Approved Therapies for Myelofibrosis
A comprehensive overview of ruxolitinib, fedratinib, and pacritinib, the approved therapies for the treatment of myelofibrosis.
Transcript:
Aaron Gerds, MD, MS: The first medication approved for the treatment of myelofibrosis and the first JAK [Janus kinase] inhibitor approved for myelofibrosis is a drug called ruxolitinib [Jakafi]. Ruxolitinib is a JAK1/JAK2 inhibitor. Its approval was based on the COMFORT-I and COMFORT-II studies. These were prospective randomized trials pitting ruxolitinib vs placebo or best available therapy. Ultimately, ruxolitinib showed in the primary analysis to reduce spleen size significantly as well as improved symptom burden. I think a key point here is ruxolitinib really paved the way for regulatory approval of agents on improving these more patient-reported or quality-of-life type end points. Survival was not an end point that led to the approval of this drug, which I think is a key piece. Other therapies and even in other disease states have taken a cue from this and incorporated patient-reported outcomes and quality-of-life metrics in their efforts to get drugs approved.
However, further follow-up of ruxolitinib—there’s a pooled long-term analysis of the COMFORT-I and COMFORT-II studies—did show a survival advantage for patients who were randomized to ruxolitinib over best available therapy or placebo. This is despite a crossover effect that was seen in these studies because crossover was allowed. Moreover, since its approval in 2011, we see that outcome for patients diagnosed with myelofibrosis has improved. Survival has effectively doubled since the approval of ruxolitinib in 2011 for patients diagnosed and treated for myelofibrosis here in the United States. Certainly, an incredibly important moment for the treatment and care of patients with MPN [myeloproliferative neoplasm] was the approval of ruxolitinib for myelofibrosis.
The second JAK inhibitor approved for the treatment of myelofibrosis is a drug called fedratinib [Inrebic]. This was approved in 2019. The fedratinib story is a little bit longer than ruxolitinib and a little less straightforward. The JAKARTA studies served as the basis for approval for fedratinib and were actually contemporaries to the COMFORT studies that led to the approval of ruxolitinib. However, a clinical hold was placed on fedratinib during its development over the concern of Wernicke’s encephalopathy. A deep dive into the few patients that reported having encephalopathy on these clinical trials showed that 1 patient truly did have Wernicke’s encephalopathy and the others were less likely to have had Wernicke’s encephalopathy.
Ultimately, this combined with the data that showed that fedratinib does not inhibit thymine uptake allowed fedratinib to continue into development. Of course, on the package insert, there is a warning about encephalopathy and an advisory to check thymine levels in patients who are about to start and who are on treatment with fedratinib. Nonetheless, the JAKARTA and the JAKARTA2 studies were pivotal in the approval process for fedratinib.
JAKARTA was a prospective trial randomizing patients between fedratinib and best available therapy. In that study, patients were not previously treated with a JAK inhibitor, so in the upfront setting. Ultimately, fedratinib showed that it could reduce spleen sizes and improve symptom burdens on par or maybe slightly even better than ruxolitinib. I think the JAKARTA2 study is the more important study of the 2. JAKARTA2 was in patients who had previously received ruxolitinib or JAK inhibitors and then went on to fedratinib, showing that even in previously exposed patients, patients who’ve already had a JAK inhibitor, you can see a significant number of spleen volume and symptom burden responses. Fedratinib differs from ruxolitinib in a couple of different ways. Fedratinib is primarily a JAK2 inhibitor as opposed to a JAK1/JAK2 inhibitor. It also has some direct inhibition of the JAK2 V617F protein. It also has an effect on FUT3 [fucosyltransferase 3], and like all FUT3 inhibitors, it does lead to some GI [gastrointestinal] toxicity, namely nausea and diarrhea, which need to be preemptive when starting treatment. Ultimately, it was a welcomed addition to the armamentarium in treating patients with myelofibrosis.
The third, and most recently approved, JAK inhibitor for myelofibrosis is pacritinib [Vonjo]. This was based largely on the PERSIST-2 trial, where patients who were previously treated with JAK inhibitors, who were thrombocytopenic, meaning they had platelet counts less than 100,000, were randomized between pacritinib and best available therapy. Most often, the best available therapy in this study was low-dose ruxolitinib. There’s an additional study called the PAC203 study, which was a randomized dose-finding study that was also done. This study was done because there was also a clinical hold put on the development of pacritinib over concern of increased risk of bleeding and cardiac events. We now know that major adverse cardiac events are a class effect. We see them with ruxolitinib and fedratinib and other JAK inhibitors as well, and even in JAK inhibitors used to treat other indications, like rheumatologic disorders. So, certainly, something to keep in mind when using JAK inhibitors in the clinic.
Bleeding events, of course, were seen in these patients because they were thrombocytopenic. Upon going back and reviewing the data from the PERSIST studies as well as the data from the PAC203 studies, it seems that most of the bleeding events were not due to therapy, but mostly because of the patient population evaluated in these studies. Nonetheless, pacritinib was approved largely based on the PERSIST-2 study and was approved for patients with platelet counts less than 50,000 as well as patients who had prior JAK inhibitors. It’s often used in that manner. Really kind of focusing on this whole cytopenic myelofibrosis idea. The reason that pacritinib is different and maybe more effective in this population is that it is, like fedratinib, a JAK2 inhibitor with some effect on FUT3 but also hits IRAK [interleukin-1 receptor-associated kinase] which is another molecule we think is important in the pathogenesis of cytopenic myelofibrosis.
The really exciting update at the ASH [American Society of Hematology] annual meeting in 2022 was the discovery or the rediscovery that pacritinib also inhibits ACVR1, which is a master regulator of hepcidin. We know that hepcidin is important in iron regulation in the body and is often elevating patients with anemia as a result of inflammation or anemia of chronic disease, or anemia inflammatory block is what it’s also called. By attacking this hepcidin pathway here, we can often see improvements in anemia. Reanalysis of the PERSIST-2 data showed that yes, a significant number of patients had improvement in their anemia and transfusion dependency in PERSIST-2 and that largely…to inhibition of ACVR1. It seems like pacritinib is an excellent ACVR1 inhibitor, and there are more efforts looking into how pacritinib can actually not only treat the myelofibrosis symptoms and spleen size but also improve anemia.
Transcript edited for clarity.
