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Positive Phase III Results for Myelofibrosis Treatment

JAK2 inhibitor reduces spleen volume (May 17)

The pivotal phase III JAKARTA trial, which evaluated the selective JAK2 inhibitor SAR302503 (Sanofi) for myelofibrosis, has met its primary endpoint — a reduction of at least 35% in spleen volume — in both dosage groups (400 mg and 500 mg once daily). The most common adverse events were anemia, diarrhea, nausea, and vomiting.

Myelofibrosis is a rare, debilitating, and life-threatening hematologic malignancy characterized by abnormal blood-cell production and by scarring (fibrosis) in the bone marrow.

SAR302503 is being developed for the treatment of the three main types of myeloproliferative neoplasms: primary myelofibrosis, including those previously treated with ruxolitinib (Jakavi, Novartis); polycythemia vera; and essential thrombocythemia.

The randomized, double-blind, placebo-controlled phase III JAKARTA study evaluated once-daily oral SAR302503 versus placebo in 289 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. Eligible patients with platelet counts of ≥ 50,000/µL were randomized to receive a once-daily oral dose of 400 mg of SAR302503, 500 mg of SAR302503, or placebo for 24 weeks (six cycles).

The study’s primary endpoint was the proportion of patients with a reduction in spleen volume of ≥ 35% after 24 weeks of treatment. After the completion of therapy or disease progression, crossover from the placebo arm to SAR302503 was allowed.

Normal functioning of the JAK/STAT pathway is essential for the development of blood cells. Dysregulated JAK/STAT signaling is associated with the development of MF and other related myeloproliferative neoplasms, such as polycythemia vera and essential thrombocythemia. Dysregulation of the JAK/STAT pathway in these diseases occurs with mutations of the JAK2 and MPL genes (notably JAK2V617F and MPLW515L). In addition, up to 50% of patients with myelofibrosis are considered wild-type, meaning no detectable JAK2 or MPL mutations are present, and yet the patients demonstrate dysregulated JAK2 signaling.

SAR302503 selectively inhibits the JAK2 kinase, and has shown activity against myelofibrosis cells containing either the JAK2V617F or MPLW515L mutation in preclinical studies. In earlier phase I and II studies, SAR302503 demonstrated activity in myelofibrosis patients with both wild-type and mutated JAK2 (JAK2V617F). Another phase II trial in ruxolitinib-exposed patients who are either resistant to or intolerant of ruxolitinib is ongoing.

Source: Sanofi; May 17, 2013.

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