Polycythemia Vera: Novel JAK Inhibitors

Transcript:

Harry P. Erba, MD, PhD: Let’s turn to the last segment, and that’s what’s coming. Fortunately, on this panel, we have key investigators on these clinical trials. I want to jump right into it, but let’s start with you, Jamile. Why do we need new therapies? Why is it important to find these alternatives?

Jamile M. Shammo, MD, FASCP, FACP: I think that for 1 thing, it’s important to have options. Ruxolitinib is a good option for people who have myelofibrosis, but a lot of my patients are actually somewhat resistant to starting on the only available drug for the treatment of myelofibrosis because they feel like they’re getting to the end of the line. It must be anxiety provoking for them to feel that way. I really think we owe it to our patients to be able to have alternatives for the treatment of this very difficult disease.

Harry P. Erba, MD, PhD: Let’s get into some of these agents that are hitting the news right now. We’ll start with fedratinib for myelofibrosis. Srdan, would you tell us about the JAKARTA-2 trial?

Srdan Verstovsek, MD, PhD: We mentioned many times that the underlying problem is hyperactivity of the JAK/STAT pathway. We also said that there are other mutations—somatic mutations—that contribute to aggressiveness of the disease, and obviously the most of that is in myelofibrosis. Now, hitting the JAK/STAT pathway with ruxolitinib in the frontline setting for the great majority of patients would lead to improvement in quality of life and splenomegaly, but it does not work forever. It works for some time. In studies, on average, it’s about 3 years, and the longer you follow patients, [the] more and more you see progressive loss of that benefit. Spleen issues [come] back, symptoms come back, and anemia may develop. The patients are in need of something else, perhaps a different JAK inhibitor.

Fedratinib is a JAK2 inhibitor. It does not touch much of JAK1, it’s a little bit qualitatively different. It does touch on the FLT3 mutation. It may have a different activity profile and a little bit different toxicity profile, as well. The drugs are in the same class, ruxolitinib and fedratinib, but they are different. Fedratinib was studied. JAKARTA-2, the study you mentioned, is the study in patients who were previously exposed to ruxolitinib. In that setting, fedratinib was very active. More than half of the patients had significant decrease in spleen, measuring 35% by volume, and improvement in quality of life. This tackles what we now consider the primary objective of our efforts and an area of unmet need. Life after ruxolitinib is not good, and it’s short. People suffer, with no good quality of life. We need another medication. Fedratinib is leading the pack with these promising, very exciting results from the JAKARTA-2 trial.

Harry P. Erba, MD, PhD: Was there a clinical hold on that drug at one point?

Srdan Verstovsek, MD, PhD: There was because of [Wernicke] encephalopathy, a central nervous system toxicity that was ascribed to interference or uptake of thiamine with fedratinib from the gut, which may or may not be the case. The 8 cases out of about 800 patients [who] experienced that were scrutinized recently, and it does not appear that this is such a clinical problem that requires us to forget that drug. Quite contrarily, the drug has been renewed, and we are looking forward to further testing and perhaps, in the near future, approval of this drug in either the frontline or second-line setting.

Harry P. Erba, MD, PhD: Along those lines, you presented on pacritinib last year or so?

Ruben A. Mesa, MD, FACP: Correct, here at this ASCO [American Society of Clinical Oncology] meeting. Pacritinib, similarly, is an active JAK inhibitor. It’s an agent with a differentiation we sought to be able to use in individuals with marked thrombocytopenia. It’s an agent that similarly had gone on a clinical hold but that subsequently was resolved.

Harry P. Erba, MD, PhD: It was cardiac issues?

Ruben A. Mesa, MD, FACP: There were concerns. Individuals were allowed to be enrolled even if they had marked thrombocytopenia, so it included a lot of people who had pretty advanced disease. Because of that, there was an increased risk of hemorrhage and some cardiac events. Over time, it seemed we learned a few things. One: There was probably advanced patient selection influencing these adverse events. Patients were very advanced when they went into the study, so they had higher risk. Two: There were probably dosing opportunities regarding the safety of the drug, and that was in part borne out by the study that Srdan led, the PERSIST-2 study, for individuals with a platelet count under 100,000. Certainly, there is an ongoing study seeking to complete accrual soon—the PAC203 study—that is delving into deeper detail, trying to find the minimally effective dose, and trying to inform us of the entire data package, if you would, on what a pacritinib indication in myelofibrosis could look like.

Harry P. Erba, MD, PhD: So, JAK2 inhibitors are still being developed here in myelofibrosis.

Transcript Edited for Clarity