JAK Inhibitors Build Momentum in Myelofibrosis Treatment


With additional JAK inhibitors under exploration in the myelofibrosis pipeline, such as momelotinib and pacritinib, FDA-approved options continue to be utilized heavily in the paradigm, explained John O. Mascarenhas, MD.

John O. Mascarenhas, MD

John O. Mascarenhas, MD

With additional JAK inhibitors under exploration in the myelofibrosis pipeline, such as momelotinib and pacritinib, FDA-approved options continue to be utilized heavily in the paradigm, explained John O. Mascarenhas, MD.

Most recently, a rolling submission of a new drug application has been initiated for pacritinib as a treatment of patients with myelofibrosis who have severe thrombocytopenia, which is defined by having 50 x 109/L platelet counts. The application will be supported by findings from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 studies (NCT02055781).

Combination approaches are exploring the potential safety and efficacy of JAK inhibitors, such as ruxolitinib (Jakafi) and fedratinib (Inrebic) with other novel agents, such as venetoclax (Venclexta) or the BET inhibitor CPI-0610.

In an interview with OncLive;John O. Mascarenhas, MD, a clinical investigator in myeloproliferative neoplasms, associate professor of medicine at the Icahn School of Medicine, and director of the Adult Leukemia Program at Mount Sinai Hospital, discussed how the positioning of JAK inhibitors in myelofibrosis has shifted, and also pointed to new agents under investigation.

OncLive: What are some of the most exciting, recent updates in myelofibrosis?

Mascarenhas: Myelofibrosis is a hematopoietic stem and progenitor cell malignancy. It's a complex disease, as it often results in multiple hematologic issues. Anemia is one of the major issues, as well as thrombocytopenia, increase in blasts, and transformation to acute leukemia, and patients often have a significant spleen and symptom burden.

To that effect, JAK inhibitors, such as ruxolitinib and now fedratinib as of August 2019, have been fundamental in addressing certain aspects of these diseases like spleen and symptom [burden], but don't effectively, unfortunately, address anemia or reliably alter the natural history of the disease.

For those reasons, [these burdens are] still an intense, and in some cases, urgent unmet need that's being addressed by ongoing clinical trials to evaluate therapies that could be used in the salvage setting. [This would be optimal for] patients who fail the JAK inhibitor, in which we know that the outcomes of those patients tend to be poor.

We have drugs like CPI-0610, which is a BET inhibitor, as well as venetoclax, which is a BCL-2 inhibitor, with phase 2 data that suggest activity both from the spleen and symptom [burden] standpoint—also from a bone marrow fibrosis reduction and anemia standpoint in a subset of patients. These could be used as monotherapy and also as add-on strategies for patients with myelofibrosis who have failed ruxolitinib, for example. These drugs are now being taken into the frontline setting to be added to ruxolitinib. Once they have demonstrated a safety profile and efficacy in the second-line setting, there is a tendency to evaluate whether there could be effects upfront.

Now there are randomized phase 3 studies that are opening and enrolling across the country comparing for example, CPI-0610 plus ruxolitinib to placebo/ruxolitinib in patients with treatment-naïve or JAK inhibitor—naïve MF, with the hope that we will replicate what was seen in the phase 2 setting in terms of deeper spleen and symptom responses, bone marrow fibrosis reduction, and mitigate the anemia that is usually with JAK inhibitor therapy. Ultimately, we're hoping that these novel agents, whether it's a BET inhibitor or BCL-2 inhibitor, will improve the outcomes and natural history of these diseases.

One other novel drug that fits in this discussion is imetelstat, which is a telomerase inhibitor. It's an intravenous drug given every 3 weeks. It is associated with myelosuppression, but in phase 2 data, it does appear to have the potential to prolong survival, which is an important end point. The phase 3 study of imetelstat versus best available therapy is now going to be activated and will accrue patients who failed ruxolitinib, where the primary goal is extension of life and improved survival.

For me, as an investigator in this field, it's really exciting to see the field move forward and see these end points evolve. The goals of therapy go beyond, for example, speed and symptom which are not unimportant, but importantly, to try to change the natural course of this diseases.

How would you describe the significance of pacritinib in myelofibrosis?

Pacritinib is an important drug and potential agent available in the commercial space; it's the sole JAK2 inhibitor, of the many that have been evaluated, that appears to have the least amount of myelosuppression as it relates particularly to thrombocytopenia. Patients with platelet counts less than 50,000, which is defined as extreme thrombocytopenia, are an unmet need.

We can't effectively and safely deliver the current JAK inhibitors that are approved, and in fact, there are very therapies for these patients. These patients are typified by a myelodepleted phenotype, so they don't always have large spleens, but they usually are characterized by low blood counts and poor outcomes.

Pacritinib, at least in the randomized, phase 3 PERSIST-2 study, showed efficacy at 20 mg twice daily in both spleen and symptom improvement in these low platelet patients. The PAC203 was a dose-finding phase 2 randomized study looking at 3 different dose levels: 200 mg twice daily, 100 mg twice daily, and 100 mg once daily. The importance of that study was to document and confirm that the drug can be delivered safely. The 200-mg twice daily dose is effective in almost 17% of patients in achieving spleen volume reduction, without incurring significant thrombocytopenia. These are patients with less than 50,000 platelets. The niche for pacritinib is patients with myelofibrosis who have less than 180 days of prior JAK2 inhibitor therapy that have a platelet count below 50,000.

It's a niche; it's a special niche, and it's an unmet need. I would define it as an urgent unmet need, as we can't effectively treat these patients with current available therapies. This randomized phase 3 study will hopefully provide us with the data to allow us to have commercial access to the drug.

I personally think this drug should be approved already based on the studies that have been done, and the data that's at hand, because we owe it to our patients with low platelets to provide them with some at least palliative benefit with spleen and symptom burden. I look forward to the PACIFICA study, and I'm very hopeful that the study will allow us to confidently move that drug from clinical trial testing to commercial use.

Do other novel JAK inhibitors or potential combination strategies in the pipeline look particularly hopeful?

There is more room for other JAK inhibitors. Ruxolitinib and fedratinib are welcomed in this space. Pacritinib would fill the niche of 50,000, but there's really also this unmet need of anemia, which is frequent at presentation and expected through the course of the disease.

Momelotinib, which is a JAK1/2 inhibitor that also appears to inhibit activating receptor signaling and hepcidin expression, has been shown in phase 2 testing to have an anemia response, which we don't see with the other JAK inhibitors. This is important because for those patients we see with anemia as part of their picture and have spleen and symptom burden, it would be advantageous to be able to deliver the benefits of JAK inhibition without the detriments of anemia and actually improving anemia in patients.

That's what the MOMENTUM study is designed to do, and that's a randomized phase 3 study testing momelotinib versus danazol. It's a double-blinded, placebo-controlled study, and the primary end point is symptom improvement, but a key secondary end point is anemia response, so I'm hopeful that study, importantly, will hit its primary end point and allow for secondary end point assessment and join the armamentarium so that we have multiple options for our patients and can cycle JAK inhibitors as well.

What challenges remain in this setting?

The problem we have in myelofibrosis is that it is a disease where you have both a clonal hematopoietic stem cell disorder in the context of a microenvironment in the bone marrow and spleen that are also corrupted. Trying to address both or finding 1 agent to address both is probably unrealistic, so it needs combination therapies, which, as we discussed, with BET inhibitors or BCL-2 inhibitors, or multiple other drugs that are in testing right now that are usually combined with the backbone, which is a JAK inhibitor at this point. However, I do think that paradigm will change, and you will see various combinations of therapies, hopefully, that are informed by preclinical studies that suggest that the 2 agents work well in combination because that's the way we will move the field forward.

It is a complex disease, and it's hard for patients to wrap their heads around the disease because it is a blood cancer, but it often results in bone marrow failure. It's hard to explain to patients what's driving it and how to address it and the complex issues that surround it because most patients are either older in age or have significant comorbidities and are not amenable to hematopoietic stem cell transplantation, which is the only curative option.

For most of these patients in whom we know that the median survival can range anywhere in low-risk patients from 10 to 15 years, to high-risk patients in whom the survival can be 1 to 2 years, it's very hard to predict for a given individual how they will behave and how to approach their disease. The older and sicker they are, the more complicated that is in balancing risks and benefits of the disease versus the therapies that we can offer.

Do you have any final thoughts to share regarding this research?

I encourage physicians in the community and patients alike to consider referral to tertiary centers where clinical trial options are available because this is really how we move the field forward. If it weren't for those brave folks who enrolled on the COMFORT studies, we wouldn't have ruxolitinib approved today, or similarly, for the JAKARTA studies, we wouldn't have fedratinib available. I'm hoping we'll continue that momentum and deliver more effective drugs, but really, it's a union between academia, pharmaceutical industry, and patients.


TI BioPharma initiates rolling submission of new drug application (NDA) for pacritinib in myelofibrosis patients with severe thrombocytopenia. News release. CTI BioPharma, Inc. October 13, 2020. Accessed November 9, 2020. https://bit.ly/3iSx8WU

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