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Clinical Review of ropeginterferon alfa-2b Suggests Amended Dosing Schedule May Support Improved Clinical Outcomes in Polycythemia Vera

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Review of studies published in Frontiers in Oncology highlights dosing considerations that may help more patients achieve earlier complete hematological response

BURLINGTON, Mass.–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced the publication of a review of clinical literature in the journal, Frontiers in Oncology. The research indicates that an amended dosing schedule, with higher initial dose and faster dose titration of ropeginterferon alfa-2b (marketed as BESREMi®), may correlate to earlier complete hematological response (CHR) in polycythemia vera (PV) in adults. The analysis titled, “An alternative dosing strategy for ropeginterferon alfa-2b may help improve outcomes in myeloproliferative neoplasms: An overview of previous and ongoing studies with perspectives on the future,” was co-authored by PharmaEssentia researchers.

“This latest research will help support more informed dialogue among physicians regarding their patients with PV.”

“This publication delves into the critical connection between an accelerated dosing regimen for ropeginterferon alfa-2b and the key efficacy, safety and tolerability outcomes we aim to achieve for our patients,” said John Mascarenhas, M.D., Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai and study author. “The data from these clinical and investigational studies suggest that a higher starting dose and faster titration could be an appropriate approach to attain clinical outcomes earlier while minimizing the risk of thrombosis and hemorrhage in patients with PV.”

PV is the most common myeloproliferative neoplasm (MPN) and a long-term, potentially life-threatening disease with limited treatment options. Recent clinical investigations suggest the potential for rapid titration and higher starting doses to benefit those with PV.1

The publication highlights the findings from multiple studies supporting the efficacy, safety and tolerability of a 250-350-500 mcg titration dosing regimen of ropeginterferon alfa-2b:

  • A compassionate use program (CUP) study in Taiwan (n=14; hydroxyurea and/or anagrelide resistance or intolerance patients) resulted in a CHR rate of 73% at 52 weeks vs 51% observed in a study with a slower titration method. No new safety signals were detected.
  • Interim results from an ongoing, Phase 2, single-arm study in Chinese PV patients (n=49; resistant or intolerant to hydroxyurea) showed that amended dosing achieved a CHR rate of 52% at Week 24 compared to 43% at Week 52 observed in PROUD-PV. Treatment-related Grade >3 adverse events (AEs) were reported in five patients (10.2%).
  • Data from an investigator-initiated trial in Korea (n=45; hydroxyurea naïve or pre-treated PV patients) indicated higher hematologic and molecular responses at 6 months. Dose reductions were required in 4.4% of patients and the majority of AEs were Grade 1 or 2 with no treatment-related serious AEs reported.

Across the studies, ropeginterferon alfa-2b was generally well-tolerated. No thromboembolic complications have been reported with the accelerated titration regimen in PV. Rather, the review authors indicate that it is reasonable to believe that the accelerated dosing regimen may potentially minimize the risk of thrombosis and hemorrhage associated with an under-dosing during dose titrations.

“As more clinicians gain familiarity with BESREMi®, we want to support treatment goals by ensuring patients can effectively achieve and maintain their target clinical and molecular responses, as this may help reduce the risk of disease progression over time,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs. “This latest research will help support more informed dialogue among physicians regarding their patients with PV.”

PharmaEssentia is interested in the attributes of the amended dosing approach with ropeginterferon alfa-2b that may extend into related MPNs with unmet needs such as essential thrombocythemia (ET) and pre-fibrotic primary myelofibrosis (pMF). Several planned or ongoing Phase 3 clinical trials will further evaluate this regimen of ropeginterferon alfa-2b in ET (SURPASS and EXCEED trials) and PV (ECLIPSE trial). Plans for a Phase 3 clinical trial in pMF are also underway.

Follow PharmaEssentia USA on Twitter and LinkedIn for news and updates.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.2

About BESREMi® (ropeginterferon alfa-2b-njft)

BESREMi is an innovative monopegylated, long-acting interferon. With its unique pegylation technology, BESREMi has a long duration of activity in the body and is aimed to be administered once every two weeks (or every four weeks with hematological stability for at least one year), allowing flexible dosing that helps meet the individual needs of patients.

BESREMi has orphan drug designation for the treatment of polycythemia vera (PV) in adults in the United States. The product was approved by the European Medicines Agency (EMA) in 2019, in the United States in 2021, and has recently received approval in Taiwan and South Korea. The drug candidate was invented by PharmaEssentia and is manufactured in the company’s Taichung plant, which was cGMP certified by TFDA in 2017 and by EMA in January 2018. PharmaEssentia retains full global intellectual property rights for the product in all indications.

Indication

BESREMi is indicated for the treatment of adults with polycythemia vera.

Important Safety Information

WARNING: RISK OF SERIOUS DISORDERS

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

CONTRAINDICATIONS

  • Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt
  • Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi.
  • Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment
  • History or presence of active serious or untreated autoimmune disease
  • Immunosuppressed transplant recipients

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Myeloproliferative Neoplasm Management: Future Directions in Care

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Feb 2, 2023

Naveen Pemmaraju, MD
John Mascarenhas, MD

 

Closing out their discussion on myeloproliferative neoplasms, key opinion leaders share excitement for future evolutions in the treatment paradigm.

Transcript:

Naveen Pemmaraju, MD: So team, what I want to do is, I’m going to go to each of you and get some final comments, and ask you to give me 2 or 3 things. Maybe 1 is something that you learned, maybe at ASH [American Society of Hematology meeting] or in the last few months leading up to ASH, and then 2 and 3 is what’s your wish list? What do you want us as the field to think about and focus on in 2023, either in the setting of clinical trials, transplant symptom burden, to give folks out there a sense of what you are thinking about and what you’re excited about? Dr Palmer, we’ll start with you, and we’ll go down the panel.

Jeanne M. Palmer, MD: This year at ASH, it was great to hear some of the updated information and to try to understand the new drugs that are coming out and have discussions with people about where we think they’re going to fall into the landscape of the therapy. I look forward to exploring that further. Although I recognize it’s certainly going to be a goal for the next 5 years, probably more than the next year, I’m hopeful that we’ll be able to do that. One of the things that’s on my wish list is I think we need to better understand the response criteria we’re looking at, so what is the meaningful response that we have for a patient? Right now, we’ve been using spleen size, reduction, and symptom burden, which are very important factors that contribute to it, but what are the markers that are going to predict survival? Because it takes a long time to see survival. We must figure that out. What are the markers that are most meaningful to patients? What can we anchor with something like the Global Impression of Change that tells us this makes the patient feel a lot better. It doesn’t just make me feel better to look at their numbers or look at different things, but it makes them feel better also, more importantly, associated with survival. That’s my wish list is to come up with the best way to figure out what works.

Naveen Pemmaraju, MD: Wonderful. Dr Oh, your final thoughts?

Stephen Oh, MD, PhD: We are at a very exciting time for this field with more new agents becoming available, and many are now in phase 3 that may soon become approved. It continues to be an extremely exciting time for the field. In terms of specific things that I will highlight, I’ll be the broken record and keep coming back to inflammation and anemia, and more recognition that this is something important in terms of the clinical features of patients with mild fibrosis, anemia related to inflammation, targeting these pathways, hepcidin. It’s also something as far as updates on the lab side that is increasingly being investigated. What I continue to say as far as that’s concerned is, we all ask, can we more potently target the abnormal inflammation? But I think there is an opportunity to leverage these abnormal inflammatory signaling pathways in a way that not just reduces symptoms and improves bone marrow function, but can turn it on its head to target the malignant cone as well in a more effective way. That’s what I would highlight. The last thing I would say, we talked about this new monoclonal antibody for mutant calreticulin. The other obvious approach, and along those lines, is something specific for mutant JAK2 [Janus kinase 2]. We still don’t have that. There are obvious reasons why that has not been the case over the years, but I think there is a growing hope, maybe it’s the best way to say it, that a truly mutant selective JAK2 inhibitor may be here in the coming years.

Naveen Pemmaraju, MD:Wow. That’s exciting. I’ll share my thoughts with the panel. At this year’s ASH, the exciting thing for me was mainly in our myelofibrosis sessions, the emphasis on what all of you discussed here, which was the elucidation and understanding of disease biology and biomarkers that you can hang your hat on, or at least have a sense of what’s going on. The one that really captured that for me was what Dr Oh presented, which was the ACVR1 [activin A receptor type I] story in pacritinib [Vonjo], our third approved JAK inhibitor. We now have several JAK inhibitors, momelotinib and pacritinib, which can be not only delivered in the setting of cytopenias, but actually improving the cytopenias, including the holy grail of anemia. I want to see how the combination therapies do, not only in terms of overall survival, spleen and symptoms, but how they do with the anemia, and how durable that is. I thought that was an exciting finding. For the future, as you all know in our own discussions, I hope you’ll allow me to say a unified theory of disease modification, what we’ve all talked about, and I still think it’s an aspirational goal. It can be something like overall survival as the top most important thing for our patients and for us, coupled with the traditional factors that Ruben and Serge pioneered of spleen size reduction symptoms, and then coupled with some of the newer markers that Steve, Dr Angela Fleischman [University of California, Irvine] and our colleagues are working on, including VAF, variant allele fraction, cytokine state, and maybe even bone marrow fibrosis. Can we couple all those into something meaningful for our patients? John, let me turn it to you, and then Ruben for your final thoughts.

John Mascarenhas, MD:It’s difficult to be the fourth person in a row to do this. I thought that’d be Ruben, because he set all the right things you said all the top line.

Naveen Pemmaraju, MD:It’s all supervised here, OK.

John Mascarenhas, MD:I agree with you all, and I know you share this enthusiasm. As a clinician investigator in this field, this is a great time to be in it because the science is driving the medicine and translating directly into the clinic. What we learned in the clinic feeds back and then helps us understand how to refine and go about it the right way. I’m most impressed with beyond the things I’ve been talking about, is how we sit down and listen carefully to a lot of the scientific sessions. You start to realize that there’s so much interconnectivity here between the pathways, seemingly redundancy here, and what we end up often doing is trying to target 1 pathway that we think is relevant, not understanding that there’s so many other pathways that are activated, and that compensate and sometimes overcompensate for shutting down 1 pathway. There’s a lot of examples of this, one clear example is if you shut down BET [bromodomain and extraterminal] regulated transcription, you have a consequence of down regulating NF-kappaB [nuclear factor-kappa B] activity, and down regulating BCL-2 [B-cell lymphoma 2] expression, c-MYC expression, all relevant nodes in the pathobiology of myelofibrosis. It begs the question, is there 1 specific target? Or is what we’re looking at such a complex interplay that we need to be approaching this from various angles at the same time? Which I think reinforces the theme that we’ve been discussing, which is rational combination, mechanism-based combination. I’m excited that a lot of the scientific abstracts that were presented today will in 2 years, 3 years, translate into the next wave of clinical trials. I think that’s fabulous. That’s why we’re here.

Naveen Pemmaraju, MD:That’s fantastic. Ruben, take us home and give us your final thoughts.

Ruben Mesa, MD:One thing I’ve learned this year is don’t let the perfect be the enemy of the good. Meaning, when ruxolitinib [Jakafi] was first approved, there were many detractors saying, “This is supportive care. I could just give patients 10 milligrams of prednisone, and they’d be the same.” That is just pure nonsense. The rate at which patients pass away from myelofibrosis is clearly decreased significantly over the years. Is it perfect? No. I think the expansion we’ve had now to hopefully have 4 JAK inhibitors is important. These drugs make an important difference. They each have their own role. I still agree with John, I want to look at novel combinations, but a combo that includes a JAK inhibitor probably is logical, based on several things that we have learned. Although these are not perfect, these are good drugs that make a real impact on patients both in terms of length of life and quality of life. Now my wish list is, I envisioned the situation where we’re 18 months from now, and we have 6 phase 3 clinical trials that have data that looks similar, we improve spleen and symptoms more than singulation ruxolitinib, and we have a toxicity profile that includes diarrhea, nausea, and vomiting. That’s what we’re going to be stuck with. So how do we sort through which patient goes on which drug because they’re going to be patients that have a fabulous response to rux [ruxolitinib] and pelabresib, rux [ruxolitinib] and parsaclisib, rux [ruxolitinib] and navitoclax, rux [ruxolitinib] and HDM2 inhibitor, on and on, but not everyone. How do we sort through that? I think the correlative studies are going to be important. How do we sort through so that we have any science behind I’m going to give which drug just comes to top of mind because they have very different mechanisms of action, and the patients are different? Those that develop these trials hope that the patients are going to be eligible, of course, but we realize that a drug has a 20% response rate. It means it has 100% response rate for 20% of the patients and has a 0% response rate for the other 80%. That’s my wish list. Our work is not done when we have the top line data on those phase 3 studies, but a tremendous sense of progress and hope. As Naveen and I were talking earlier at ASH, when you think about what ASH looked like in MF [myelofibrosis] in 2002. In 2002, I gave the oral presentation on thalidomide [Thalomid] and prednisone, and it was like the Super Bowl. There were so many people there because we showed some improvement in anemia, but that was it, no spleen, no symptoms, no disease modification. There was a bouncer outside keeping people out, so the progress we’ve made is unbelievable.

Naveen Pemmaraju, MD:Well, I must tell you, team, we have lovely discussions. This was one of the best yet. On behalf of my colleagues Ruben, John, Steve, and Jeanne, I want to thank you all for this very rich and informative discussion. I want to thank our audience for taking time to view this, and we hope that you found this OncLive Peer Exchange discussion to be useful and informative for your practices. With that, I’m Naveen Pemmaraju. We will sign off for now and see you next time. Thank you all so much.

Transcript edited for clarity.

 

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A Phase 1 Study of Ruxolitinib plus Abemaciclib to Treat Myelofibrosis

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Purpose

In this study, researchers want to find the highest dose of the drug abemaciclib that can be given safely with ruxolitinib in people with myelofibrosis that has developed on its own (primary myelofibrosis) or as a complication of the blood diseases polycythemia vera or essential thrombocythemia. In people with myelofibrosis, the bone marrow is not able to make enough blood cells. The spleen is bigger than normal, making the stomach feel very full. Patients may also have fever and night sweats.

Doctors think that giving ruxolitinib, a standard medication for myelofibrosis, in combination with abemaciclib (a breast cancer medication that is investigational in this study) may be a useful treatment. Both ruxolitinib and abemaciclib block specific proteins that play a role in cancer growth. By blocking these proteins, the drugs may cause myelofibrosis to stop growing.

Participants in this study will receive one of three doses of abemaciclib in combination with ruxolitinib. Both medications are taken orally (by mouth).

Eligibility

To be eligible for this study, patients must meet several requirements, including:

  • Participants must have intermediate-risk or high-risk primary myelofibrosis or myelofibrosis associated with polycythemia vera or essential thrombocythemia.
  • Patients must have been taking ruxolitinib for at least 12 weeks and had an inadequate response, such as a persistently enlarged spleen or other symptoms.
  • Patients must be able to walk and do routine activities for more than half of their normal waking hours.
  • This study is for people age 18 and older.

Contact

For more information and to ask about eligibility for this study, please contact the office of Dr. Raajit Rampal at 646-608-3746.

Protocol

22-075

Phase

I

Disease Status

Newly Diagnosed & Relapsed/Refractory

Investigator
Raajit K. Rampal

Co-Investigators
Michael J. Mauro

Momelotinib May Effectively Reduce Anemia and Other Symptoms for Patients With Myelofibrosis

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Posted: 1/31/2023 10:49:00 AM
Last Updated: 2/2/2023 2:43:15 PM

 

The targeted therapy momelotinib may offer clinically significant improvement in disease-related symptoms, including anemia and spleen enlargement, for patients with myelofibrosis, according to a novel study published by Srdan Verstovsek, MD, PhD, and colleagues in The Lancet.

The findings support the use of momelotinib—a potent ACVR1/ALK2 and JAK1/2 inhibitor—over the standard therapy danazol in treating patients with myelofibrosis who were resistant, refractory, or intolerant to first-line therapy—especially patients who were symptomatic and those with anemia.

Srdan Verstovsek, MD, PhD

Srdan Verstovsek, MD, PhD

Background

Myelofibrosis, a type of myeloproliferative neoplasm, is characterized by dysregulated JAK signaling—which can disrupt the body’s normal production of blood cells and can lead to common symptoms such as an enlarged spleen and anemia. Chronic anemia in these patients is associated with poor prognoses.

Currently approved JAK inhibitors can improve spleen responses and other disease-related symptoms, but they also can worsen anemia. In this trial, momelotinib improved anemia and reduced transfusion dependency in patients with myelofibrosis who were previously treated with JAK inhibitors. Momelotinib can be administered and maintained at full dosage because it does not suppress bone marrow activity like other JAK inhibitors.

“Current options for managing anemia in our patients [with myelofibrosis] provide only modest and temporary benefits, so we are excited about these findings,” explained lead study author Dr. Verstovsek, the United Energy Resources, Inc, Professor of Medicine and Director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “The trial results suggest that momelotinib is safe, well-tolerated, and can improve one of the most common and debilitating clinical problems for this patient population,” he highlighted.

MOMENTUM: Study Methods and Results

The new study—one of the first of its kind to evaluate JAK1/2 and ACVR1/ALK2 inhibition in patients with myelofibrosis and anemia—was designed to compare the clinical benefits of momelotinib with those of danazol, a synthetic androgen currently used to treat anemia in patients with symptomatic myelofibrosis.

In the international, randomized phase III MOMENTUM trial, researchers randomly assigned 195 adult patients to receive either momelotinib plus placebo (n = 130) or danazol plus placebo (n = 65). Among the trial participants, 63% of them identified as male and 37% identified as female. The participants for both groups had a median age of 71 to 72 years.

The trial’s primary endpoint was symptom reduction after 24 weeks of treatment, defined as a 50% or greater reduction in the Myelofibrosis Symptom Assessment Form Total Symptom Score. The researchers discovered that 25% of patients who received momelotinib saw benefits in their disease symptoms compared with 9% of those who received danazol.

Patients treated with momelotinib also experienced a significant reduction in their spleen size, with 25% responding after 24 weeks of therapy. Additionally, these patients required fewer blood transfusions compared with those receiving danazol.

Conclusions

The safety profile of momelotinib was comparable to the safety observed in previous clinical trials. The most common nonhematologic side effects experienced by trial participants in the momelotinib group included diarrhea, nausea, weakness, and itchy or irritated skin.

“If approved, momelotinib could offer an effective option for patients with myelofibrosis to improve anemia, splenomegaly, and other disease-related symptoms over other approved medications so far,” Dr. Verstovsek emphasized. “Momelotinib may also be an ideal partner for combinations with other investigational agents in development to further control myelofibrosis symptoms,” he concluded.

The researchers noted that they continue to monitor the effectiveness of momelotinib through ongoing patient follow-ups and long-term survival.

Disclosures: The research in this study was supported by Sierra Oncology. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

 

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Accelerated Phase of MPN: What It Is and What to Do About It

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Anand Patel, Olatoyosi Odenike

 

Abstract

Progression of Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) to the accelerated phase (AP) or blast phase (BP) is associated with poor outcomes. As our understanding of the molecular drivers of MPN progression has grown, there has been increasing investigation into the use of novel targeted approaches in the treatment of these diseases. In this review we summarize the clinical and molecular risk factors for progression to MPN-AP/BP followed by discussion of treatment approach. We also highlight outcomes using conventional approaches such as intensive chemotherapy and hypomethylating agents along with considerations around allogeneic hematopoietic stem cell transplant. We then focus on novel targeted approaches in MPN-AP/BP including venetoclax-based regimens, IDH inhibition, and ongoing prospective clinical trials.

Introduction

The classic Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are hematopoietic stem cell diseases characterized by activated JAK/STAT signaling pathways and a variable propensity to evolve toward accelerated or blast phase disease (MPN AP/BP). Outcomes are poor in MPN AP/BP and have not changed substantially in the past decade. Our increasing understanding of the molecular-genomic factors and pathways that drive MPN progression have the potential to lead to meaningful targeted therapeutic approaches. This argues for consideration of a personalized approach that takes the mutational spectrum of the individual patient into account, in addition to clinical factors, when fashioning a therapeutic strategy1. For example, emerging retrospective data with IDH inhibitors in MPN AP/BP lend credence to this approach and are now informing prospective early phase clinical investigation2,3.

By consensus definition, MPN-AP refers to the presence of peripheral circulating or bone marrow blasts in the 10-19% range and MPN-BP refers to 20% ≥ blasts in the peripheral blood or marrow, in an individual with a pre-existing MPN4,5. Overall survival (OS) in both MPN-AP and MPN-BP is limited particularly in the absence of allogeneic hematopoietic stem cell transplantation (allo-HCT). Even in the current era of myeloid therapies, outcomes for MPN-AP/BP are quite poor with median OS of 9 months reported in a multicenter retrospective study6.

The median survival in MPN-AP is in the 16- to 18-month range. Of note however, a relatively large series from the Mayo clinic shows that patients with primary myelofibrosis (PMF) with peripheral or marrow blasts in the 5-9% range have a survival outcome that is indistinguishable from that of patients with 10 to 19% blasts7. Similarly, data reported by MD Anderson demonstrates that a blast range of 5-9% in PMF has similarly poor outcomes when compared to 10-19% even in the era of ruxolitinib8,9. Overall, patients with 5% or more circulating or marrow blasts can therefore be viewed as being on a continuum towards progression to MPN-BP, which has a particularly dismal survival outcome measured in the 3-5 month range. Therefore, it is reasonable to propose that therapeutic strategies designed for particularly high risk populations such as MPN-BP should similarly be applied to MPN-AP, including those with blasts in the 5% or greater range. For those who are fit enough to undergo allo-HCT, this should be entertained early on, with a view to bridging patients to allo-HCT as soon as there is effective disease control.

Risk factors for progression to MPN AP/BP include MPN subtype and is highest for PMF. In a large contemporary series, the 20-year cumulative estimate of blast phase transformation was 3.8%, 6.2% and 14.2% for essential thrombocythemia (ET), polycythemia vera (PV) and PMF, respectively10. Other risk factors for progression to MPN-BP include clinicopathologic features, previous treatment, laboratory values, genetic features of disease, and prognostic scoring systems (Table 1). The mutational landscape of MPN -AP/BP is complex, and in addition to the canonical driver mutations in JAK2, MPL and CALR, includes acquisition of co-mutations (Table 2) which segregate along various pathways including DNA methylation, chromatin modification, DNA repair and RNA splicing11, 12, 13. The evolutionary pathway to MPN-BP is far from linear however, and in some instances, evidence has pointed towards bi-clonal disease or the existence of a pre-JAK2 ancestral clone14, 15, 16. Acquisition of high molecular risk mutations including ASXL1, EZH2, IDH1/2, SRSF2, and TP53 coupled with worsening clinical parameters including increasing circulating blasts and worsening thrombocytopenia can point towards those patients with advanced MPNs, who are on a trajectory toward MPN-AP/ BP. Early consideration of potentially curative approaches such as allo-HCT is important in these scenarios while in the chronic phase, given the paucity of effective interventions once the disease progresses to MPN AP/BP17.

Therapeutic interventions range from intensive induction chemotherapy to less intensive approaches such as hypomethylating agent (HMA) based therapies. Much of the experience regarding outcomes with these approaches are retrospective in nature and are largely derived from the treatment of patients in the blast phase. It is likely however, that the general principles and lessons learned in this regard would also be applicable to MPN-AP1. Outcomes across a number of targeted therapy approaches are summarized in Table 3.

Given the relative chemoresistance of MPN AP/BP, with response rates in the 35-45% range and short remission durations, the benefit of intensive chemotherapy as a therapeutic strategy is limited to those situations where allo-HCT can be utilized for consolidation1,11,18,19. HMA-based approaches are associated with CR rates in approximately 25% range in most series, with overall response rates in the 40-50% range1,19. In reported retrospective comparisons, there has been no survival advantage to an intensive chemotherapy approach over a less intensive one, in the absence of consolidative allo-HCT11,12. Of note, there are no randomized studies comparing these approaches. While JAK inhibition has a well-established role in the management of chronic-phase MPNs, JAK inhibitor monotherapy is largely ineffective for MPN-AP/BP20 and there is no evidence yet that JAK inhibition significantly changes natural history with regard to likelihood of evolution to AP/BP21. There have also been several prospective studies evaluating ruxolitinib in combination with HMAs in MPN-AP/BP. Response rates have ranged from 26-45% with median OS of less than one year22, 23, 24. In the absence of randomized trials or a matched historical population, it remains unclear if the addition of ruxolitinib to an HMA offers additional benefit beyond HMA monotherapy.

While allo-HCT is considered the only curative approach for MPN-AP/BP, considerations around the appropriate time for transplantation and which patients may derive the most benefit from allo-HCT continue to evolve. Blast percentage certainly has prognostic implications in the setting of survival outcomes in MPNs, however the impact of blast burden on patients undergoing allo-HCT is less clear. A clinical/molecular score in patients with MF undergoing allo-HCT found no impact of blast percentage on post-transplant outcomes25. In addition, a recent analysis of 35 patients with AP MF that underwent reduced-intensity conditioning (RIC) allo-HCT reported a 5-year OS of 65% which compared favorably to the chronic-phase MF group (n=314) that also underwent RIC allo-HCT26. This suggests that in patients with MPN-AP that are eligible for transplant consideration should be given to proceeding with allo-HCT even if blast burden is not reduced. The impact of blast reduction in MPN-BP prior to allo-HCT is also not well defined1,17. Some studies have demonstrated that while achievement of a CR prior to allo-HCT may offer some benefit, overall survival is still poor27, 28, 29, 30. Furthermore, the ability to achieve a deep remission prior to allo-HCT with current therapies is quite limited. Molecular factors also have an impact on outcomes after allo-HCT in MPN-BP; in particular the presence of TP53 mutation is associated with poor survival even in patients with blast reduction prior to allo-HCT31. These findings starkly highlight the need for prospective novel therapies in this patient population.

The B-cell lymphoma 2 (BCL-2) family of proteins are involved in the regulation of mitochondrial outer membrane permeability and the resultant apoptosis of cells. The family is comprised of BCL-2 along with other proteins such as BCL-xL and MCL-132. Pre-clinical studies established the reliance of AML cells on BCL-2 for survival and mitochondrial dependence on BCL-2 as an anti-apoptotic mechanism; inhibition of BCL-2, on the other hand, was found to drive apoptosis of AML cells and inhibit growth of AML progenitor cells33, 34, 35. Pre-clinical studies of JAK2-driven hematologic malignancies have demonstrated overexpression of the BCL-2 family of proteins and that resistance to JAK inhibition can be overcome with addition of a BCL-2/BCL-xL inhibitor36. The clinical benefit of the BCL-2 inhibitor venetoclax in combination with azacitidine has been confirmed in AML and the use of venetoclax in combination with intensive chemotherapy is under investigation37,38. In addition, the use of the BCL-2/BCL-xL inhibitor navitoclax in combination with ruxolitinib for patients with myelofibrosis and lack of response to ruxolitinib has demonstrated promising results in the Phase II setting39. There is much interest in ascertaining the role of venetoclax in MPN-AP/BP; the majority of data is based in retrospective analysis at this time.

There are several retrospective analyses that have investigated venetoclax-based combination therapies in MPN-AP/BP. The initial experience reported by Tremblay et al analyzed 9 patients with MPN-AP/BP (8 MPN-BP, 1 MPN-AP) that received HMA+Venetoclax. CR/CRi rate was 33% and 3 patients proceeded to allo-HCT. The median OS was 4.2 months for this cohort40. Masarova et al reported on 31 patients with MPN-BP that received venetoclax-containing regimens at a single center. Fourteen patients were treated in the frontline setting and 17 had R/R disease; 18 patients received an HMA, 5 patients received cladribine and low-dose cytarabine (LDAC), 6 patients received intensive chemotherapy, and 2 patients received an IDH inhibitor in combination with venetoclax. CR/CRi rate was 19% with all responses occurring in the frontline population and 2 patients received an allo-HCT; median OS for the cohort was 4 months. Of note, 83% of patients developed a Grade 3+ infection and the 8-week mortality of the 32-patient cohort was 32%41. Gangat et al reported on 32 patients with MPN-BP treated with HMA+Venetoclax across 3 centers; 23 received HMA+Venetoclax in the frontline setting and 9 received HMA-Venetoclax in the relapsed/refractory (R/R setting). CR/CRi rate in the frontline patient cohort (n=23) was 44% and 6 patients went onto receive allo-HCT. There was no significant difference in median OS when comparing patients treated with HMA+Venetoclax to a historical population treated with HMA monotherapy (n=26) or intensive chemotherapy (n=69) (8 months vs 5.5 months vs 8 months, respectively; p=0.13)42. A multi-center retrospective analysis by King et al analyzed outcomes of 27 patients with MPN-AP/BP treated with venetoclax-containing combination therapies. Twenty-one patients had MPN-BP while 6 patients had MPN-AP at time of treatment; 24 patients received an HMA combined with venetoclax while 3 patients received LDAC. The acute leukemia response-complete (ALR-C) rate was 30% and 5 patients received an allo-HCT; the median OS was 6 months for patients with MPN-BP and median OS of 3.6 patients for those with MPN-AP43.

While BCL-2 inhibition in MPN-AP/BP may hold promise, its current role in management is unclear. An analysis of 80 patients with MPN-AP/BP diagnosed and treated from 2017 onwards found no significant difference in overall survival between patients treated with HMA-Venetoclax in the frontline setting (median OS 0.59 years) when compared to those treated with other HMA-based regimens (median OS 1.1 years)6. Given pre-clinical work elucidating the role of BCL-xL and MCL-1 dependency in MPNs and erythroid/megakaryocytic AML, prospective evaluation of navitoclax in MPN-AP/BP is underway (NCT05455294, NCT05222984) and may provide a means of overcoming the resistance to venetoclax seen in MPN-AP/BP36,44, 45, 46.

Isocitrate dehydrogenase (IDH)1 and 2 are essential enzymes within the tricarboxylic acid (TCA) cycle and catalyze the formation of alpha-ketoglutarate, which is necessary for appropriate epigenetic regulation. Mutations in IDH1 and IDH2 are seen across a variety of malignancies and lead to accumulation of the oncometabolite R-2-hydroxyglutarate (R-2HG)47. Accumulation of R-2-HG inhibits alpha-ketoglutarate dependent dioxygenases such as Jumonji C-domain lysine demethylases and ten-11 translocation (TET) enzymes. In myeloid malignancies this promotes leukemogenesis via proliferation and differentiation block of immature hematopoietic cells. In MPNs, both IDH1 and IDH2 mutations are associated with inferior OS and increased risk of progression to MPN-BP17. Pre-clinical work has demonstrated the efficacy of IDH inhibition as monotherapy and in combination with JAK inhibition in the treatment of IDH-mutated MPNs48. The incidence of IDH1/2 mutations is enriched in MPN-AP/BP and ranges from 19-26%, making IDH inhibition an intriguing targeted therapy approach11, 12, 13. Ivosidenib and enasidenib, inhibitors of the IDH1 and IDH2 mutant enzymes respectively, have provided a novel lower-intensity approach in the treatment for IDH-mutated AML49, 50, 51, 52, 53. The efficacy of this approach in AML has spurred investigation in MPN-AP/BP as well. In our single-center analysis of 8 patients with IDH2-mutated MPN-AP/BP treated with enasidenib-based regimens; 7 patients had MPN-BP while 1 had MPN-AP. Six patients were treated in the frontline setting while 2 received treatment in the R/R setting; 7 of these patients received enasidenib monotherapy while one received enasidenib in combination with azacitidine. Using 2012 MPN-BP consensus criteria54 the response rate was 75% with an ALR-C rate of 25%. The 1-year OS was 50% and the longest response surpassed 4 years. Differentiation syndrome was seen in 25% of patients. Of note, even in patients with durable responses, there were molecular and histopathologic findings of chronic-phase MPN that persisted, which suggests that IDH inhibition did not address the underlying chronic-phase MPN2. Chifotides et al retrospectively analyzed 12 patients with IDH-mutated MPN-BP at their institution (7 IDH1 mutated, 5 IDH2 mutated) that received IDH inhibitor-based therapy. A variety of IDH inhibitor-including approaches were employed including IDH inhibitor monotherapy or in combination with ruxolitinib, venetoclax, HMA therapy, or intensive chemotherapy. Seven patients were treated in the frontline setting while 5 were treated in the R/R setting; 25% of patients achieved a CR and the median OS of the entire cohort was 10 months3. A prospective study of ruxolitinib combined with enasidenib for patients with IDH2-mutated MPN-AP/BP and MF is ongoing (NCT04281498); amongst the 5 patients with MPN-AP/BP treated the CR rate was 40% with the longest duration of treatment being 13 cycles and ongoing55. Other prospective efforts investigating IDH inhibition are include utilization of a novel IDH1/2 inhibitor (NCT04603001).

Section snippets

Conclusions

MPN-AP remains an ongoing therapeutic challenge. There is no standard treatment approach. Our current knowledge of molecular pathogenesis, and the emerging promise of select targeted therapeutics dictates consideration of a personalized approach (Figure 1). Given the relative chemo-resistance of this group of diseases, approaches that have the potential to be tolerable and to bridge transplant eligible individuals to an allo-HCT should be considered whenever possible. For those who are

COI

AAP: Research Funding (Institutional) from Pfizer, Kronos Bio, Celgene/BMS; honoraria from Abbvie and Bristol-Myers Squibb

OO: advisory board of Bristol-Myers Squibb, Celgene, Novartis, Taiho and Kymera Therapeutics; DSMB for Threadwell Therapeutics; research funding (institutional) from ABBVIE, Agios, Aprea, Astex, Astra Zeneca, Bristol Myers Squibb, Celgene, CTI, Daiichi, Incyte, Janssen, Kartos, Loxo, Novartis, NS-Pharma and Oncotherapy Sciences.

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Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms

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TRANSLATIONAL CANCER MECHANISMS AND THERAPY| JANUARY 20 2023
Lindsay M. Gurska; Rachel Okabe; Alexandra Schurer; Meng Maxine Tong; Mark Soto; Daniel Choi; Kristina Ames; Shira Glushakow-Smith; Allison Montoya; Ellen Tein; Linde A. Miles; Haiying Cheng; Pamela Hankey-Giblin; Ross L. Levine; Swati Goel; Balazs Halmos; Kira Gritsman
Abstract
Purpose:

The Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAK/STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation.

Experimental Design:

Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/MET/RON/ROS1 inhibitor approved for the treatment of non–small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation.

Results:

We found that crizotinib suppresses proliferation and activation of JAK/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAK/STAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN.

Conclusions:

In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of patients with MPN.

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TP-3654 Showcases Early Signs of Tolerability, Clinical Activity in Myelofibrosis

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By Chris Ryan

The PIM1 kinase inhibitor TP-3654 was well tolerated and showcased preliminary signs of activity, including spleen volume reduction, symptom improvement, and broad cytokine reduction, in patients with myelofibrosis who were previously treated with or were ineligible for a JAK inhibitor.

The PIM1 kinase inhibitor TP-3654 was well tolerated and showcased preliminary signs of activity, including spleen volume reduction (SVR), symptom improvement, and broad cytokine reduction, in patients with myelofibrosis who were previously treated with or were ineligible for a JAK inhibitor, according to results from the dose-escalation portion of a phase 1/2 trial (NCT04176198).

Data presented at the 2022 ASH Annual Meeting showed that among 8 evaluable patients who were on treatment for at least 12 weeks, 6 experienced SVR. The median SVR was 11%; 5 patients had a SVR of at least 10% and 2 had a SVR of at least 35%. Additionally, 7 of the 8 patients experienced an improvement in total symptom score (TSS). The median TSS improvement was 66%, and 5 patients experienced a TSS improvement of at least 50%.

“Dose escalation is ongoing and TP-3654 appears to be well tolerated, [with] no dose-limiting toxicities [DLTs] to date,” said Firas El Chaer, MD, the lead study author and an assistant professor of medicine in the Department of Hematology/Oncology at University of Virginia Health System in Charlottesville, Virginia, in a presentation of the data. “The most common adverse effects are grade 1 gastrointestinal toxicities that resolved in 1 to 2 weeks.”

PIM1 is a proto-oncogene regulated in part through the JAK/STAT pathway, and PIM1 kinase plays a vital role in cytokine-induced signal transduction by controlling transcription factors. The upregulation of PIM1 kinase results in increased cytokines relevant to immune activation and fibrosis. In bone marrow and peripheral blood mononuclear cell samples collected from patients with myelofibrosis, a significant increase of PIM1 expression has been observed. Investigators have hypothesized that novel therapies that selectively inhibit PIM1 may provide disease-modifying effects and avoid instances of cytopenia.

“In an aggressive murine MLP myelofibrosis mouse model, PIM1 inhibition led to reduced bone marrow fibrosis, [reduced] splenomegaly, and increased [overall] survival [OS],” El Chaer added.

The phase 1/2 trial is evaluating the TP-3654 in patients with primary, post–polycythemia vera (PV), or post–essential thrombocythemia (ET) myelofibrosis who are relapsed, refractory, intolerant, or ineligible to receive treatment with JAK inhibitors.

To participate on the trial, patients are required to have a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1, intermediate-2, or high risk; a platelet count of at least 25 x 109 cells/L; an ECOG performance status of 0 to 2; splenomegaly with a volume of at least 450 cm3; and at least 2 symptoms per the Myelofibrosis Symptom Assessment Form v. 4.0.

Thus far in the dose-escalation portion of the trial, patients were treated with single-agent TP-3654 across 5 dose levels, including 480 mg per day, 720 mg per day, 360 mg twice per day, 480 mg twice per day, and 720 mg twice per day. Dose escalation is ongoing, and investigators plan to examine doses up to 1440 mg twice per day. The trial will then determine the maximum tolerated dose (MTD) and the recommended phase 2 dose of the agent before advancing to dose expansion in phase 2.

The primary end points of the trial are safety and tolerability. Secondary end points consist of SVR, TSS reduction, OS, bone marrow fibrosis change, and pharmacokinetics.

Among 9 patients enrolled in the dose-escalation portion of the research, the median age was 71 years (range, 61-77). The median spleen length was 12 cm (range, 0-25), the median spleen volume was 2231 cm3 (range, 857-4407), and the median TSS was 18 (range, 4-62). Additionally, the median platelet count was 120 x 109cells/L (range, 68-237), and 6 patients had a platelet count of at least 100 x 109 cells/L. The median hemoglobin was 10.1 g/dL (range, 5.9-13.7), and 5 patients had a hemoglobin level of at least 10 g/dL. Notably, 2 patients were transfusion dependent.

Patients enrolled to the trial had the following myelofibrosis subtypes: primary (n = 4), post-PV (n = 4), and post-ET (n = 1). They had a DIPSS score of intermediate-1 (n = 3), intermediate-2 (n = 4), or high risk (n = 2). Additionally, 7 patients had tumors that harbored JAK2 V617F mutations, and 2 patients had a CALR mutation.

All 9 patients received prior treatment with ruxolitinib (Jakafi) for a median of 33 weeks (range, 10-268), and 2 patients received prior fedratinib (Inrebic) for a median of 36 weeks (range, 36-49). Three patients were primary refractory to JAK inhibitors, 4 experienced a loss of response, and 2 were intolerant to these agents.

As of the data cutoff date of October 11, 2022, 4 patients were still receiving treatment; this included 2 patients who received TP-3654 at 480 mg twice daily, 1 patient who was given the agent at 720 mg once daily, and 1 patient who received the drug at 720 mg twice daily. Reasons for discontinuation included physician withdrawal (n = 2), disease progression (n = 2), and patient withdrawal (n = 1). Notably, no patients discontinued due to adverse effects (AEs).

Additional data showed that cytokine reduction was observed as early as week 4 for the initial dose cohorts, and this reduction correlated with TSS reduction. Cytokines associated with myelofibrosis—including IL-6, IL-10, IL-12, IL-18, TGF-b, EGFR, ferritin, GRO-a, IL-1RA, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, and VCAM-1—showed reduction after treatment.

Regarding safety, no DLTs or serious treatment-related AEs were reported. The most common treatment-emergent AEs (TEAEs) that were grade 1 or 2 included diarrhea (n = 7), nausea (n = 5), vomiting (n = 4), abdominal distention (n = 2), urinary tract infection (n = 2), muscle spasms (n = 2), insomnia (n = 2), fatigue (n = 2), dyspnea (n = 2), abdominal pain (n = 1), and increased bilirubin (n = 1). Grade 3 vomiting, abdominal pain, and increased bilirubin were experienced by 1 patient each.

Grade 1/2 hematological TEAEs included a decreased platelet count (n = 2), anemia (n = 1), and leukocytosis (n = 1). Grade 3 decreased platelet count, anemia, and leukocytosis were observed in 1 patient each. No patients required a dose reduction or discontinued treatment due to AEs.

“Enrollment continues as [TP-3654] monotherapy to identify the MTD, and [data] support the development of TP-3654 in combination with JAK inhibitors,” El Chaer concluded.

Reference

El Chaer F, McCloskey J, Rein LAM, et al. Preliminary data from the phase I/II study of TP-3654, a selective oral PIM1 kinase inhibitor, in patients with myelofibrosis previously treated with or ineligible for AK inhibitor therapy. Blood. 2022;140(suppl 1):594-595. doi:10.1182/blood-2022-159086

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Momelotinib Continues to Prove Itself as a Potential Treatment for Myelofibrosis

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In an interview with Targeted Oncology, Srdan Verstovsek, MD, discussed the potential use of momelotinib as a treatment for patients with myelofibrosis if approved by the FDA in June 2023.

As updated findings from the MOMENTUM trial (NCT04173494) continue to demonstrate positive results, momelotinib continues to prove its potential as a future treatment option for patients with anemic myelofibrosis.

Momelotinib is an investigational oral treatment for patients with myelofibrosis. The JAK1 and JAK2 inhibitor recently showed benefit in patients with myelofibrosis as momelotinib induced durable symptoms, transfusion independence, and splenic responses through 48 weeks of treatment.

The findings come from the phase 3 open-label, crossover phase of the MOMENTUM study (NCT04173494) which were presented at the American Society of Hematology (ASH) 2022 Annual Meeting.

In this trial, patients were either administered momelotinib or crossed over from danazol to receive momelotinib. Week 24 symptom responses continued through week 48 of treatment in 97% of patients on the momelotinib-to-momelotinib arm compared with 100% in the danazol-to-momelotinib arm.

Further, 29% of patients who crossed over to momelotinib at week 24 and did not have a Total Symptom Score (TSS) response to danazol and achieved TSS responses at week 48. Among patients, 20% who continued momelotinib in this phase of the trial were also new responders at week 48.

According to Srdan Verstovsek, MD, these findings from the MOMENTUM study confirm what have previously been reported in other phase 3 studies, including Simplify 1 study (NCT01969838) and SIMPLIFY 2 study (NCT02101268).

“Improvements in the spleen symptoms and anemia were seen significantly better than danazol. Now we know that these are long lasting benefits, the therapy does not need to be changed, the dose not need to be modified, it is very safe over a prolonged period, it works for a long period of time, and there is a strong suggestion that there may even be a survival benefit in some groups of patients in this setting where life is typically short. I would expect based on this blinded, randomized study that the momelotinib would be approved in United States next June,” stated Verstovsek, MD, associate professor of medicine in the Leukemia department at the University of Texas MD Anderson Cancer Center, in an interview with Targeted OncologyTM.

In the interview, Verstovsek discussed the potential use of momelotinib as a treatment for patients with myelofibrosis if approved by the FDA in June 2023.

Targeted Oncology: Can you discuss the mechanism of action of momelotinib?

Verstovsek: Momelotinib is an interesting medication that inhibits JAK1 and JAK2, which is something that we would expect to benefit patients with the myeloproliferative neoplasms, particularly myelofibrosis, in inhibiting proliferation and inflammation and leading to some clinical benefits like improving quality-of-life, and the reduction in the spleen. It also uniquely improves anemia and that is because it’s an ACVR1 inhibitor. ACVR1 is also called ALK-2, [which is] a receptor on the liver where inhibition of that receptor would alter the iron metabolism. It decreases hepcidin, a master regulator of iron metabolism, and allows more iron to be available for erythropoiesis, the blood making process. Therefore, this medication would inhibit more than what you would expect with the JAK inhibitor and lead to clinical benefits on all 3 fronts: The spleen, the symptoms, and the anemia benefits.

Can you discuss the MOMENTUM study of momelotinib in patients with symptomatic and anemic myelofibrosis?

At this age, we have learned a lot from the MOMENTUM study. This is the 1 that finally confirmed what we have seen earlier on in 2 other phase 3 studies. The study is the phase 3 randomized study, blinded, between 2 therapies, momelotinib and danazol in the second-line setting. The standard practice frontline therapy is ruxolitinib [Jakafi], a JAK inhibitor that improves the spleen and symptoms but can worsen anemia. Anemia is the leading cause of why you stop ruxolitinib. Many patients, most of them are anemic when they get to the second-line, so that would be the setting for the development of a new drug like momelotinib. This is where the phase 3 study was done.

Improvements in the spleen symptoms and anemia were seen significantly better than danazol. Now we know that these are long lasting benefits, the therapy does not need to be changed, the dose not need to be modified, it is very safe over a prolonged period, it works for a long period of time, and there is a strong suggestion that there may even be a survival benefit in some groups of patients in this setting where life is typically short. I would expect based on this blinded, randomized study that the momelotinib would be approved in the United States next June.

What studies complement the MOMENTUM trial?

There is a study called the Simplify 1 study which was a frontline study comparing momelotinib with ruxolitinib where momelotinib was as effective as ruxolitinib in controlling the spleen. It was also better than ruxolitinib in the control of anemia, so anemia benefit was already seen in the past. The Simplify 2 study is a phase 3, randomized study in people who had the hematological toxicities from ruxolitinib. They were randomized between momelotinib or best radiotherapy. In that setting as well, there were anemia benefits and symptomatic improvements. There are multiple sources, several phase 3 studies, when you put them together to tell us that this drug is unique [and has the] ability to help a good proportion of patients on anemia, on the spleen, and on the symptoms.

What are some of the data from the studies? What sets them apart from one another?

Transfusion independence is a hallmark of a drug that we seek, in a good way, because anemia may be of a different degree. We talk of anemia, loosely described, as a hemoglobin less than 10. There are patients that have hemoglobin less than 10 but are not symptomatic and don’t need intervention. When you start transfusions, you become transfusion-requiring or even transfusion-dependent [where you need] 2 transfusions monthly for a few months, and that is the different ballgame. Here, we talk about the therapy that would prevent transfusions to happen or eliminate the need for transfusions in about a third of the patients in a second-line setting. Similar happened earlier in studies of momelotinib, the Simplify 1 or Simplify 2 studies, in frontline or intolerant patients. Therefore, we have plenty of evidence of the uniqueness of this medication. We will account for its use in a wider group of patients when it comes, and hopefully it will become available for us in community settings.

What are the next steps for this research?

[The next step is looking at] how to optimize the therapy amount further. If we have on 1 hand the ruxolitinib medication as a frontline choice to control the spleen symptoms and for the second setting, we have momelotinib in addition to pacritinib and fedratinib [Inrebic], where else can we see improvements? Well, combination studies with the novel agents may complement what the JAK inhibitors do further. Further improvement in anemia, further improvement in spleen, and the symptoms. Finally, [looking at] potential combinations with the non-JAK inhibitors. Clinical studies of combinations are underway [and evaluating] what would set them apart, not only enhancement of these 3 benefits, but your ability of a control the disease signs and symptoms to say hey, with this combination, maybe with a momelotinib-based combination with another agent, we are going to enhance the control of anemia, spleen, and symptoms, but it will last much longer where overall survival is prolonged. This is where we are heading.

What other ongoing research in the MPN space seems exciting to you?

Momelotinb is the 1 that will be practice changing as it comes available next summer. In a plenary session [at ASH], there was a clinical presentation of something that may have a significant impact on the subgroup of patients with myelofibrosis or MPN in general. I’m talking about the development of the antibody that would target mutated calreticulin. Now, what is muted calreticulin? We know that everybody has hyperactivity over the JAK/STAT pathway, an intracellular signaling pathway, that drives this process. We also know that about a third of the patients have a mutation in a gene called calreticulin, it makes muted calreticulin that comes outside the cell and binds to the receptors from outside the cells in the bone marrow and makes the cells grow without control. That is the case in about a third of the patients. Developing the antibody that would attach itself to the mutated calreticulin and destroy that malignant cell is a desirable next step in the development of our medications. Targeting a genetically identifiable group of people with the marker that you can then utilize for the elimination of malignant cells.

This is where we all aspire to go. To start to talk about the molecular response. Not only control the signs and symptoms, but elimination of the disease and molecular response. So it was very exciting for a plenary session and hopefully within a few years, we will have a study with the calreticulin antibody.

In this past year, what would you say has been the most impactful research in the MPN space?

Understanding the preclinical complexity of the disease over the last 5-10 years led to the development of many different drugs that have nothing to do with the hyperactivity of the JAK/STAT pathway which is present in every case. We now potentially have 4 different JAK inhibitors. But understanding the 4 as I mentioned, the ACVR1 contribution to anemia, contribution of the epigenetic modifications or BCL-xl enhancement, or telomerase role in the disease process, these types of discoveries led to clinical studies with these specific medications for the different molecular or biological abnormalities in myelofibrosis cells. Understanding the biology better leads to clinical development of new drugs and that on its own is exciting. We have about 7 or 8 phase 3 randomized studies underway in myelofibrosis for the development of new drugs with medications that are not JAK2 inhibitors.

How do you foresee this research on momelotinib potentially impacting clinical practice?

As June of [this] year comes, we are expected to get the decision by FDA to approve or not approve momelotinib. I hope it will because the study was well done and clearly shows the benefit of the anemia symptoms and spleen. Right away we would find its place in the management of our patients with myelofibrosis, particularly where the phase 3 randomized study was done in the second-line setting where we struggle. We don’t have any therapies for anemia, people may have low platelets, and this drug can be given to people with lower platelets. Of course, it can control the spleen. The spleen has major problems, so I would say that these drugs may become the number 1 choice as a therapy in a secondary setting in myelofibrosis in the near future.

REFERENCE:
Gerds AT, Mesa RA, Vannucchi AM, et al. Updated results from the Momentum phase 3 study of momelotinib (MMB) versus danazol (DAN) in sympatomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 627

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Cellenkos Announces First Patient Dosed with CK0804 Cell Therapy in LIMBER-TREG108 Clinical Trial

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Category: DNA RNA and Cells

Published on Saturday, 07 January 2023 18:23

  • First patient dosed with CK0804 Treg cells as an add on therapy to ruxolitinib in patients with myelofibrosis who experience a suboptimal response to ruxolitinib.
  • On-going Phase 1b study evaluating safety of CK0804

HOUSTON, TX, USA I January 06, 2023 I Cellenkos Inc, a clinical stage biotechnology company focused on the development of allogeneic, off-the-shelf, T regulatory cell therapies targeting inflammatory disorders and autoimmune diseases, today announced that the first patient was dosed in the Phase 1b LIMBER-TREG108 study evaluating CK0804 as an add on therapy to ruxolitinib in patients with myelofibrosis who experience a suboptimal response to ruxolitinib. CK0804 is a novel allogeneic, CXCR4 enriched, T regulatory cell therapy product that utilizes Cellenkos’ proprietary CRANE™ technology to generate disease specific products.

The LIMBER-TREG108 trial (NCT05423691) is part of a development collaboration between Cellenkos and Incyte.

“This is an exciting milestone for our company. The initiation of this study of CK0804 as on add on therapy to ruxolitinib is an important achievement that brings us closer to delivering a potential new treatment which may have a life-changing impact for myelofibrosis patients who have less than optimal response to treatment with ruxolitinib,” said Tara Sadeghi, Chief Operating Officer of Cellenkos Inc., “Myelofibrosis patients who do not respond to ruxolitinib have limited treatment options and can progress to leukemia. This experimental immunotherapy treatment in combination with the standard of care may represent a new hope for the patients with myelofibrosis potentially enhancing the efficacy of current JAK inhibitor therapy while also offering possible immune modulation and restoration of impacted hematopoiesis.”

LIMBER-TREG108 is a multicenter study at The University of Texas MD Anderson Cancer Center, The University of Columbia Hospital and University of California, Davis. The study is led by principal investigator Lucia Masarova, M.D., Assistant Professor of Leukemia at MD Anderson. This Phase 1b study will evaluate the safety, pharmacodynamics and immunogenicity of intravenous CK0804, administered monthly for up to 6 doses. The study will consist of 2 phases: an open-label safety run-in of 9 patients (Stage 1) and an expansion cohort of 15 additional patients (Stage 2).

“We are pleased that the first patient first dose milestone in the LIMBER-TREG108 study – one of several studies in our LIMBER clinical program evaluating multiple monotherapy and combination strategies to improve and expand treatments for patients with MPNs – has been achieved. We look forward to the results of the study, and to continuing our partnership toward important scientific advances for these patients,” said Ekaterine Asatiani, M.D., Division Vice President and Head of Early Development at Incyte.

About Myelofibrosis

Myelofibrosis is a rare, chronic and progressive blood cancer that is part of a group of diseases known as myeloproliferative neoplasms. In myelofibrosis, scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells. This can result in an enlarged spleen, as well as symptoms such as fatigue, itching and night sweats, which can severely impact a patient’s quality of life. About 16,000 to 18,500 people in the U.S. are living with myelofibrosis1. Patients who have had a suboptimal response to the standard of care treatment have limited options and a poor prognosis.

About CK0804

CK0804 is a novel allogenic cell therapy product consisting of T-regulatory cells that exploit the CXCR4/CXCL12 axis and are derived from clinical-grade umbilical cord blood units and manufactured using Cellenkos’ proprietary CRANE™ process. Multiple doses of CK0804 can be manufactured from a single umbilical cord blood unit, where the final cryopreserved product is readily available for use. No requirement for HLA matching to the patients makes CK0804 an ideal therapy that can be infused intravenously, in the outpatient setting.

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