as MF without any other etiology. Secondary MF includes post-polycythemia vera MF and post-essential thrombocythemia MF, which are progressions of polycythemia vera or essential thrombocythemia.

Polycythemia vera is a blood cancer characterized by the overproduction of red blood cells which increases blood viscosity and leads to elevated thromboembolic risk. Increased levels of white blood cells and platelets are also common. In advanced disease, patients frequently exhibit spleen enlargement and debilitating symptoms including pruritus, night sweats, fatigue, and muscle and bone pain.

Essential thrombocythemia is characterized by uncontrolled proliferation of myeloid lineage cells, especially megakaryocytes, leading to the overproduction of platelets. Common complications include thrombotic events and bleeding. Patients with advanced essential thrombocythemia may also experience splenomegaly as well as symptoms including fatigue, headache, night sweats, and muscle and bone pain.

Ongoing development: The RESPONSE Trial
INCB18424 is currently in Phase III development for patients with myelofibrosis and for patients with advanced polycythemia vera. A global Phase III registration trial called RESPONSE (Randomized, open label, multicenter phase III study of Efficacy and Safety in POlycythemia vera subjects who are resistant to or intolerant of hydroxyurea: JAK iNhibitor INC424 tablets verSus bEst available care) is now open to enrollment in the U.S. The trial will be opened in other countries in early 2011.

For more information:
Controlled Polycythemia Vera Study with Oral JAK inhibitor Treatment
Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: The RESPONSE Trial

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