John Mascarenhas, MD: Ruxolitinib is a JAK1/2 selective inhibitor. So it’s equally potent against JAK1 and JAK2, whereas fedratinib is really a selective JAK2 inhibitor. In addition, it’s known to have FLT3 and BRD4 inhibition as well. And it’s these nuances in the other signaling pathways that are inhibited, which likely explain differences in toxicity profile but perhaps also explain some of the differences in efficacy that can be seen.
Ruben Mesa, MD, FACP: Fedratinib is not a JAK1 inhibitor, so that is a separation. They have differential effects on JAK2, and of course they have different impact potentially on other kinases that may be involved with the course of the disease. In the conduct of the studies there was certainly a discussion whether fedratinib had a greater impact on bone marrow fibrosis or aspects of a disease like that. Further validation of those differences I think are ongoing.
Fedratinib is clearly quite active both in the frontline and second-line setting. And the treatment algorithm will very much depend on what the landscape is at that moment of course. Without question, if fedratinib were the next approved agent in patients with myelofibrosis, that would include individuals that really have a suboptimal response to ruxolitinib, individuals in which the spleen has remained enlarged, to there was benefit, but they’ve lost a benefit. They have residual symptoms. There may be some differential effect potentially on cytopenias. We are now looking at the correlative data that were not available at the time of the conduct of this study as it relates to the mutation profile. Without question we are having greater granularity as to the impact of additional mutations on response. ASXL1, splices mutation and others. If there is a mutation-driven consideration of the utilization of these therapies, we are not there yet, but I think that it will be an additional important part.
Ruxolitinib and fedratinib are 2 different agents, and I think we will learn more over time how they might intersect.
Fedratinib is a very active JAK2 inhibitor that demonstrated significant activity in both the frontline setting as well as the second-line setting. The presence of a potentially rare toxicity in less than 1% of patients, I think we need to better understand. I think as we use any therapy that has potential toxicities, we need to be mindful of those toxicities. We may find that we may be able to abrogate that toxicity in the future as well. There was some suspicion that it was related to thiamine or thiamine metabolism, or adequate amounts of thiamine. So again things to be clarified in the subsequent clinical trial. But I have little doubt that there will be significant numbers of patients with myelofibrosis who will benefit from the use of fedratinib, and these final studies are meant to best be able to help inform that decision making as it relates to the utilization of the drug, as well as the optimal dose.
In the phase 3 study there were 2 dose arms that were utilized, 400 and 500 mg, and through that process I think a subsequent commercial use of the drug will have a very clarified dose in structure.