Pacritinib and the Practical Implications

Transcript:

John Mascarenhas, MD: The PERSIST program was evaluating pacritinib, which is a JAK2 FLT3, IRAK1 inhibitor. PERSIST-1 was a study evaluating pacritinib versus best available therapy in patients who were JAK inhibitor naïve. And in that case, best available therapy excluded ruxolitinib. And I have to mention, in PERSIST-1 there was no baseline platelet count. You could have a low platelet count; you could have a high platelet count. In PERSIST-2 it really focused in on a very sick patient population. These were patients who had low platelet to baseline, so less than 100,000, and could have seen ruxolitinib or any JAK inhibitor previously, in which 50% of them did. And they were randomized to 2 doses, pacritinib at 200 mg twice daily, or pacritinib 400 mg once daily, versus best available therapy, which could then include, again, ruxolitinib.

So PERSIST-2, it’s an unusual study. Patients could have seen ruxolitinib previously. They could be randomized to ruxolitinib, and the co-primary endpoint of that study was spleen volume reduction and symptom improvement.

Ruben Mesa, MD, FACP: From the PERSIST-1 study we had included individuals with very advanced myelofibrosis because of the marked thrombocytopenia. There was a period of a clinical hold on the drug that the FDA had instituted due to concerns regarding some mortality that occurred on the study. Subsequent data from the PERSIST-1 study and the PERSIST-2 study helped to demonstrate that that probably was a reflection of adverse patient selection rather than necessarily toxicity from the drug.

In the PERSIST-2 study, there appeared to be superiority of a lower dose of the drug administered twice a day versus a higher dose of the drug administered once a day. So there was a pharmacokinetic benefit in terms of efficacy and safety for a split dose. So they are currently completing accrual, the PAC203 study, trying to further refine this minimally effective dose and the safety profile to lead potentially to a more formal indication.

John Mascarenhas, MD: Pacritinib, again, is a JAK2 inhibitor, but it’s also a FLT3 inhibitor and IRAK1 inhibitor, and a CSF1 receptor inhibitor, too. So none of these drugs are truly specific for JAK2. And I think that’s the most important point, specifically for a clinician who’s trying to understand why these drugs would be different and how they could offer clinical improvement where maybe another drug cannot. It really boils down to the fact that although they’re all JAK2 inhibitors, they share differences in targets too. And again that probably explains why there’s differences in toxicity, but also probably explains why 1 drug may be more effective and may be more beneficial either in lieu of or in sequence to another drug.

You know all 3 of them are targeted in the sense that they’re JAK2 inhibitors. But all 3 of them also have a specificity for other receptors as well. One of the things that I think we as a research community have to keep in mind is we often think that targeted is the way to go. We need a super-selective targeted agent. Where in reality we sometimes stumble upon a fact that having a dirty agent that can affect multiple pathways can actually be more beneficial because the reality is that these diseases are not so simple. They’re complex and multiple pathways are activated. So it’s not always true that the super selectivity of a targeted agent will necessarily make it better than a drug that has a multikinase inhibition profile.

I think if pacritinib was commercially available, the place I could see it fitting into the treatment algorithm would be first-line therapy in patients with platelet counts less than 50,000, which is an unmet need that ruxolitinib cannot fill. To me that’s the most obvious, and that’s probably about 10% to 15% of patients up front. I think pacritinib could also fit the need second-line for patients who develop significant thrombocytopenia on ruxolitinib, or even in that matter, for patients who have significant anemia on ruxolitinib.

Ruben Mesa, MD, FACP: Pacritinib will most clearly be indicated in individuals with marked thrombocytopenia with myelofibrosis. In particular, those with a platelet count of under 50,000, for which ruxolitinib is currently not indicated. Now the benefits may well extend beyond that group for other individuals with more advanced disease. Further data, as they relate to the analysis of molecular mutations’ differential effect I think will come at play.

If pacritinib were the next agent approved, I think we would be considering its use in 2 groups. One, potentially as up-front therapy in individuals with marked thrombocytopenia, and second, potentially a second-line therapy in individuals that have failed ruxolitinib.

John Mascarenhas, MD: So luspatercept is a very interesting drug. This is a drug that’s really geared at addressing anemia. It’s not a drug intended to improve spleen or symptoms. Its mechanism of action is novel. For example, for many years hematologists in both the treatment of myelodysplastic syndrome and myelofibrosis have used drugs called erythropoiesis-stimulating agents, ESAs. These are drugs that essentially mimic the hormone erythropoietin and try to stimulate the bone marrow to make red cells.

Luspatercept is an example of an EMA an erythropoiesis maturation agent. And this is a drug that is a ligand trap. So it’s a receptor for active in receptor 2 ligands that’s conjugated to an immunoglobulin, and essentially blocks the interaction of activins, which are TGF [transforming growth factor]-beta superfamily members, with their receptor. And by doing so downregulate SMAD signaling, which ultimately leads to the double negative of removing repression of erythropoiesis. So it allows for erythrocytes to mature.