Targeting JAK2 in Myeloproliferative Neoplasms - Episode 10

Ongoing Studies and Combination Therapy in MPNs

Combination trials and new agents for MPNs, such as parsaclisib and momelotinib, are discussed in the context of recent ASCO presentations.

Srdan Verstovsek, MD:The development of new drugs is going in 2 ways, it looks like to me. Now that we approach the second-line setting—you obviously need more drugs in that setting—but you can also think about improving what we do in the frontline setting. There are 2 types of studies—the combination started from the very beginning, or combinations where you have patients on aJAKinhibitor with suboptimal response, and then there are the studies in the second-line setting once you say, “No more JAK inhibitors; let’s do something else.” It can be another JAK inhibitor, like fedratinib, but it can be something else.

Let’s talk a bit about the frontline combination studies. There are a number of studies here that are being done. To give a little overview, we have a combination between the ruxolitinib and BET inhibitor CPI-0610; we have a BCL-XL inhibitor, navitoclax; and a PI3 kinase inhibitor that all make sense biologically. I think biology is being understood so much more than in the past. We are moving from the hyperactivation of the JAK-STAT pathway. Yes, those are the basics, but then there are other factors here we are exploring. How do you see this evolving with all these possibilities?

Andrew Kuykendall, MD:It is exciting. I think, for a long time, after the successes of JAK inhibitors, we were lulled into thinking this is a simpler disease than it was. I think now we are understanding how complex the disease is and realizing that a multipronged approach is more likely to be beneficial, certainly in the salvage setting, but also up front. I think the increasing preclinical data are showing that you have upregulation of the JAK-STAT pathway, which certainly dominates the disease, but you also have parallel activation of other inflammatory pathways. If we can block multiple of those, then we are likely to provide more benefits up front and really suppress this disease, get more durable responses, and not just increase the percentage of patients responding but also bring about longer responses for those who are responding. I think what is exciting is all these, as you said, have a preclinical rationale. They have a biological rationale for why they may provide a benefit. I think they are all exciting and they have all shown good activity in the phase 2 setting to warrant further investigation.

Srdan Verstovsek, MD:At this ASCO [American Society of Clinical Oncology annual meeting 2021], one of these frontline studies was highlighted in the abstract session on myeloproliferative neoplasms. That is the combination of ruxolitinib with the PI3 kinase inhibitor parsaclisib, which biologically makes sense. We have some preliminary results where parsaclisib is added for people who are on ruxolitinib and do not have an optimal response. There are decent improvements in the spleen and symptoms. That is actually one of the phase 3 studies that is being devised from these preliminary results.

One phase 3 study is adding a PI3 kinase inhibitor on top of ruxolitinib for people who are already on it but do not have optimal response, and the other phase 3 study is focusing on people in the front line who are not yet treated with JAK inhibitors for whom you do a combination of the 2 versus ruxolitinib alone. We are trying to figure out which is the best way to combine the medications to enhance the overall response and perhaps also get that durability of response, which is paramount for extension of life. I think this search for the winning combination—but also in the winning population of patients—is the key, as is exemplified by the PI3 kinase inhibitor. Now, there are other drugs that are being tested in the second-line setting, and one of them is momelotinib, a JAK2 inhibitor, but it is quite different. Tell us a bit about momelotinib. What is this all about now, with anemia responses?

Andrew Kuykendall, MD:Yes, momelotinib is, at its forefront, a JAK2 inhibitor, so it has been looked at and had a challenging development process. I think from the SIMPLIFY 1 and SIMPLIFY 2 studies—these are phase 3 studies in the front line and also in the post-ruxolitinib setting—it seemed to show activity. It shows activity as far as spleen responses and symptom responses go, but for a variety of reasons it has not received regulatory approval yet. What it also has that is different is this ability to improve anemia parameters. Whether that is actually improvement in hemoglobin or fewer patients being transfusion dependent at the end of the trial compared to the comparator arm, it seems to have some benefit as far as hemoglobin improvements go that are not seen with other JAK inhibitors. Largely, this is attributed to inhibition of ACVR1, which provides some rationale as to why this might have this benefit. But I think realistically this is a huge deal for patients with myelofibrosis because, Srdan, as you mentioned earlier, this is one of the main problems we have run into with the current JAK inhibitors. We are dealing with anemia all the time, we are dose reducing people, we are taking people off, and we are transfusing people. This is a huge challenge, so the idea that we can have an agent that is relatively good at improving spleen size, symptom burden, and can improve or at least stabilize anemia is a huge game changer for many patients who struggle with that as one of their primary complaints.

Srdan Verstovsek, MD:I think this is fascinating because we are learning a lot about the JAK-STAT pathway and associated abnormalities with the PI3 kinase inhibitors. We are trying to enhance the spleen and quality of life. Combinations make sense; that hypothesis has been proven in the clinic already. We are looking at the phase 3 studies for the approval of parsaclisib, but here we are talking about a completely new mode of action that has nothing to do with the JAK-STAT pathway. It is not associated with that. It is really about the iron metabolism, high hepcidin—redistribution of iron within the body of the patients and allowing iron to be available for erythropoiesis through inhibition of the ALK2 receptor, basically. That is an additional benefit that was not talked about in the past and is opening the door for other, more specific drugs to target the hepcidin and the ALK receptors, and perhaps give us a new tool for counteracting anemia in the future, because anemia is a major problem, as we discussed.

One abstract about momelotinib’s past experience that was presented at ASCO caught my attention because we talk about prognostic factors in outcome of the patients, and now we have a retrospective review of what happened with momelotinib in the frontline study where it was compared to ruxolitinib. It did show influence on anemia, but it failed for other parameters—the quality of life—so overall the study failed. But for anemia benefits, it appears that, in this post-hoc analysis, people who had anemia benefits lived longer. That is quite interesting. The anemia is a bad prognostic factor, transfusions give you an extra bad point, and now, if you are improving anemia, the suggestion is you may be living longer. That is an alternative way of prolonging life, I would say.

Andrew Kuykendall, MD:Yes; I think it is an exciting abstract and good to see that result. I do not think it is particularly surprising, but I’m happy it is there, because I think we focus so much on spleen responses and symptom responses. We have said, “OK, we should really push through for patients who are on ruxolitinib, and they may develop some anemia.” We should push through, and the anemia that occurs when patients are treated with ruxolitinib is not really prognostic, so we can just go for a transfusion. It is a challenging sell to patients, I think, to say we are just going to push through this, but that is because we did not have many agents that could improve anemia consistently for patients with myelofibrosis.

Now, to have an agent that can do that, I think it is natural to say, “OK, now we know this can improve anemia, but we also have to prove that this improvement is relevant.” That is what this abstract shows, that those patients who did achieve transfusion independency, did have a prolonged rate of survival compared to those who did not. This says that, when you are evaluating a drug like momelotinib, the way to know it is benefitting a patient is not just if the patient has a spleen response or a symptom response, but a patient who can achieve anemia benefit has, potentially, survival benefits associated with that. That is really encouraging.

Srdan Verstovsek, MD:Momelotinib is being developed as a drug for the second-line setting, where many people have more issues with anemia or thrombocytopenia, and not as many, as you may think, with the spleen. You may have fedratinib there, and you may have momelotinib in the future, but I think we should say that, first and foremost, one needs to optimize the care in the frontline setting before switching. Just because you have an option in the second-line setting does not mean you should be giving up on the frontline setting. These combinations being studied, or just optimizing the dose and the mode of delivery of ruxolitinib itself, make a difference for the patients and for the durability of the benefit. Let’s focus on optimizing the front line and developing the combinations, and only then thinking about the switch. Why not delay the switch to the second line, and buy some time with the first line, then buy some time with the second line? Everybody will be, at the end, happy.

Transcript edited for clarity.