Trial of JAK Inhibitor Fedratinib For Blood Cancer Discontinued

Dr. Ayalew Tefferi, M.D.Department of Medicine, Mayo Clinic Rochester, Minnesota Interview with:
Dr. Ayalew Tefferi, M.D.
Department of Medicine,
Mayo Clinic
Rochester, Minnesota

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Tefferi: William Vainchenker discovered and reported an activating JAK2 mutation (JAK2V617F) in myelofibrosis and related myeloproliferative neoplasms in 2005 (Nature. 2005;434:1144-1148). This seminal observation led to the recognition of activated JAK-STAT as the potential disease-driving pathway in myeloproliferative neoplasms and development of several JAK inhibitors, including fedratinib, ruxolitinib and momelotinib, for treatment of myelofibrosis. In phase 2 studies, these JAK inhibitors showed similar activity in alleviating constitutional symptoms and reducing spleen size. However, none of them were able to induce complete or partial remissions or reversal of bone marrow fibrosis or significant lowering of JAK2 mutant allele burden. A subsequent phase 3 study provided the information required for FDA approval of ruxolitinib and the current phase 3 study was meant to do the same for fedratinib.

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Tefferi: The study was positive in terms of the activity of fedratinib in reducing spleen size and alleviating constitutional symptoms. A little more than one-third of the study patients experienced a spleen response defined by MRI or CT documented decrease in spleen volume of over 35% and a similar proportion achieved symptoms relief defined by 50% or more reduction in total symptom score, at both dose levels of 400 and 500 mg daily. These outcome results were significantly better than those seen in patients receiving placebo. Adverse events previously noted in phase 2 studies, including anemia, gastrointestinal symptoms, liver and pancreatic enzyme abnormalities, were also seen in the phase 3 study. However, an unexpected and serious neurotoxicity, clinically consistent with Wernicke encephalopathy, was also seen in 4 women receiving the drug at the higher dose level of 500 mg daily. This led to a unilateral decision from the sponsor to discontinue further development of the drug.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Tefferi: The value and limitations of JAK inhibitors in myeloproliferative neoplasms are now clear; they are capable of alleviating symptoms and reducing spleen size in about a third of patients but this activity is not durable (average duration of response is one to two years) and the drugs have not shown convincing evidence of disease-modifying activity. It is unlikely that additional JAK inhibitors (e.g. momelotinib) are going to do any better in the latter regard but might provide a better toxicity profile in some (e.g. anemia) but not in other (e.g. peripheral neuropathy) regard. There continues to be unmet need for patients with myelofibrosis and other myeloproliferative neoplasms in terms of disease-modifying drugs and patients might be best served by participating in clinical trials with drugs that might be capable of achieving this important goal.


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Dr. Ayalew Tefferi, M.D.Department of Medicine,, Mayo Clinic, & Rochester, Minnesota (2015). Trial of JAK Inhibitor Fedratinib For Blood Cancer Discontinued