Category Archives: Polycythemia Vera

Understanding Hematocrit Thresholds in Polycythemia Vera Treatment

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March 19, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

In early March, The American Journal of Managed Care® spoke with Andrew Kuykendall, MD, a clinical researcher at Moffitt Cancer Center who focuses on myeloproliferative neoplasms (MPNs), myelodysplastic syndrome/MPN overlap syndromes, and systemic mastocytosis. Kuykendall is an investigator on the phase 3 VERIFY trial (NCT05210790) of the injectable hepcidin mimetic rusfertide (Takeda) to treat polycythemia vera (PV) by enabling patients to achieve and sustain hematocrit control.1 Hematocrit is the measure of the percentage of red blood cells in the body.2

Treatment guidelines in PV currently recommend maintaining hematocrit below 45%, with a higher threshold for men vs women.2 For part 2 of this interview, Kuykendall explains the reasoning behind having different hematocrit thresholds.

In the first part of the interview, Kuykendall discussed how PV manifests and common ways to reduce its negative impact on patient quality of life.

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Managing Polycythemia Vera to Reduce Risks and Improve Lives

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March 5, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

Polycythemia vera is a classic myeloproliferative neoplasm and a chronic type of leukemia, which often leads to overproduction of various blood cells. Several medications are approved to treat this condition—among them ruxolitinib (Jakafi; Incyte), in December 2014,1 and ropeginterferon alfa-2b-njft (Besremi; PharmaEssentia), in November 20212—and others remain in clinical development. Rusfertide (Takeda) is currently being investigated in the phase 3 VERIFY trial (NCT05210790), with an estimate study complete date of June 2025.3 The hepcidin mimetic has already received breakthrough therapy, orphan drug, and fast track designations from the FDA.

In this interview, Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center and a VERIFY investigator, breaks down how polycythemia vera manifests and common ways to reduce its negative impact on patient quality of life while reducing the risk of clinically worsening events.

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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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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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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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Getting Closer to Disease Modification in Polycythemia Vera

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February 2025 Vol 11 No 1

Dr. Lucia Masarova

Polycythemia vera was first recognized by French physician Louis H. Vaquez in 1892 and was known then as maladie de Vaquez.1 The name poly-cyt-[h]emia originates from the Greek and Latin, and literally means many-cells-in the blood. In 1951, Dr. William Dameshek included polycythemia vera in the category of classic Philadelphia chromosome–negative myeloproliferative disorders (now classified as myeloproliferative neoplasms, MPNs; myelo refers to the bone marrow, proliferative refers to rapid growth of blood cells, and neoplasm describes abnormal and excessive growth). It is the only one among the 3 classic MPNs that exhibits erythrocytosis, the increased production of red blood cells. Polycythemia vera is a condition associated with overproduction of all blood cells, including white cells and platelets.

Polycythemia vera is a chronic, incurable disease of the hematopoietic stem cells, the primary cells that can develop into different types of blood cells and are responsible for the production of blood cells during a human’s entire life. It is a clonal disease, meaning it occurs when a mutated hematopoietic stem cell starts making clones—cells with the same genetic mutation. Most affected patients can live a relatively normal and long life.

A breakthrough discovery of a genetic “driver” of polycythemia vera was made in 2005—a mutation in the JAK2 gene was found in 95% of cases, typically JAK2V617F, a mutation that leads to the constitutive activation of the JAK-STAT protein pathway causing unregulated overproduction of hematopoietic cells. This discovery led to improved understanding of the biology, pathogenesis, and long-term behavior of the disease and initiated numerous efforts to develop novel therapies focused on the inhibition of the JAK-STAT pathway.

The abnormal function of the immune system and the subsequent increased inflammation, powerfully driven by the JAK-STAT pathway as the major regulator of inflammatory signaling, contribute to disease progression and an impaired quality of life. Despite the relatively slow progression of the disease course in most patients, the disease possesses its challenges and risks, including a lifetime risk of developing thrombosis (blood clots); the evolution into myelofibrosis, a chronic type of leukemia; or development into acute leukemia. Both blood clots and leukemia are consequences that can shorten life expectancy significantly.

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Genetic Links to High Altitude Found to Reduce Inflammation, Speed Response to PV Therapy

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December 10, 2024

Author(s): Mary Caffrey

Questions about why an indigenous population living the Andes Mountains of South American had elevated hemoglobin led to the discovery that a variant linked to living at high altitude is also tied to reduced inflammation, as well as improved response to a therapy used to treat myeloproliferative neoplasms (MPNs).1

Jihyun Song, PhD | Image credit: University of Utah

The research to be presented today at the 66th American Society of Hematology Annual Meeting & Exposition in San Diego, California, could lead to more precise treatments for polycythemia Vera (PV) and essential thrombocythemia (ET). Today, these 2 are treated with ropeginterferon-α (Besremi), and the work led by Jihyun Song, PhD, of Huntsman Cancer Institute at the University of Utah, now shows that populations with Andean enriched NFKB1 haplotype respond better to ropeginterferon-α.

The study has been accepted for publication in Nature Communications.

PV and ET are both associated with overproduction of blood cells; PV causes the bone marrow to produce too many red blood cells, while ET produces too many platelets. Both PV and ET can lead to chronic inflammation, increase the risk of blood clots, and progress to leukemia. These conditions also increase hypoxia-inducible factors (HIFs), which can impact the survival of cancer cells in low-oxygen environments.

At a press briefing prior to Song’s presentation today, senior author Josef T. Prchal, MD, a physician scientist who holds the Charles A. Nugent, MD, and Margaret Nugent Endowed Professorship in Medicine/Hematology at the University of Utah, explained that the genetic variants that developed over time to allow the Aymara people survive in the Andes can be seen in some other populations—and they correlate with some differences in MPN phenotypes.

Josef Prchal, MD | Image credit: Photo supplied by ASH

“Our study suggests that with genotyping, the NFKB1 variant can be used as a biomarker for determining which patients may be more or less responsive to ropeginterferon-α treatment,” Prchal said.

He opened his remarks with an overview of how populations evolve with their environments; not only the Aymara but also Tibetans and Ethiopians have adapted to altitude in different ways, which he explored in earlier papers in Science2 and Nature Genetics,3 among others.

It is known that when humans spend time high altitude, their bodies adapt to reduced oxygen levels by increasing hemoglobin concentrations in the blood. This allows the body to carry more oxygen. Prchal explained how Song took this knowledge further. “We set up to try to find the gene which explains the hemoglobin,” he said.

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Ten years of experience with ruxolitinib since approval for polycythemia vera: A review of clinical efficacy and safety

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Lucia Masarova MD1 | John Mascarenhas MD, MS2 | Raajit Rampal MD, PhD3 | Wilson Hu MD4 | Robert A. Livingston MD, MPH4 | Naveen Pemmaraju MD1

Abstract
The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was approved by the US Food and Drug Administration in 2014 for the treatment of patients with polycythemia vera (PV) who have an inadequate response to or intolerance of hydroxyurea (HU). PV is a chronic myeloproliferative neoplasm defined by primary absolute erythrocytosis, bone marrow hypercellularity, and JAK mutations such as JAK2V617F. Patients with PV experience burdensome symptoms and are at risk of thromboembolic events, in particular those with resistance to or intolerance of initial treatments such as HU. Other risks for patients with PV include progression of disease to more aggressive forms with worse prognoses, such as myelofibrosis or blast‐phase myeloproliferative neoplasms. This review summarizes the efficacy and safety of ruxolitinib from key phase 2 and 3 trials (MAJIC‐PV, RESPONSE, RESPONSE‐2, RELIEF, and Ruxo‐BEAT), large real‐world studies, and a decade of postmarketing surveillance safety data. The authors focus on improved blood count control, rates of thromboembolic events, symptom improvement, and markers of disease modification such as reduction of JAK2V617F allele burden in patients treated with ruxolitinib. They also discuss the well‐characterized safety profile of ruxolitinib regarding hematologic and other adverse events of interest. In the 10 years since its approval, ruxolitinib remains a safe and effective standard‐of‐care treatment for PV. As the treatment landscape for PV continues to evolve in the coming years, the efficacy and safety profiles of ruxolitinib suggest it will remain a
preferred treatment as monotherapy and as a potential backbone of future combination regimens.

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Rusfertide Reduces Phlebotomy Need, Improves Symptom Control in Polycythemia Vera

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November 21, 2024

Author(s): Alexandra Gerlach, Associate Editor

Rusfertide (Takeda; Protagonist Therapeutics Inc) controlled erythrocytosis, maintained a hematocrit of less than 45% and reduced or eliminated the use of phlebotomy in patients with polycythemia vera (PV), according to data from the REVIVE trial (NCT04057040). Published in The New England Journal of Medicine, the results suggest the agent could become an additional therapeutic tool to reduce disease-related symptoms and the need for phlebotomy.1,2

Blood cells | Image Credit: © Ifti Digital – stock.adobe.com

PV is a rare type of blood cancer characterized by the overproduction of red blood cells in the bone marrow, contributing to blood clots, as well as the development of other blood disorders, such as myelofibrosis (MF). Both PV and MF are types of BCR‐ABL1‐negative myeloproliferative neoplasms with shared mutations and are associated with risk of thrombosis, hemorrhagic complications, and progression to acute myeloid leukemia. Approximately 1 in 4 patients with PV will develop MF, which is referred to as post–polycythemia vera myelofibrosis.3-5

Standard-of-care treatment for PV focuses on symptom reduction including treatments for to reduce itching or control blood cell counts, using agents such as hydroxyurea (Droxia; Bristol Myers Squibb) or ruxolitinib (Jakafi; Incyte Corp). The most common treatment for PV is frequent blood withdrawals to decrease blood volume, which is done via phlebotomy.5

Rusfertideis is an injectable, peptide mimetic of hepcidin. Hepcidin, produced in the liver, is a master regulator of iron trafficking. Some preclinical models suggest that increasing hepcidin could help control red blood cell production in patients with PV. In the phase 2 REVIVE trial, rusfertide demonstrated favorable safety and efficacy, with the potential to greatly decrease or eliminate the need for phlebotomy.2

The international, phase 2 REVIVE trial is divided into 2 parts. In part 1, patients were enrolled in a 28-week dose-finding assessment of rusfertide. In part 2, a double-blind, randomized withdrawal period, patients were assigned 1:1 ratio to receive either rusfertide (n = 30) or placebo (n = 29) for 12 weeks. The primary end point was response, which was defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Outcomes were reported by patients and were assessed using the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).2

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Ropeginterferon Alfa-2b Demonstrates Similar Pharmacokinetics Across Ethnic Groups With PV

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Andrea S. Blevins Primeau, PhD, MBA

The pharmacokinetic (PK) profile of ropeginterferon alfa-2b (Ropeg) was consistent between Chinese and Caucasian populations with polycythemia vera (PV), according to a modeling study published in Frontiers in Pharmacology.

These results confirm “its efficacy and safety in the global treatment of PV” and “support the broader application of Ropeg in diverse patient populations,” the researchers wrote in their report.

The researchers used data from studies of Ropeg in subjects without myeloproliferative neoplasms (MPN) and among patients with PV to perform modeling analyses for PK parameters, efficacy, and safety in Chinese and Caucasian populations.

PK was assessed using a population PK model using data from phase 1 studies of Chinese and Caucasian volunteers without MPN. There was no significant difference in Ropeg clearance, volume of distribution, or absorption rate between the groups.

In an exposure-response analysis, data from phase 2 clinical trials were used to inform the model. A higher complete hematologic response (CHR) rate was observed in the study of Chinese patients due to a higher starting dose. The CHR was 63% among Chinse patients and 35% among Caucasian patients at 24 weeks. The CHR rates reported from the trials were similar at 61.2% and 27%, respectively.

Our results support the use of Ropeg as an effective and tolerable first-line treatment for PV regardless of ethnic variations.

This “indicates that there is a similar exposure-response relationship between Chinese and Caucasian populations,” the researchers explained.

Phase 2 data were also used to inform the exposure-safety analysis. In the Chinese group, the high dose level of Ropeg was associated with asymptomatic higher liver transaminase levels. There was no association between exposure and gamma-glutamyl transferase, white blood cell count, or neutrophil count.

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