Therapy in Myelofibrosis: Pacritinib

EP: 1.Overview on Essential Thrombocythemia and Polycythemia Vera Management

EP: 2.Role of Symptom Burden in Thrombocythemia and Polycythemia Vera

EP: 3.Novel Therapy in Myelofibrosis: Momelotinib

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EP: 4.Therapy in Myelofibrosis: Pacritinib

EP: 5.Myelofibrosis: Nuancing the Potential of Disease Modification

EP: 6.Therapy in Myelofibrosis: Fedratinib and Ruxolitinib Strategies

EP: 7.What is the Role of Transplant in Managing Patients With Myelofibrosis?

EP: 8.Myeloproliferative Neoplasms: Targeting CALR With Novel Therapy

EP: 9.An Expanding Armamentarium in MPNs: Therapeutic Strategies Under Investigation

EP: 10.Sequencing and Managing Combination Therapy in Myeloproliferative Neoplasms

EP: 11.Myeloproliferative Neoplasm Management: Future Directions in Care

Transcript:

Naveen Pemmaraju, MD: We heard about momelotinib from Ruben and now I want to turn to another exciting JAK [Janus kinase] inhibitor, our third and our latest JAK inhibitor approval, pacritinib. I’m going to bring in both John and Stephen. John, with your leadership, congratulations to you and your team bringing this novel agent to FDA approval. I’d like to ask you to give us the background in history and the overview of pacritinib, how it got to approval, and then I’m going to ask Stephen to update on his exciting novel finding at ASH [2022 American Society of Hematology Annual Meeting & Exposition]. John, go ahead.

John Mascarenhas, MD: Pacritinib is a selective JAK2 inhibitor. It spares JAK1, so that makes it fundamentally different than ruxolitinib, and more like fedratinib in that way. It’s also a FLT3 inhibitor, so it’s like fedratinib. It uniquely also targets IRAC 1, IL-1, receptor-associated kinase-1, and this is an important player in a certain pathway that ultimately activates NF-κB. Stephen will talk about the importance of NF-κB, its overexpression, and its contribution to the inflammatory process. It was recognized early in the development of pacritinib that it’s also less myelosuppressive than the other JAK inhibitors. Its development started to move toward patients with low blood counts, and the PERSIST-2 trial [NCT02055781] was a pivotal study for patients who may or may not have [received] ruxolitinib previously. By definition, they had to have this cytopenic myelofibrosis phenotype, and they had to have the platelet count less than 100,000. This is distinctly different than the COMFORT studies in which they had to have platelet count greater than 100,000. They were [randomly assigned] to 3 arms, pacritinib 400 [mg] once a day, 200 [mg] twice daily, or BAT [best available therapy], which could also include ruxolitinib. You could have [received] ruxolitinib previously, you could get ruxolitinib as a BAT option, and [approximately] half the patients [received] it as a BAT. It’s an interesting study because it gave us information both as JAK inhibitor–naïve but also pretreated patients, and it gave us some comparison because ruxolitinib was in that control arm. The primary end point was quite stringent for a phase 3 study [such as] this: it was a coprimary end point of spleen volume reduction and symptom improvement at week 24. To get to the meat of the matter, if you look at the 200 mg twice daily arm, that was the winning arm in which you had superiority of spleen volume response, symptom improvement, and that beat out BAT. That became the approved dose as of March [2022]. What we see with the drug is there’s some gastrointestinal toxicity. It’s low grade, easy to manage, and rarely leads to discontinuation, and there was not a signal of cardiovascular toxicity, which was an initial concern from the FDA. Perhaps some increased bleeding risk, which is an interesting topic, which we see in other JAK inhibitors too. It’s not always clear what mediates that. These are very ill patients in a very vast disease, heavily pretreated in many cases, with low platelet [count that is the] hallmark of this advanced patient population. A new option as of March, particularly for patients with low platelets, and the label indicates less than 50,000 [platelet count] irrespective of line of therapy. I’ll turn this over to Steve because I think the story evolves with a focus towards anemia.

Stephen Oh, MD, PhD: As John pointed out, the approval for pacritinib, for first line use at least, is for a patient specifically with platelet count less than 50,000, but the updated and new analysis that we represented this year at ASH calls attention to the potential for pacritinib to provide anemia benefit. This has actually been identified in the original analysis from the PERSIST-2 study that there was clinical improvement in hemoglobin in patients treated with pacritinib 200 mg, twice daily from the PERSIST-2 study. It had not been fully examined in terms of the clinical response as it pertains to anemia benefit, and additionally, understanding the mechanism by which pacritinib could potentially drive anemia benefit had not been explored. There have been recent studies highlighting the role of ACVR1 as a key regulator of hepcidin production, which controls iron homeostasis, and therefore impacts the anemia of inflammation in myelofibrosis. It was logical to see that pacritinib inhibited ACVR1. When that was examined using in vitro kinase assays, pacritinib potently inhibited ACVR1 activity, and the experiments that were done looked more potent than any other JAK inhibitor against ACVR1. Furthermore, using exposure modeling with the 200-mg, twice daily, FDA-approved dose of pacritinib, it suggests that there may be sustained inhibition of ACVR1, essentially all times, in patients who are taking this drug. That is different than momelotinib, which also inhibits ACVR1, but based on that exposure modeling analysis you might not get that sustained potent inhibition of ACVR1. That’s ACVR1, but you want to show that this translates to an actual impact on hepcidin. We were focused on connecting the dots, and we first started by looking downstream of ACVR1 and at SMADs that are downstream of ACVR1, and conclusively demonstrated that pacritinib inhibits downstream signaling through the SMADs in terms of SMAD phosphorylation in liver cells, [because] the liver is the source of hepcidin. Those are the relevant cell types. We did that and then looked specifically at hepcidin production, hepcidin gene expression, and in response of stimulation of BMP6, which would activate signaling through ACVR1. Pracritinib also suppressed hepcidin gene expression; in fact, even lower than the control cells in which they weren’t even stimulated with BMP6. Clearly, pacritnib potently suppresses ACVR1 signaling to then translate to the reduction of hepcidin.

And you want to know that this mechanistic new information connects back to the clinical data of course. To understand that, we went back and looked at the PERSIST-2 data, specifically in those patients who are receiving the 200-mg twice-daily dose, which we use in practice, and looking at those patients who are not transfusion independent at baseline to see if they eventually converted to transfusion independence. We did that and compared it [with] the patients in the BAT arm, and there was a stark difference in terms of patients who achieved TI [therapeutic index] with pacritinib 200 mg twice daily versus BAT. It’s important to note that patients in the BAT arm, a substantial percentage, received other erythroid support agents such as danazol, iMeds, steroids, and such. These agents were not allowed in the pacritinib arm. In that sense you’re almost stacking the deck against pacritinib. So it’s quite clear there is some degree of anemia benefit for patients in the study. It connects to the mechanism. It also comes back to inflammation even more broadly with IRAK1 being a target of pacritinib and downstream signaling through NF-κB. We know that inflammation, JAK STAT signaling, these things all contribute to inflammation; they contribute to the anemia or inflammation. It makes sense that you have a drug that targets all these pathways so that it can potentially provide immediate benefit.

Transcript edited for clarity.