New Phase II data shows that treatment with a novel, investigational, selective JAK2 inhibitor (SAR302503) reduced spleen size and improved constitutional symptoms in patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF), a hematologic malignancy with unmet medical needs.[1]

The data were presented today during the Annual Meeting of the American Society of Hematology (ASH) in Atlanta, GA., December 8-11, 2012. ?The results observed in our trial with SAR302503 are encouraging,? said Moshe Talpaz, M.D.,Professor, Department of Internal Medicine,University of Michigan and lead investigator of the study. ?New treatment options are needed to fulfill existing treatment gaps for patients with these debilitating blood disorders, and specifically targeting the Janus kinase 2 or JAK2 enzyme appears to offer a promising approach.?

SAR302503 Phase III JAKARTA trial
Results from this Phase II trial support the two doses (400 mg and 500 mg) selected for the SAR302503 Phase III JAKARTA trial that is currently under way. The JAKARTA trial, which enrolled 289 patients over nine months and initial results are expected in the second quarter of 2013, is Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of SAR302503 in Patients with Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis with Splenomegaly.

Difficult-to-treat patient population
?I am very pleased with how much progress has been made in the development of our JAK2 inhibitor. This study confirms the once-daily oral administration of SAR302503 identified for use in the Phase III trial in this difficult-to-treat patient population,? said Debasish Roychowdhury, M.D., Senior Vice President and Head, Sanofi Oncology. ?We believe SAR302503 could provide a benefit to these patients with primary and secondary myelofibrosis and we look forward to our Phase III results next year.?

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Study Design
The Phase II, open label, randomized dose-ranging study evaluates the efficacy of once-daily oral doses of 300 mg, 400 mg, and 500 mg of SAR302503 for the reduction of spleen volume. The primary endpoint is change in spleen volume at the end of cycle three assessed by MRI with independent central review. Secondary endpoints include spleen response (reduction in spleen volume greater than or equal to 35% vs. baseline), safety and symptom response using the MPN-SAF scale. According to the study results, treatment was associated with reductions in spleen size and other disease symptoms in 31 randomized patients.[1]

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The data showed a mean percentage reductions in spleen volume vs. baseline were 30% (n=10), 33% (n=10) and 42% (n=11), in each group, respectively. Also, the proportion of patients who achieved a ?35% reduction in spleen volume by MRI was 30%, 50% and 63.6% in each group, respectively. The proportion of patients who achieved ?50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) score, a sum of six key constitutional symptoms (night sweats, itching, abdominal discomfort, abdominal pain, bone pain, early satiety), was
similar in all dose groups (44%, 50% and 44%).

Adverse events
Consistent with data reported in previous trials, the most common serious (grade 3-4) hematologic adverse event was anemia with rates across the 300, 400, and 500 mg doses of 33%, 30% and 55%, respectively. Rates of grade 3-4 thrombocytopenia were 20%, 0% and 9%, respectively.

The most common grade 3-4 non-hematological events were diarrhea (10%, 20%, 0%), nausea (10%,10%, 0%) and vomiting (10%, 10%, 0%). Two patients in the 300 mg group discontinued treatment due to an adverse event (grade 3 anemia, grade 4 transaminase elevation).[1]

Debilitating and life-threatening
Myelofibrosis (MF) is a rare, debilitating and life-threatening progressive malignant hematologic disease characterized by abnormal blood cell production and fibrosis (scarring) within the bone marrow. Scarring in the bone marrow interferes with blood cell production; the spleen and liver try to produce and store extra blood cells, which can cause these organs to become enlarged.

Most patients with MF have greatly enlarged spleens (splenomegaly) that can result in a range of vague symptoms with dramatic impact on quality of life. These include fatigue, abdominal pain, night sweats, feeling full without eating,cough or shortness of breath and decreased physical activity. Other signs and symptoms of MF include anemia, thrombocytopenia, weight loss and severe itching.

The exact prevalence of MF is not known. The latest research estimates that the prevalence of MF ranges from 4.2 to 5.6 per 100,000 people in the U.S., or approximately 15,000 patients. Prevalence estimates in Europe are less clear. People over age sixty are most likely to develop this disease, with men and women equally at risk.

JAK2 and SAR302503
Janus kinase 2 or or JAK2has been implicated in signaling bytype II cytokine receptor family (e.g. interferon receptors), the GM-CSF receptor family (IL-3R, IL-5R and GM-CSF-R), the gp130 receptor family (e.g. IL-6R), and the single chain receptors (e.g. Epo-R, Tpo-R, GH-R, PRL-R). It isa key enzyme for blood cell development. Mutations in JAK2 can lead to dysregulated JAK2 signaling and are thought to be a cause of Myelofibrosis (MF). Patients with wild type JAK2 have also been shown to have persistent, dysregulated activation of the JAK2 signaling pathway.[2]

SAR302503 is a novel, investigational, selective inhibitor of the JAK/STAT signaling pathway that preferentially inhibits JAK2. Sanofi Oncology is developing the compound for the treatment of the three main types of myeloproliferative neoplasms: primary myelofibrosis, polycythemia vera and essential thrombocythemia. The companyis also studying the effect of the compound on reducing/reversing scarring in the bone marrow.

References
[1] Talpaz, et al. A Phase II randomized dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV)MF, or post-essential thrombocythemia (ET) MF. Abstract #2837 ASH 2012
[2] Abdel-Wahab, O, et al. Primary Myelofibrosis: Update on Definition, Pathogenesis, and Treatment. Annu Rev Med. 2009;60:233-45. doi: 10.1146/annurev.med.60.041707.160528.

For more information
JAKARTA-trial: A phase III clinical trial in patients with certain forms of myelofibrosis [For Healthcare Professionals]

Photo: Moshe Talpaz, M.D.,Professor , Department of Internal medicine, University of Michigan and lead investigator in this trial. Courtesty: University of Michigan. Jakarta study logo courtesy Sanofi-aventis U.S. LLC.

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