Behind the FDA Approval: Pacritnib for Myelofibrosis and Severe Thrombocytopenia

John Mascarenhas, MD

Pacritinib, an oral macrocyclic selective JAK2, RAK1, and CSFIR inhibitor, was recently granted accelerated approval by the FDA for the treatment of patients with myelofibrosis and severe thrombocytopenia, defined as a platelet count less than 50x109/L. The agent provides a new treatment option in the frontline setting as well as the second-line setting for patients who do not benefit from other available JAK inhibitors.

“It'll give an option for treatment for patients upfront who are JAK inhibitor naive, particularly with low platelets, as well as an option in the second line for patients who are discontinuing ruxolitinib [Jakafi], particularly with cytopenia. It is a less myelosuppressive drug, and I think that's really the major benefit of this drug,” John Mascarenhas, MD, told Targeted Oncology™.

Findings from PERSIST-1 (NCT01773187), PERSIST-2 (NCT02055781), and the PACIFICA (NCT03165734) studies supported the FDA’s decision making. These studies collectively showed pacritinib to be safe and effective for the treatment of patients with myelofibrosis and severe thrombocytopenia. As a post-marketing requirement, the benefit of pacritinib is being confirmed in ongoing analyses of the PACIFICA study, which included patients with primary myelofibrosis, post polycythemia vera, myelofibrosis, or post-essential thrombocythemia (ET) myelofibrosis.

In an interview with Targeted Oncology, Mascarenhas, professor of medicine at Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute, discussed the introduction of pacritinib to the treatment landscape for myelofibrosis and severe thrombocytopenia, and the research supporting the recent FDA approval. He also discussed pacritinib’s potential future in treating other myeloid malignancies.

TARGETED ONCOLOGY: What did the treatment paradigm look like before the recent approval of pacritinib?

Mascarenhas: The treatment for myelofibrosis has first and foremost been the use of a JAK inhibitor to try to address mainly spleen and symptom burden. Ruxolitinib was approved in 2011 based on the COMFORT studies and then fedratinib [Inrebic] was approved in 2019, based on the JAKARTA and JAKARTA-2 studies, and is mostly relegated to the second-line setting and these 2 drugs have been a big step forward in improving symptoms and spleen burden for patients. However, their uses are relegated to those with platelets above 50,000, and that represents an unmet need for those patients with myelofibrosis and thrombocytopenia, I would argue [treating platelet counts] less than 100,000, but specifically less than 50,000, is an unmet need in which we do not have effective therapies that we can be delivered in a safe manner that can afford this same type of benefit that those patients who have higher platelets.

We know that patients with myelofibrosis that have low platelets have poor survival outcomes. There are limited treatment options, and these patients are in need of therapy. So, that really left a window open for the final development and approval of pacritinib, which I'm excited to see finally happen.

Can you describe pacritinib’s mechanism of action and what differentiates it from other agents in the space?

So, ruxolitinib is a JAK1/2 inhibitor and fedratinib is a selective JAK2 inhibitor. Pacritinib is a JAK2 selective inhibitor that also inhibits IRAK1, and it is likely that some of these non-JAK receptor kinase inhibition aspects of these drugs likely provide differences both in tolerability and safety but also in efficacy and have the potential to address niches.

So, in this case, as a JAK2/IRAK1 inhibitor that down regulates the IL-1 toll like receptor mitogenome NF-κB axis, it also reduces inflammatory cytokines through a nonJAK2-dependent pathway can complement JAK2 inhibition. And it may be for this reason that one can deliver pacritinib at 2 mg twice daily to patients, particularly with thrombocytopenia, that are the hallmark of the cytopenic myelofibrosis patient, and for the spleen and symptoms which we really can't achieve with drugs like ruxolitinib.

The approval was supported by data from 3 clinical trials. What are your key takeaways from those studies?

The approval was based on data that came from PERSIST-1, and those were patients who were JAK inhibitor naive that were randomized either to pacritinib or best available therapy, which excluded ruxolitinib and it was irrespective of platelet count.

PERSIST-2 was a patient population that was more advanced and had platelets under 100,000. So, this was the thrombocytopenic patient population who could have seen ruxolitinib previously, which 40% to 50% did. The control arm was best available therapy that could also include ruxolitinib. So, this was really an important trial to add to PERSIST-1, demonstrating activity in myelofibrosis patients with thrombocytopenia, who in many cases have received ruxolitinib previously, and then the [PACIFICA study] was a dose-finding phase 2 study evaluating lower doses than 200 mg twice daily, which was the winning dose in the PERSIST-2 study, which also continued to demonstrate safety from a cardiac and bleeding perspective, particularly to optimize the patients who are receiving the treatment therapy, and again highlight the activity of this drug, particularly in the less than 50,000 [platelet] patient population, which, again is the unmet need.

Also, the PACIFICA study is ongoing, which is a randomized phase 3 study in patients with less than 50,000 platelets, which will be supportive data for this accelerated approval, and patients would have seen less than 90 days of ruxolitinib therapy. So, this is really a niche that most trials and most therapies exclude.

How would you further describe the safety profile of pacritinib in patients with myelofibrosis and severe thrombocytopenia?

It has a favorable safety profile. It is a FLT3 inhibitor too, so there's some gastrointestinal (GI) toxicity that's mostly low grade and easy to manage early on. It is rarely a reason for discontinuation, and for hematologists/oncologists, this is not a big obstacle. The label does not have any black box warnings.

From the analysis that we presented at the American Society of Hematology Annual Meeting in 2021, there was not a clear signal of cardiac toxicity that was any different than best available therapy. There may be slight increase in bleeding risk associated with the pacritinib, and one needs to be aware of coagulopathies or patients who have clear bleeding tendencies in order to optimize patients. And there really isn't any safety signal that would outweigh the potential benefit of pacritinib in these patients that have low platelets and have a poor prognosis. So, I think for practitioners in the community, it really provides a well-tolerated and reasonable therapeutic approach for this vulnerable group of patients.

What toxicity management advice can you provide to community oncologists who use this agent?

I think monitoring the patient [is important]. So, following the patients, particularly early on in the treatment. For patients of this nature, I would have them in the office every week to follow blood counts, to make sure that they're not taking concurrent anticoagulants. And this can help set expectations in terms of the GI toxicity, and oncologists should perhaps have zofran or Imodium available for the patient. The reality is that most patients will do very well. But you want to be sure that for the patients who may have some GI toxicity, that they're aware of that potential, and they have the right tools at home to address it.

What do you think the overall impact of pacritinib will be in the treatment landscape?

It'll give an option for treatment for patients upfront who are JAK inhibitor naive, particularly with low platelets, as well as an option in the second line for patients who are discontinuing ruxolitinib, particularly with cytopenia. It is a less myelosuppressive drug, and I think that's really the major benefit of this drug. It's an interesting drug as an IRAK inhibitor as there's a lot of data that suggests inhibiting the IL-1 pathway also has benefit in myeloid malignancies across the board, but also specifically in myelofibrosis.

So, I think the potential as a combination partner with other drugs is also quite good as it does have this property of IRAK inhibition and is less myelosuppressive. So, it may make an ideal calming tutorial partner. I look forward to not just having the drug commercially available for patients in the community with low platelets upfront or second line, but also for the potential for clinical trial evaluation in a myelodysplastic syndrome (MDS) combination in other related diseases like chronic myelomonocytic leukemia (CMML), and other overlap syndromes. So, I think it has a lot of potential to move the field forward and to learn more about the role of IL-1 and IRAK signaling in these diseases.

Are there other myeloproliferative neoplasms (MPNs) that could potentially benefit from this drug in the future?

I think that essential thrombocytopenia is a very difficult subtype of MPN to develop drugs. I don't know that pacritinib would specifically make sense to evaluate in ET. And even in polycythemia vera, I would argue that the field is moving in directions that may be different than JAK inhibitors at this point.

So, I would see pacritinib as a drug that would have potential and should be further evaluated and is being evaluated in related myeloid malignancies like MDS, overlaps like CMML, and/or [acute myeloid leukemia]. So, I think there's a lot of potential across those boards, and I think we need to learn more about the activity of pacritinib and specifically the benefit of IRAK suppression.