How Essential Thrombocythemia and Polycythemia Vera Affect Blood Flow

Posted on May 27, 2025May 27, 2025 by MPN Advocacy & Education

May 27, 2025

Author(s): Dr. Tiziano Barbui

Fact checked by: Spencer Feldman

Excess blood cell production in two myeloproliferative neoplasms (MPNs) — essential thrombocythemia, or ET, and polycythemia vera, also known as PV — can impair circulation, according to Dr. Tiziano Barbui.

Barbui is a professor of hematology and founder of the department of hematology at Bergamo Hospital. He is currently the scientific director of clinical research foundation at Papa Giovanni XXIII Hospital, Bergamo, Italy.

In a video interview with CURE, Barbui explained that both diseases begin in the bone marrow and are marked by abnormal increases in blood cell counts. In polycythemia vera, red blood cells are overproduced, increasing blood viscosity and making it harder for blood to flow through small vessels. In essential thrombocythemia, the problem lies with excess platelet production.

Barbui emphasized that treatment is essential not only to relieve symptoms but also to prevent more serious complications linked to impaired blood circulation in both MPNs.

Molecular Response to Therapy Linked With Event-Free Survival in PV

Posted on May 27, 2025May 27, 2025 by MPN Advocacy & Education

May 23, 2025

Author(s): Jared Kaltwasser

Fact checked by: Rose McNulty

Molecular response to therapy appears to correlate with event-free survival in patients with early polycythemia vera (PV), according to a new analysis. The findings were published in a research letter in the journal HemaSphere.¹

While clonal expansion of JAK2V617F-mutated hematopoietic stem cells is implicated in almost all cases of PV, the potential implications of molecular response to therapy (MR) as demonstrated by reduced frequency of the variant allele have been disputed, the authors explained.

The question is difficult to study, they noted, since the early onset of PV is associated with nonspecific symptoms. However, the authors cited a 2023 study assessing ruxolitinib (Jakafi; Incyte) in patients with high-risk PV found molecular response was correlated with superior outcomes, including event-free survival (EFS).²

In the new report, researchers examined data from the phase 3 PROUD-PV study and its extension trial, CONTINUATION-PV, to see whether there was a meaningful relationship between MR and EFS in patients with early-stage PV.¹

The PROUD-PV trial involved participants with low- or high-risk PV requiring cytoreduction who were treatment naive or who had been pretreated with hydroxyurea for less than 3 years without resistance or intolerance. Participants were randomized on a 1:1 basis to receive either ropeginterferon alfa-2b (Besremi; PharmaEssentia) or hydroxyurea for 12 months. In CONTINUATION-PV, participants remained in their same treatment arm, though control-arm patients were allowed to switch from hydroxyurea to any standard treatment.

The final analysis of CONTINUATION-PV included 95 participants in the ropeginterferon alfa-2b cohort and 74 in the hydroxyurea/best available therapy control group. The median treatment duration for the two study arms was 6.3 years and 6.0 years, respectively.

The authors found that patients in the ropeginterferon alfa-2b arm had a reduction of median JAK2V617F variant allele frequency from 37.3% at baseline to 8.5% at year 6, with 66.0% of patients achieving MR. Patients in that cohort spent a median cumulative proportion of time in MR of 66.7%.

FDA Grants Fast Track Designation to Givinostat for Polycythemia Vera

Posted on May 19, 2025May 19, 2025 by MPN Advocacy & Education

May 6, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

The FDA has granted fast track designation to givinostat (Duvyzat), an orally administered histone deacetylase (HDAC) inhibitor, for the treatment of patients with polycythemia vera (PV).¹

The agent is being evaluated in the ongoing phase 3 GIV-IN PV trial (NCT06093672), which aims to compare the efficacy and safety of givinostat to hydroxyurea in patients with JAK2 V617F–positive, high-risk PV, which is characterized by the clonal overproduction of erythroid, myeloid, and megakaryocytic lineages within the bone marrow. By targeting aberrant gene expression, givinostat may suppress pathologic cell proliferation associated with driver mutations such as JAK2 V617F, which are common in patients with PV.

“The FDA decision to grant givinostat fast track designation underscores the urgent need for innovative treatments for PV and highlights the potential of givinostat to make a meaningful difference,” Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco Group, stated in a news release. “We look forward to working closely with the FDA as we plan for completion of our phase 3 clinical trial.”

The FDA and European Medicines Agency both previously granted orphan drug designation to givinostat for PV. In the United States, the FDA previously approved givinostat for the treatment of patients 6 years of age or older with Duchenne muscular dystrophy.²

Fatigue, Quality of Life Improve With Rusfertide: Andrew Kuykendall, MD

Posted on April 29, 2025April 29, 2025 by MPN Advocacy & Education

April 27, 2025

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

Bringing this interview with Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center, to a close, he addresses safety concerns that have been linked to the injectable hepcidin mimetic rusfertide (Takeda) and its overall impact on patient quality of life. Rusfertide is under investigation for treatment of polycythemia vera, a myeloproliferative neoplasm, in the ongoing phase 3 VERIFY trial (NCT05210790), on which Kuykendall is an investigator.

Previous segments of this interview focused on managing polycythemia vera, understanding hematocrit thresholds, reducing thrombotic risk, and reducing patient dependence on phlebotomy.

Prediction of resistance to hydroxyurea therapy in patients with polycythemia vera: a machine learning study (PV-AIM) validated in a prospective interventional phase IV trial (HU-F-AIM)

Posted on April 29, 2025April 29, 2025 by MPN Advocacy & Education

Published April 25, 2025

Florian H. Heidel, Valerio De Stefano, Matthias Zaiss, Jens Kisro, Eva Gückel, Susanne Großer, Mike W. Zuurman, Kirsi Manz, Kenneth Bryan, Armita Afsharinejad, Martin Griesshammer & Jean-Jacques Kiladjian

Abstract

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased thromboembolic (TE) risk and hematologic complications. Hydroxyurea (HU) serves as the most frequently used first-line cytoreductive therapy worldwide; however, resistance to HU (HU-RES) develops in a significant subset of patients, leading to increased morbidity and necessitating alternative treatments. This study, part of the PV-AIM project, employed machine learning techniques on real-world evidence (RWE) from the Optum® EHR database containing 82.960 PV patients to identify baseline predictors of HU-RES within the first 6–9 months of therapy. Using a Random Forest model, the study analyzed data from 1850 patients, focusing on laboratory parameters and clinical characteristics. Key predictive markers included red cell distribution width (RDW) and hemoglobin (HGB), showing the strongest association with HU-RES. A synergistic interaction between RDW and HGB was identified, enabling TE risk stratification. This study provides a robust framework for early detection of HU-RES using readily available clinical data, facilitating timely intervention. These findings underscore the importance of personalized treatment approaches in managing PV and highlight the utility of machine learning in enhancing predictive accuracy and clinical outcomes. Based on the results of PV-AIM we initiated an open-label, prospective, single-arm, interventional, phase IV study (HU-F-AIM) evaluating HU-resistance/intolerance. Validation of predictive biomarkers may facilitate identification of patients at risk of HU resistance who may benefit from alternative treatment options, possibly preventing ongoing phlebotomy during HU treatment, a frequent therapeutic choice in high-risk PV associated with early disease progression and increased thromboembolic complications. We propose an updated terminology that differentiates between true molecular resistance and clinical resistance, that may indicate the requirement for alternative therapeutic strategies.

Rusfertide Cuts Phlebotomy Need in Polycythemia Vera: Andrew Kuykendall, MD

Posted on April 14, 2025April 14, 2025 by mpn_admin

April 10, 2025

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

With an expected completion date sometime in June, the phase 3 VERIFY trial (NCT05210790) will soon conclude its investigation of rusfertide (Takeda) as add-on therapy to a patient’s current course of treatment for their polycythemia vera. The investigative agent has already received breakthrough therapy, orphan drug, and fast track designations from the FDA.

In this fourth part of a discussion with The American Journal of Managed Care^®, Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center and VERIFY investigator, speaks to the impressive patient-reported outcomes seen thus far.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

Can you summarize the key findings seen so far in the phase 3 VERIFY study?

Super exciting results that we saw. The study design, a lot of this was really built on a phase 2 study that was published in The New England Journal of Medicine that took patients with polycythemia vera who were requiring phlebotomies on a regular basis. That study basically put everyone on rusfertide and assessed over time their need for phlebotomy. There are a couple of different nuances to that study, but I would say the take home point of what we saw is that rusfertide very effectively eliminated the need for these patients that were regularly needing phlebotomies to need any phlebotomies at all—really rapidly reduced that and so certainly paved the way for designing a phase 3 clinical trial that could show that in comparison to standard therapy.

This trial took patients that had polycythemia vera that were requiring regular phlebotomy—so at least 3 over the preceding 28 weeks or 5 over the course of the prior year—and it randomized them to either stay on their standard therapy and add rusfertide or stay on their standard therapy and add a placebo. Everyone was treated in kind of the standard way, even if you were randomized to the “placebo arm”; that was just the standard therapy. If you were on cytoreductive therapy like hydroxyurea or interferon or ruxolitinib—these are agents we use to treat the disease as well—you stayed on those agents and you continued to get phlebotomies, as you would if you if you were kind of in routine clinical care. Then the other group did the same thing, but they added on rusfertide as a weekly subcutaneous injection. For 20 weeks, there was a a dose-finding period where rusfertide, the doses were increased based on hematocrit level and various different control of the disease.

The primary end point, at least in the US, was looking at the number of patients that were “phlebotomy eligible,” meaning that they needed a phlebotomy to control their disease—and that was being looked at between weeks 20 and 32. What we found is significantly more patients in the placebo group, so in the patients that were not receiving rusfertide, were “phlebotomy eligible” during that period of time. Another way to say that is, more patients in the rusfertide group did not need a phlebotomy during that that critical time period. Just another way of showing the control that rusfertide has, and that was the primary end point. Based on the phase 2 data, we certainly were optimistic that this was going to be reached.

Reducing Polycythemia Vera–Associated Thrombotic Risk Through Iron Regulation

Posted on April 7, 2025April 7, 2025 by mpn_admin

April 1, 2025

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

The investigational rusfertide (Takeda), is currently being evaluated in the phase 3 VERIFY trial (NCT05210790) as an injectable therapeutic to treat polycythemia vera (PV) through achieving and sustaining hematocrit control. This agent has already breakthrough therapy, orphan drug, and fast track designations from the FDA.

In part 3 of a discussion, Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center and VERIFY investigator, talks of rusfertide’s ability to free patients from being tethered to the need for regular phlebotomies and live a more viable life.

Part 1 and part 2 of this interview are also available to learn more about this potential novel PV treatment.

Understanding Hematocrit Thresholds in Polycythemia Vera Treatment

Posted on March 20, 2025March 20, 2025 by mpn_admin

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.

Managing Polycythemia Vera to Reduce Risks and Improve Lives

Posted on March 10, 2025March 10, 2025 by mpn_admin

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.

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

Posted on March 5, 2025March 5, 2025 by mpn_admin

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.”