Protagonist and Takeda Announce Positive Topline Results from Phase 3 VERIFY Study of Rusfertide in Patients with Polycythemia Vera

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March 3, 2025

− Study met the primary endpoint, with a significantly higher proportion of clinical responders on rusfertide compared to placebo

− All four key secondary endpoints were met, including EU primary endpoint and patient-reported outcomes

− Rusfertide was generally well tolerated; no new safety findings were observed in the study

NEWARK, Calif. & OSAKA, Japan & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Protagonist Therapeutics, Inc. (“Protagonist”) (NASDAQ:PTGX) and Takeda (TSE:4502/NYSE:TAK) today announced positive topline results for the Phase 3 VERIFY study, in which phlebotomy-dependent patients with polycythemia vera (PV) were randomized to treatment with either rusfertide or placebo, as an add-on to standard of care treatment. The study met its primary endpoint and all four key secondary endpoints. Rusfertide is a first-in-class investigational hepcidin mimetic peptide therapeutic, which has received Orphan Drug designation and Fast Track designation from the U.S. Food & Drug Administration (FDA).

Key findings from the study include:

  • The primary endpoint of the study was met, with a significantly higher proportion of clinical responders1 among rusfertide-treated patients with PV (77%) compared to those who received placebo (33%) during weeks 20-32; p<0.0001. The primary endpoint of the study was the proportion of patients achieving a response, which was defined as the absence of phlebotomy eligibility.
  • The first key secondary endpoint, which is the pre-specified primary endpoint for European Union (EU) regulators, was also met, with a mean of 0.5 phlebotomies per patient in the rusfertide arm compared to 1.8 phlebotomies per patient in the placebo arm during weeks 0-32; p<0.0001.
  • The other three pre-specified key secondary endpoints, namely hematocrit control2 and patient-reported outcomes using PROMIS Fatigue SF-8a3 and MFSAF TSS-74, were also achieved with statistical significance.
  • Rusfertide was generally well tolerated in the Phase 3 VERIFY trial, and safety was in line with previous rusfertide clinical studies. No new safety findings were observed in the study. The majority of adverse events were grade 1-2 injection site reactions and all serious adverse events reported were deemed to be not drug related. There was no evidence of an increased risk of cancer in rusfertide-treated patients compared to those on placebo.

“The positive results of the Phase 3 VERIFY study across the primary and all key secondary endpoints provide compelling evidence of the potential for rusfertide as a first-in-class erythrocytosis-specific agent to address unmet medical needs in patients with PV who are unable to achieve adequate hematocrit control despite standard of care treatments,” said Arturo Molina, M.D., M.S., Chief Medical Officer of Protagonist. “We plan to submit additional details of these promising results for presentation at upcoming medical conferences in 2025. We are immensely grateful to the patients, study staff and principal investigators who made the VERIFY study possible.”

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Genetic Testing Breakthroughs in Blood and Lymph Cancers

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February 28, 2025

Hematopoietic and lymphocytic neoplasms (HLNs) are a diverse group of malignancies affecting blood and lymphatic systems, with outcomes varying from manageable conditions to fatal diseases. Traditional classifications rely on morphology, karyotyping, and fluorescence in situ hybridization (FISH). However, recent advancements in next-generation sequencing (NGS) allow simultaneous genetic profiling of multiple genes, enhancing diagnostic precision and therapeutic strategies. This review examines key molecular applications in diagnosing and managing HLNs, addressing current challenges and proposing solutions to optimize clinical utility.

Chronic Myeloid Leukemia (CML)

CML, historically identified by leukocytosis, is characterized by the BCR::ABL1 fusion gene resulting from the Philadelphia chromosome translocation. This oncogenic fusion drives aberrant tyrosine kinase activity, promoting unchecked proliferation. The introduction of imatinib, a targeted tyrosine kinase inhibitor (TKI), revolutionized CML treatment, leading to normalized white blood cell (WBC) counts within months. However, resistance mutations necessitate molecular monitoring via quantitative PCR, FISH, and karyotyping, ensuring optimal therapeutic adjustments.

Molecular Applications in BCR::ABL1-Negative Myeloid Neoplasms

Certain myeloid neoplasms, such as chronic neutrophilic leukemia (CNL) and chronic eosinophilic leukemia (CEL), lack the BCR::ABL1 fusion gene but exhibit distinct genetic markers like CSF3R mutations in CNL. Classical myeloproliferative neoplasms (MPNs) include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, driven by JAK2, MPL, or CALR mutations. The application of NGS enables comprehensive mutational profiling, aiding accurate diagnosis and prognostication.

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Patients With MF Who Failed Ruxolitinib Treatment May Benefit From Fedratinib

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Özge Özkaya, MSc, PhD
Publish Date

Fedratinib treatment is effective in patients with myelofibrosis (MF) who discontinued ruxolitinib due to treatment failure, according to data from a real-world study published in the scientific journal Future Oncology.

The findings of this study offer a new option for patients with MF whose disease does not respond to ruxolitinib treatment.

To assess the real-world treatment patterns with fedratinib as well as clinical outcomes in patients with primary or secondary MF after ruxolitinib discontinuation, a team of researchers conducted a retrospective, noninterventional medical record review of 196 patients with MF in Germany, Canada, and the United Kingdom.

Data about the patients was provided by 70 physicians of whom 78.6% were primarily hematologists or oncologists.

Of these 196 patients, the majority (76.5%) had primary MF and started treatment with fedratinib at a mean age of 67.7 .

The median duration of treatment with fedratinib was 11.5  months and the median follow-up period was 13.8  months.  Almost half (49.5%) of patients started fedratinib at the dose indicated on the label, i.e. 400  mg per day.

Six months after the start of treatment with fedratinib, 77.7% of patients had symptom response and 66.8% had spleen response.

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Comparison of recognition of symptom burden in MPN between patient- and physician-reported assessment – an intraindividual analysis by the German Study Group for MPN (GSG-MPN)

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Kirsi Manz, Florian H. Heidel, Steffen Koschmieder, Rudolf Schlag, Jörg Lipke, Frank Stegelmann, Martin Griesshammer, Martine Klausmann, Carl Crodel, Andreas Hochhaus, Holger Schulz, Joachim R. Göthert, Haifa Al-Ali, Heiko Becker, Andreas Reiter, Gernot Beutel, Kim Kricheldorf, Tim H. Brümmendorf, Wolfgang Hoffmann, Konstanze Döhner & Susanne Isfort On behalf of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Abstract

Myeloproliferative neoplasms (MPN) are associated with a variety of symptoms that severely impact patients’ quality of life and ability to perform daily activities. Recent studies showed differences in the perception of physician- versus patient-reported symptom burden. However, studies directly comparing patient- and physician-reported ratings are lacking. Here, a retrospective analysis on symptom burden of 3979 MPN patients of the Bioregistry of the German Study Group for MPN was conducted to intra-individually compare physician and patient reports collected at the same time. Cohen’s kappa was calculated to assess the degree of agreement between patient and physician reports. Factors influencing baseline symptom severity were identified using linear regression and adjusted Cox models were calculated to investigate the effect of symptom burden on survival. MPN patients had a high symptom burden, which neither decreased over time nor upon cytoreductive therapy. All symptoms were more frequently reported by patients compared to physicians. Agreement remained low and only slightly improved when considering a higher threshold for patient symptom severity. Patients with severe symptom burden had inferior survival compared to patients with less severe symptoms. Assessment of symptom burden in MPN is therefore insufficient and patient-reported outcome tools need to be implemented into clinical routine.

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Divesiran Is Tolerable and Shows Positive Early Signals in Polycythemia Vera

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February 26, 2025

Author(s): Kyle Doherty

Fact checked by: Megan Hollasch

Divesiran (SLN124), a novel small interfering RNA (siRNA), was safe and displayed signals of efficacy in the treatment of patients with polycythemia vera, according to findings from the phase 1/2 SANRECO trial (NCT05499013).1

Initial results from SANRECO presented during the 2024 ASH Annual Meeting showed that divesiran reduced phlebotomy frequency in patients (n = 21). A total of 79 phlebotomies occurred across all patients prior to dosing; there were 5 phlebotomies during the treatment period and 2 during follow-up among all patients. Divesiran also induced hepcidin in all patients and decreased hematocrit in all cohorts of patients treated.

Additionally, patients did not experience any dose-limiting toxicities. Most treatment-emergent adverse effects (TEAEs) were grade 1 in severity (84%) and there were no TEAEs above grade 2 reported. There were also no treatment-related serious AEs or TEAEs leading to treatment discontinuation.

Divesiran is a first-in-class GalNAc-conjugated siRNA that targets TMPRSS6, a negative regulator of the HJV/BMP/SMAD signaling pathway that induces hepcidin expression. The agent is designed to have a long duration of action, and, notably, it’s target sequence is unique to TMPRSS6 and was selected to maximize TMPRSS6 knock down. Investigators hypothesized that inhibiting TMPRSS6 would raise hepcidin levels and lower iron delivery to the bone marrow, leading to reduced erythropoiesis.

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Management of Bleeding, Thrombotic and Pregnancy-Related Complications in Women with Myeloproliferative Neoplasms: A Case-Based Review Focusing on Sex-Specific Challenges

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February 25, 2025

by Thita Chiasakul and Ross I. Baker

Abstract

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic disorders that pose unique challenges in women, particularly regarding thrombosis, bleeding, fertility, and pregnancy. Women with MPN exhibit distinct thrombotic and sometimes contradictory bleeding profiles, including a higher prevalence of unusual thrombosis such as cerebral and splanchnic vein thrombosis and increased risk of hemorrhage from anti-thrombotic medication, acquired von Willebrand syndrome and platelet dysfunction. Estrogen-containing contraceptives should generally be avoided due to thrombotic risk. Around 10–20% of newly diagnosed MPN cases are women of childbearing age and the number is increasing annually. MPN patients when compared to controls have a lower rate of live birth rate of 71% vs. 80% with a hazard ratio of 0.78 (95% CI: 0.68–0.90), and increased preterm birth (14% vs. 4%), low birth weight (<2500 g, 10% vs. 4%), and increased cesarean section rate (32% vs. 17%). Management of MPN-related pregnancy requires specific considerations regarding the prevention of thrombosis, bleeding, and pregnancy-related complications. Management strategies during pregnancy include low-dose aspirin and consideration of low-molecular-weight heparin and interferon. Despite these challenges, most women with MPN can achieve successful pregnancies with optimized care. In this case-based review, we present two cases that illustrate key aspects of managing MPN in women, summarize the current literature, and propose a diagnostic and management framework tailored to these complexities.

Fedratinib Shows Safety, Potential as Post-Transplant Therapy in MPNs

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February 21, 2025

Fedratinib (Inrebic) as a maintenance therapy following allogeneic hematopoietic cell transplant given at a 400 mg daily dose was determined to be safe and established as the maximum tolerated dose (MTD) for patients with myeloproliferative neoplasms (MPNs).1 

Findings come from a recent phase 1 trial where experts explored the potential of fedratinib, a JAK2 inhibitor already approved for pre-transplant myelofibrosis, as a post-transplant maintenance therapy to reduce relapse risk and mitigate graft-vs-host disease (GVHD).

In an interview with Targeted OncologyTM, Hany Elmariah, MD, associate member at the Moffitt Cancer Center in the department of bone marrow transplant and cellular immunotherapy, discussed the trial’s findings, the safety profile of fedratinib, and its evolving role in the post-transplant setting.

Targeted Oncology: Could you discuss the background of this study and what motivated the research?

Elmariah: One of my areas of research is transplant for myelofibrosis and myeloproliferative neoplasms. While transplant can be curative, the cure rate, depending on the study, is generally in the 40% to 60% range. The main reason patients are not cured by transplant is largely the risk of relapse, which [occurs when] the cancer returns after the transplant. For those who do not relapse, there is also the risk of toxicity, such as GVHD, where the transplant attacks the patient’s own body. There are many strategies in development, both for myelofibrosis and other cancers, to reduce the risks of relapse and GVHD.

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Spotlight on amino acid changing mutations in the JAK-STAT pathway: from disease-specific mutation to general mutation databases

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February 20, 2025

Markus Hoffmann & Lothar Hennighausen

Abstract

The JAK-STAT pathway is central to cytokine signaling and controls normal physiology and disease. Aberrant activation via mutations that change amino acids in proteins of the pathway can result in diseases. While disease-centric databases like COSMIC catalog mutations in cancer, their prevalence in healthy populations remains underexplored. We systematically studied such mutations in the JAK-STAT genes by comparing COSMIC and the population-focused All of Us database. Our analysis revealed frequent mutations in all JAK and STAT domains, particularly among white females. We further identified three categories: Mutations uniquely found in All of Us that were associated with cancer in the literature but could not be found in COSMIC, underscoring COSMIC’s limitations. Mutations unique to COSMIC underline their potential as drivers of cancer due to their absence in the general population. Mutations present in both databases, e.g., JAK2Val617Phe/V617F – widely recognized as a cancer driver in hematopoietic cells, but without disease associations in All of Us, raising the possibility that combinatorial SNPs might be responsible for disease development. These findings illustrate the complementarity of both databases for understanding mutation impacts and underscore the need for multi-mutation analyses to uncover genetic factors underlying complex diseases and advance personalized medicine.

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Fedratinib in 2025 and Beyond: Indications and Future Applications

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Alexander Coltoff (Medical University of South Carolina, United States) John Mascarenhas (Icahn School of Medicine at Mount Sinai, United States)

Abstract

Dysregulated JAK/STAT signaling underlies the pathogenesis of myelofibrosis, a myeloproliferative neoplasm characterized by cytopenias, splenomegaly and constitutional symptoms. JAK inhibitors, such as fedratinib, are the primary therapeutic option for patients with high-risk or symptomatic myelofibrosis. Fedratinib has characteristics that distinguish it from the other commercially available JAK inhibitors, such as its preferential inhibition of JAK2 and its inhibitory effects on kinases such as FLT3 and BRD4. Fedratinib is most often used in the second-line setting after intolerance or resistance to other JAK inhibitors, but there is substantial evidence that it is an effective first-line option in the appropriate patient population. Prevention and early treatment of fedratinib-related gastrointestinal toxicity is key to maintaining adequate drug exposure, and clinicians must remain vigilant for Wernicke encephalopathy during treatment. Fedratinib’s JAK2 selectivity and kinome profile make it an appealing agent for alternative indications, such as myelodysplastic/myeloproliferative neoplasms and maintenance after bone marrow transplantation, which are under active investigation.

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4 Ways Polycythemia Vera Can Affect Your Quality of Life — and What You Can Do About It

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By Jessica Migala
Published on February 14, 2025
by Walter Tsang, MD
Just like any chronic health condition, polycythemia vera (PV) can have a negative impact on your everyday life. Research has shown that PV is associated with a lower quality of life in measures, including health, cognitive, emotional, and physical functioning.

Symptoms such as fatigue, itchy skin, and mental health issues can make it difficult to function, but they can be managed. “This is a chronic condition that people can live with,” says Jacqueline S. Garcia, MD, a medical oncologist at Dana-Farber Cancer Institute in Boston.

Here are some common challenges of living with PV and ways to cope, so you can stay healthy and live well as you manage this condition.

1. Fatigue Can Interfere With Daily Activities

Fatigue is one of the most common symptoms of PV. “Polycythemia vera is a blood disorder that stems from an error in the bone marrow,” says Dr. Garcia. As a result, bone marrow overproduces red blood cells, causing the body to use up your iron supply. This results in iron deficiency, which leads to fatigue, she explains.
Another factor that can contribute to fatigue is phlebotomy treatment, which is a procedure that involves drawing blood to reduce blood cells and blood volume. A common side effect of this treatment is increased fatigue and iron deficiency, according to Garcia.

The degree of fatigue can vary from one person to another and depend on age, menopausal status, other health conditions — such as cardiovascular disease or diabetes — and more factors, says Garcia.

What to do about it: When it comes to polycythemia vera fatigue, research found that fatigue was a bigger problem for people who had a higher BMI, continued to drink alcohol or use tobacco, and didn’t exercise.

Maintaining healthy lifestyle habits may help you feel more energized every day. For instance, Garcia recommends exercising in moderation, as long as you have your doctor’s okay and don’t push yourself if you feel faint.

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