Advances in the Treatment of Myelofibrosis - Episode 9
Second-line therapies for myelofibrosis that are available or in the pipeline for use.
Srdan Verstovsek, MD, PhD: In the second-line setting, we have a number of agents that are being tested and then we have ruxolitinib that is being used in a segment setting as a JAK inhibitor. But we have momelotinib coming along which is a very interesting concept. Maybe, Raajit, you can tell us a little bit about momelotinib because it's completely out of the ordinary for JAK inhibitors to have different benefits than what you would expect.
Raajit K. Rampal, MD, PhD: Exactly. From the simplified trials, I think one of the striking things with that is there was an anemia benefit. And hereby we're describing anemia benefit by increases in hemoglobin and also changes in the proportion of patients who are getting transfused. But of course, we know with JAK inhibitors, anemia is a nontarget effect. What we think at least with momelotinib based on its mechanisms of action and hitting other pathways, ACR, and whatnot, we think that is probably the mechanism by which it is contributing to an anemia response. So what you begin to see, I think this is a profile of the JAK inhibitors and it's not so much a one-size-fit-all, ie, not all of our JAK inhibitors are the same thing. So I think we're jumping ahead into the future. I will leap into the future here. Where might we be? We may be able to better tune our JAK inhibitors.For our cytopenic patients, we've been talking about the pacritinib and the hopeful approval of that drug which clearly has a benefit for patients with cytopenias. And it doesn't require dose modification per platelet so that becomes a really important tool in the arsenal. Then coming to momelotinib, some patients may need something beyond just a drug for anemia. The patient who has symptomatic splenomegaly and who has anemia, who isn't going to benefit from single-agent daratumumab or other related drugs. Something like momelotinib obviously could have a nice fitin that patient. We could get spleen size reduction and we could potentially get an anemia benefit so we're beginning to see, I think on the horizon, niches for these different drugs that will greatly benefit the patients.
Srdan Verstovsek, MD, PhD: It looks like having diversified the activity. Not just going through inhibition of the JAK pathway but having some other activity on top of it. Like the anemia benefit through ALK2 inhibition with momelotinib may bring extra clinical benefits. What is the alternative pathway that the pacritinib effects in addition to the JAK's pathway?
John Mascarenhas, MD: I'm so glad you asked that, Srdan. Pacritinib is interesting. There are some differentiating factors with some of the JAK inhibitors now in late-stage testing. And hopefully, will be clinically and commercially, available. Pacritinib is one of these drugs that also inhibit IRAK1 [beyond JAK2 and in doing so likely affects a signaling pathway through the toll-like receptor, myosin complex, and then downstream to NF-κB [nuclear factor kappa light chain enhancer of activated B cells]. Raajit brought up earlier that it is also a major player in inflammatory cytokine expression. By hitting this alternative but relevant pathway in addition to JAK2 likely explains why this drug compared to, for example, perhaps ruxolitinib/infigratinib is less myelosuppressive. You can give it a full dose and enjoy symptom and spleen benefits with less myelosuppression. I think some of the differences that we're going to see or we're seeing with these JAK inhibitors are likely in part due to their kinome profile and some of the other targets that they hit.
Transcript edited for clarity.