Sanofi reported that the pivotal study, JAKARTA, examining the selective JAK2 inhibitor SAR302503 for myelofibrosis (MF) has met its primary endpoint in both dose groups. The primary endpoint assessed the proportion of patients achieving >35 per cent reduction of spleen volume. Consistent with data reported in previous trials, the most common adverse events were anaemia, diarrhea, nausea and vomiting. Full results will be presented at an upcoming medical congress.

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

“Patients with myelofibrosis in advanced stages are desperately ill and in need of treatments that will improve their outcomes. I am pleased with the results of JAKARTA and would like to thank the patients and the investigators in this trial,” said Debasish Roychowdhury, MD, senior vice president and head, Sanofi Oncology. “Since Sanofi’s acquisition of the molecule, SAR302503 has moved from phase I to the completion of pivotal phase III studies in less than three years, and now we are planning regulatory filings with authorities to make this medicine available for patients.”

SAR302503 is a novel, investigational, selective JAK2 inhibitor. Sanofi Oncology is developing SAR302503 for the treatment of the three main types of myeloproliferative neoplasms: primary myelofibrosis, including those previously treated with ruxolitinib; polycythemia vera; and essential thrombocythemia.

Conducted in 24 countries, 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 >50,000/µl were randomized to receive a once-daily oral dose of either 400mg of SAR302503, 500 mg of SAR302503 or placebo for twenty-four weeks (six cycles).

The primary endpoint was the proportion of patients with a reduction in spleen volume >35% after 24 weeks of treatment. Key secondary endpoints include the assessment of associated symptoms as measured by total symptom score using six key symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MF-SAF) diary. Sanofi is also studying the effect of the compound on reversing fibrosis in the bone marrow. After the completion of 24 weeks of treatment or disease progression, crossover from the placebo arm to SAR302503 was allowed.

The JAKARTA study was granted a Special Protocol Assessment (SPA) by the US Food and Drug Administration, signifying that the phase III trial design, including clinical endpoints, is acceptable to support an application for the granting of marketing authorization in the US.

The normal functioning of the JAK/STAT pathway is key to blood cell development.  Dysregulated JAK/STAT signaling is associated with the development of MF and other related myeloproliferative neoplasms (MPN), such as Polycythemia Vera (PV) and Essential Thrombocythemia (ET). 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 per cent of patients with MF are considered wild-type, meaning there is no detectable JAK2 or MPL mutations, yet do demonstrate dysregulated JAK2 signaling.

SAR302503 is a novel, investigational, JAK2 kinase inhibitor that selectively inhibits the JAK2 kinase, and in preclinical studies it has demonstrated activity against MF cells containing either JAK2V617F or MPLW515L mutation. As demonstrated in earlier phase I and II studies, SAR302503 demonstrated activity in MF patients with both wild-type and mutated JAK2 (JAK2V617F). Results from a phase II study in patients with intermediate-2 or high-risk MF were presented last year and final results are anticipated in Q2 2013. Another phase II study in ruxolitinib-exposed patients who are either resistant or intolerant to ruxolitinib is ongoing.

Myelofibrosis (MF) is a rare, but serious blood disease characterized by abnormal blood cell production and fibrosis (scarring) within the bone marrow. Scarring in the bone marrow interferes with blood cell production, and the spleen and liver compensate by producing and storing extra blood cells, which cause an enlarged spleen. Of the mutated JAK2 associated myeloproliferative neoplasms, MF carries the poorest prognosis. Median survival for intermediate-2 and high-risk patients is approximately two and a half years; median survival for MF patients overall is approximately six years, and the 10 year risk of the disease transforming to fatal acute myelogenous leukaemia (AML) is about 20 per cent.

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 US, 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.

Sanofi Oncology is a global division of Sanofi and is dedicated to translating science into effective therapeutics that address unmet medical needs for cancer and organ transplant patients.