JAK2 and IRAK1 in Myelofibrosis - Episode 9
Drs Ruben Mesa and John Mascarenhas review therapies and drugs in development for the treatment of myelofibrosis as seen in the COMFORT, JAKARTA, MOMENTUM, PACIFICA, and PERSIST trials.
Ruben Mesa, MD: Before we delve a bit deeper into the pacritinib data set, the PERSIST studies, and the current PACIFICA study, we have 2 approved JAK inhibitors. Maybe I can share just a refresh for folks about the COMFORT study, and you could share a bit about the JAKARTA trials. But the COMFORT studies—now almost historic in nature, they’re 10 years past—were 2 studies of ruxolitinib vs placebo and ruxolitinib vs best-alternative therapy. That showed improvement in splenomegaly symptoms, and over time, as we’ve discussed, likely an improvement in survival in people with and without the JAK2 V617F mutation. It was a watershed moment that a drug could be developed successfully and an appropriate investment by a pharmaceutical company to invest that time, energy, and resource in doing so. It was about helping patients with myelofibrosis, which it clearly did, and then PV [polycythemia vera], but it also helped to show people that it was worthwhile developing drugs for these diseases. At the beginning of my career, there wasn’t an interest because these weren’t common diseases and there wasn’t a strong driver from PhRMA [Pharmaceutical Research and Manufacturers of America] to invest the resources needed to develop therapies in this. Now, remind folks about the JAKARTA story.
John Mascarenhas, MD: The JAKARTA studies involved fedratinib, which is a JAK2, FLT3 inhibitor. It’s a very selective JAK2; it spares JAK1. JAKARTA was a study of fedratinib 400-mg daily compared with placebo in patients who were JAK inhibitor naïve. That was a randomized phase 3 study. It showed very clearly that fedratinib was effective in achieving spleen in symptom improvement. JAKARTA2 was an open-label phase 2 study evaluating fedratinib after ruxolitinib exposure of at least 14 days. For those patients who either had a suboptimal response or failed ruxolitinib, they’d go on and get fedratinib. Ultimately 400-mg daily was the effective dose in that study. What that study showed, and you were involved in this, is that you can cycle JAK2 inhibitors. At least we know you can go from ruxolitinib if you’re not optimized on that drug; you can have effect. The SVR [splenic volume reduction] rate was 30% in a very rigorous analysis, and the symptom burden improvement was about 30% as well.
But many patients can achieve symptoms in spleen benefit even after being exposed to a prior JAK inhibitor. I thought that was a very important advance for the field in general, to understand that there’s still opportunity to exploit JAK inhibition even if patients have been previously exposed. Now we have fedratinib, approved in August 2019, with a label that would allow you to use it up front based on JAKARTA or second line as JAKARTA2. That’s great that we have these options. The reality is that there are 2 other drugs that are in late-stage testing. You’ve already mentioned momelotinib, in the MOMENTUM study. This is a phase 3 study in patients who’ve seen ruxolitinib previously and who continue to have symptoms in spleen burden and anemia, get randomized to momelotinib vs danazol. This is a drug we’ve used, and you and I have done studies previously to address anemia, with anemia response at about 30%. They have a primary end point in the MOMENTUM study of total symptom improvement, with key secondary end points of spleen symptom and anemia responses. As we’ve mentioned, it’s an interesting drug because it has a target that includes ACVR1, and that may underline the reason why our earlier studies have shown anemia responses that are somewhat particular to that drug. We’d welcome that to the armamentarium of treating patients.
The last drug that’s also in late phase 3 for another round of testing is pacritinib in the PACIFICA study. The PERSIST-1 and PERSIST-2 studies led the effort initially to demonstrate its efficacy. Ruben, you published the PERSIST-1 study, which included ruxolitinib-naïve patients who were randomized to pacritinib 400-mg daily vs best-available therapy, excluding a JAK inhibitor therapy. That was clearly a win for spleen and symptom burden with pacritinib and even a 25% transfusion independence rate with pacritinib. In PERSIST-2, which was a randomized phase 3 study in patients who have platelet counts less than 100,000 per mm3. That was an important study because, as you mentioned, it set the stage that it was the area that pacritinib could probably define as its own niche.
In that study at 200-mg twice daily for pacritinib, we saw symptoms in spleen benefit with mild myelosuppressive effects, which was complemented by PAC203, a random dose-finding study, which confirmed the safety and efficacy at 200-mg twice daily. We’re left with the PACIFICA study, which is the randomized phase 3 study in the very specific population of patients who are relatively JAK inhibitor naïve and have platelet counts less than 50,000 per mm3—this unmet need that we’ve highlighted already. We look forward to the readout on that, but 1 could envision a world in which multiple JAK inhibitors to benefit patients, whether it’s ruxolitinib or fedratinib, either up front or in the second line. For those patients who have anemia, you have momelotinib. For those patients with thrombocytopenia, I’d argue it’s not necessarily relegated to thrombocytopenia of less than 50,000 per mm3, but even patients who have less than 150,000 per mm3 platelets are probably appropriate patients for pacritinib. It gives us an opportunity to cover a lot of niches with inhibitors that could help aspects of the disease. In each case, as you’ve shown data, they likely improve survival.
Ruben Mesa, MD: Yes. We’ve learned quite a bit as we further refine these studies.
Transcript edited for clarity.