Pacritinib May Possess the Potential to Address Unmet Needs in Myelofibrosis

Partner | Cancer Centers | <b>Cleveland Clinic</b>

For patients with myelofibrosis who have platelets counts of less than 50,000, pacritinib represents a potential therapeutic option that can fill a need that has been unmet with other approved JAK inhibitors, such as ruxolitinib and fedratinib.

For patients with myelofibrosis who have platelets counts of less than 50,000, pacritinib represents a potential therapeutic option that can fill a need that has been unmet with other approved JAK inhibitors, such as ruxolitinib (Jakafi) and fedratinib (Inrebic), according to Aaron Gerds, MD.

“The need that is met with pacritinib for patients with myelofibrosis is [a subset of patients who have disease] that is myelodepletive or cytopenic. If we look at the FDA label for ruxolitinib or fedratinib, there is no guidance on how to dose these medications in patients with platelet counts of less than 50,000,” Gerds said. “Certainly, these patients have myelofibrosis, and they need JAK inhibition treatment to help make them not only feel better, but potentially even live longer, in some instances. That is really the population in need.”

In an interview with OncLive®, Gerds, an associate professor of medicine, deputy director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute, and medical director of the Case Comprehensive Cancer Center Clinical Research Office, highlighted the differences between pacritinib and other JAK inhibitors approved for the treatment of patients with myelofibrosis, described the safety profile of the agent, and the clinical significance of a potential FDA approval for this population.

OncLive®: What is the mechanism of action of pacritinib? What sets this agent apart from other options in the myelofibrosis paradigm?

Gerds: Currently, we already have 2 JAK inhibitors that are FDA approved for the treatment of [patients with myelofibrosis: ruxolitinib and fedratinib. Both [agents target] JAK2, as does pacritinib, but [we must also look at how] intensely they [target] JAK1, as well as other molecules that are not even in the JAK/STAT family. For example, ruxolitinib is a JAK1/JAK2 inhibitor, and we [consider] fedratinib [to be] more of a JAK2/FLT3 inhibitor. Pacritinib is a JAK2/IRAK-1 inhibitor, and it [hits] different molecules to varying degrees.

Within the JAK/STAT family, there is JAK1, JAK2, and JAK3, as well as some additional molecules they can dimerize with, but we [must] think about these different JAK inhibitors and how they [target] the different JAK molecules. Another JAK inhibitor is approved for the treatment of [patient with] rheumatoid arthritis; it [targets] JAK3, but [also] has some impact on JAK1 and JAK2. Again, this is a big family, [with] different inhibitors that all influence these different molecules, and thus, the downstream pathways, in varying ways.

You will probably ask, if we already have 2 JAK inhibitors that are FDA approved, why do we need a third? Well, these differences in the pathways they [target], even though they are all JAK inhibitors, influence differences we see in treatment responses and the potential populations [in whom] we apply these medicines. Pacritinib is particularly effective in bone marrow–depletive, cytopenic myelofibrosis, where patients on presentation, or at the time they need treatment, have a low platelet count, or are potentially also anemic with a low red cell count. We know from a collection of trials done—mainly the phase 3 PERSIST-1 [NCT01773187], the phase 3 PERSIST-2 [NCT02055781], and the phase 2 PAC203 trial—that we can safely administer JAK inhibition to these patients who have very low platelet counts.

On the flip side, when we look at ruxolitinib, we know that [agent] causes thrombocytopenia. we know it makes the platelet counts come down, and we also know it causes anemia. In patients with platelet counts of less than 50,000, there is no guidance on the label for ruxolitinib. Similarly, there is no guidance with fedratinib on the FDA label for treating patients with [platelet counts of] less than 50,000. As such, [this is] certainly a population in need [and] pacritinib addresses [this].

Studies have looked at low-dose JAK inhibitors for patients with platelet counts of less than 50,000. With ruxolitinib, 2 published studies looked at doses starting as low as 5 mg every day or 5 mg every other day, and slowly working up. However, it really seems to be a dose–response curve. The lower the dose of JAK inhibitor—in this case of these studies, ruxolitinib—the less likely there is to be significant reductions in symptom burden and spleen size. With pacritinib, we can deliver the full dose, the 200-mg twice daily dose of JAK inhibition, safely in patients with platelet counts of less than 50,000.

Although it is still early in terms of the phase 3 PACIFICA trial (NCT03165734), what does this research bring to the landscape?

The definitive study right now that is ongoing is PACIFICA; this is a randomized, controlled study that compared pacritinib with best available therapy in patients with platelet counts of less than 50,000 and minimal prior JAK inhibition, either ruxolitinib or fedratinib. Although that study is ongoing, we do have a wealth of information about patients with myelofibrosis treated with pacritinib from the PERSIST-1, PERSIST-2, and PAC203 studies.

Several subsequent analyses have been done with those databases to look specifically at that population of patients with platelet counts of less than 50,000. These predecessor studies included a variation of patients, whether they were really JAK inhibitor naïve or heavily pretreated, or had platelet counts of less than 50,000, greater than 50,000, or even greater than 100,000.

It is kind of hard to say, based on these studies for that specific population, what the results may be. [However,] if you pool all that data together with the patients who were treated on these trials, comparing with best available therapies, or even in a single-arm phase 2 fashion, we can get some clear answers on what we would expect from PACIFICA.

When looking across all these previous studies, patients with platelet counts of less than 50,000 who were treated with pacritinib at the recommended dose from the PAC203 study with 200 mg twice daily, we saw a response rate of approximately 25%; [this means] a significant reduction in spleen size and symptom burden. Again, [these patients] do not really have an FDA-directed therapy, per se. There is no guidance for how to dose those patients with ruxolitinib or fedratinib based on the label, so that would certainly show that there is efficacy in that population, addressing a dire need.

What does the safety profile of pacritinib look like?

Pacritinib has had a long and storied history. During the PERSIST program, shortly after the completion of PERSIST-1, and during the enrollment and follow-up of PERSIST-2, a hold was placed on the development of pacritinib by the regulatory authorities. This was done over a concern of increased risk of bleeding events and cardiac events that they were seeing in the preliminary data that they received.

During that hold, all the data collected on PERSIST [up to that point] were pooled together and submitted to the regulatory authorities, and it turns out, there did not seem to be any increased risk of bleeding or cardiac events with pacritinib compared with other therapies. We know that this is a very sick population. We know that this is a population with low platelet counts and they tend to bleed, independent of what treatment they are receiving. [After] going back through that data more carefully, that concern over cardiac and bleeding events was certainly lessened, and the drug was allowed to resume trials, and continue to move toward getting out there for all patients.

The key piece that was put into place after that hold was what was done in the PAC203 study: Looking closely at a patient's heart history [by using] electrocardiograms [EKG] and echocardiograms prior to going on study, and monitoring throughout treatment. That study really focused on looking at bleeding risk [of patients] coming onto the trial, and monitoring for bleeding going forward. Even in the prescreening period, we noticed that, again, this is a very sick population with very low platelet counts, so we did see a fair number of cardiac and bleeding events that happened even before the patient received the drug on the PAC203 study.

The important thing is [the need for] more intensive monitoring to lessen the likelihood that any of those events happening once on treatment. As pacritinib moves forward, we must consider [all of this]. If you have a patient in front of you, for whom you were thinking about using pacritinib in, you want to [consider] what the patient's heart history is. Do you need to get an EKG, or an echocardiogram, to ensure we have everything sorted out regarding their cardiac history? What is their bleeding history? We want to monitor [those things] more closely going forward.

What would an FDA approval for pacritinib mean for this patient population?

For any patient with myelofibrosis, an FDA approval is a big deal. It was not too long ago that no FDA-approved medications [were available] for myelofibrosis. Then, along came ruxolitinib, and just a couple years ago, we had fedratinib approved. Having 2 drugs [emerge] over the past decade is a big deal for this patient population.

In a clinical practice, we often reach for clinical trials because there are not that many lines of therapy [for our patients]. We are often very jealous of our colleagues in multiple myeloma or breast cancer, [where] it seems [that they have] endless lines of therapies for their patients. Any addition to our armamentarium is welcome—particularly for this patient population.

As I mentioned before, there is no clear guidance on how to dose and go about treating patients who have myelodepletive or cytopenic myelofibrosis. There is a dose–response curve with JAK inhibition, so the ability to deliver full-dose JAK inhibitor therapy to these patients could really improve lives.