Date: 2013-11-18
Type of information:
phase: 3
Announcement: decision to halt all clinical trials
Company: Sanofi (France)
Product: SAR302503 (fedratinib)
Action
mechanism: SAR302503 is a novel, investigational, selective JAK2 inhibitor. 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% of patients with MF are considered wild-type, meaning there is no detectable JAK2 or MPL mutations, yet do demonstrate dysregulated JAK2 signaling. In preclinical studies SAR302503 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).
Disease: myelofibrosis
Therapeutic area: Rare diseases
Country:
Trial
details: 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 theFDA, signifying that the Phase III trial design, including clinical endpoints, is acceptable to support an application for the granting of marketing authorization in the U.S. (NCT01437787)
Latest
news: * On November 18, 2013, Sanofi has announced the decision to halt all clinical trials and cancel plans for regulatory filings with its investigational JAK2 inhibitor, fedratinib (SAR302503). Following a thorough risk-benefit analysis, including consultation with the FDA, study investigators, independent expert neurologists and neuro-radiologists, Sanofi determined that the risk to patient safety outweighed the benefit that fedratinib would bring to patients. This decision follows recent reports of cases consistent with Wernicke’s encephalopathy in patients participating in fedratinib clinical trials. The FDA directed Sanofi to put all fedratinib trials on clinical hold while the company thoroughly investigated these cases to ensure the safety of fedratinib for patients. Sanofi took immediate action requesting that study investigators discontinue fedratinib treatment for patients in the trials. Sanofi has notified investigators of all ongoing fedratinib trials, as well as health authorities, of its decision to halt the trials. Patients currently in fedratinib trials should consult with their treating physician to determine the best alternative course of therapy for their myelofibrosis. * On May 17, 2013, Sanofi has announced that the pivotal study, JAKARTA, examining the selective JAK2 inhibitor SAR302503 for myelofibrosis (MF), met its primary endpoint in both dose groups. The primary endpoint assessed the proportion of patients achieving >35% reduction of spleen volume. Consistent with data reported in previous trials, the most common adverse events were anemia, diarrhea, nausea and vomiting. Full results will be presented at an upcoming medical congress. 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.
