Category Archives: Polycythemia Vera

Optimizing Hydroxyurea Management Among Patients With Polycythemia Vera

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August 8, 2023

Amber Denham

Results of a retrospective, real-world analysis determined that many patients with chronic myeloproliferative neoplasm (MPN) polycythemia vera (PV) received underdosed hydroxyurea, which led to lower complete response and toxicity rates, as well as proceeded with hydroxyurea regardless of poor clinical or hematological responses. These results highlight the need for more optimized [hydroxyurea] management and intervention in less-than-optimal responders.

“Hydroxyurea is currently the most used cytoreductive therapy for PV patients at high risk of thrombosis, with most patients achieving adequate control of the disease with acceptable tolerance,” Francesca Palandri, MD, Universitaria di Bologna, Bologna, Italy, and coauthors explained. “However, many patients may only obtain a poor response to [hydroxyurea] or develop drug-related toxicities during therapy.”

This study sought to define clinical characteristics associated with the achievement of complete response (CR) to hydroxyurea, investigate whether the type of suboptimal response may influence a decision to switch to ruxolitinib, and assess if a patient achieving CR to hydroxyurea would improve outcome parameters. The analysis included 563 patients with polycythemia vera treated with hydroxyurea for ≥12 months during an observational “PV-NET” Italian study. Among this patient population, 166 patients achieved complete response (CR), 264 achieved partial response (PR), and 133 achieved no response (NR).

In a multivariate analysis, the absence of splenomegaly (P = 0.03), pruritus (P = 0.002), and a median hydroxyurea dose of ≥1 g/day (P < 0.001) remained associated with CR. Overall, 283 patients who received either CR or PR continued hydroxyurea, and 114 patients switched to ruxolitinib. It was noted that many patients continued hydroxyurea despite a PR/NR and that splenomegaly and other symptoms were the main drivers of an early switch.

A median hydroxyurea dose of ≥1 g/day was correlated with more frequent adverse events. In the 449 patients who were receiving only hydroxyurea, rates of thrombosis, hemorrhages, progression, and overall survival (OS) were comparable among the CR, PR, and NR groups.

Palandri et al concluded, “Better [hydroxyurea] management, standardization of the criteria for and timing of responses to [hydroxyurea], and adequate intervention in poor responders should be advised.”

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New Study Demonstrates Ropeginterferon Alfa-2b-njft Is a Cost-Effective Treatment Option for a Broad Range of Patients with Polycythemia Vera

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Published August 4, 2023

Analysis published in the Journal of Comparative Effectiveness Research shows ropeginterferon alfa-2b-njft provided a cost-effective benefit in quality-adjusted life years compared to a commonly used treatment pathway

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 cost-effectiveness analysis of ropeginterferon alfa-2b-njft (marketed as BESREMi®) in the Journal of Comparative Effectiveness Research. The analysis, titled “Cost-Effectiveness of Ropeginterferon Alfa-2b-njft for the Treatment of Polycythemia Vera,” showed that ropeginterferon alfa-2b-njft provided a cost-effective benefit for a broad range of patients with polycythemia vera (PV) versus first-line hydroxyurea followed by ruxolitinib. Cost effectiveness was demonstrated in a modeled population including both low- and high-risk patients receiving first- or second-line treatment with ropeginterferon alfa-2b-njft.

“PV is a chronic blood cancer that requires lifelong therapy, which can prevent or delay negative clinical outcomes, but is also associated with additional costs to patients and payers. These new data demonstrate ropeginterferon alfa-2b-njft’s value not only to people living with PV, but also to the healthcare system at large,” said Dr. Aaron Gerds, MD, MS, Medical Director at Case Comprehensive Cancer Center and lead study author. “This study shows ropeginterferon alfa-2b-njft is a cost-effective treatment option over the modeled lifetime and that earlier initiation of treatment of PV with effective therapy can translate to more favorable cost to benefit ratios.”

PV is the most common myeloproliferative neoplasm (MPN) and a long-term, potentially life-threatening disease with limited approved treatment options. Patients with PV are at risk for disease progression to myelofibrosis (post-PV MF) or transformation to blast phase (MPN-BP) which is akin to acute myeloid leukemia1-3. Patients are also at an increased risk for arterial and venous thromboembolic events (TEs) which are associated with higher mortality, lower quality of life, and higher healthcare costs4-7.

This new study used an economic model developed from the United States healthcare system perspective. Inputs were informed by the data from randomized clinical trials, including the PROUD-PV and CONTINUATION-PV studies, and from real-world sources. The model compared ropeginterferon alfa-2b-njft used either as first- or second-line therapy versus an alternative treatment pathway of first-line hydroxyurea followed by ruxolitinib. To reflect the long-term consequences of treating PV, results were presented over a lifetime horizon.

Findings from the study conclude ropeginterferon alfa-2b-njft is a cost-effective treatment option for a broad range of patients with PV, including both low- and high-risk patients and patients with and without prior cytoreductive treatment with hydroxyurea. Of note:

  • These data show that over the modeled lifetime, patients who receive ropeginterferon alfa-2b-njft have more years alive (0.4), higher quality-adjusted life years (QALYs) (0.4), and higher cost ($60,175) as compared to the alternative treatment pathway. Weighing the additional costs versus the additional QALY gains results in a cost per QALY of $141,783.
  • This cost per QALY is less than a standard willingness to pay threshold of $150,000 per QALY8.
  • In this study, treating patients at a younger age or those with low-risk disease led to more cost-effective results, suggesting that earlier initiation of treatment of PV with effective therapy can translate to more favorable cost to benefit ratios.
  • The model was sensitive to treatment costs, the percentage of patients who discontinue hydroxyurea, the percentage of ropeginterferon alfa-2b-njft users who switch to monthly dosing, the percentage of ropeginterferon alfa-2b-njft users as 2nd line treatment, and the treatment response rates.

“Ropeginterferon alfa-2b-njft has demonstrated safety and efficacy in studies including both low- and high-risk patients and patients with and without prior cytoreductive treatment with HU. Recently, the National Comprehensive Cancer Network (NCCN) updated their treatment guidelines to include ropeginterferon as a preferred treatment regimen for both low- and high-risk PV patients9. As ropeginterferon continues to be more widely used in clinical practice, this study was imperative to demonstrate the cost-effectiveness of ropeginterferon alfa-2b-njft for a broad range of patients with PV,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs at PharmaEssentia. “This analysis also underscores the importance of treating low-risk patients and patients early in their disease journey to help minimize more severe events and their corresponding costs to the healthcare system.”

The full benefits of ropeginterferon alfa-2b-njft may not be fully captured in the model, and in particular, data on disutility of phlebotomy are lacking. Although some patients may tolerate regular phlebotomies, others can experience iron deficiency which can negatively impact quality of life. While the results from a scenario analysis incorporating a small decrement in utility had minimal impact on the cost-effectiveness results, due to the lack of data in this area, this estimate remains conservative. This study took a U.S. healthcare perspective, and the results may not generalize to other countries given the differences in healthcare resource use, costs and cost-effectiveness thresholds.

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 JAK2.10

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.

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NCCN Guidelines Update Recommends Ropeginterferon Alfa-2b for Polycythemia Vera

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July 7, 2023

Rose McNulty

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology was recently updated to include ropeginterferon alfa-2b (Besremi; PharmaEssentia) as a preferred treatment option for patients with high- and low-risk polycythemia vera (PV), according to a press release from PharmaEssentia USA Corporation.1

The updated guidelines recommend ropeginterferon alfa-2b and designate the recommendation as category 2A, which signifies a uniform NCCN consensus that ropeginterferon alfa-2b is an appropriate intervention for patients with PV. The agent was granted FDA approval for the treatment of PV in 2021 and was the first FDA-approved treatment indicated for PV regardless of previous treatment.2

“Importantly, the NCCN Guidelines update includes moving [ropeginterferon alfa-2b] to preferred status, reinforcing to treating physicians and patients that with its broad utility, [ropeginterferon alfa-2b] is recommended for proactively treating PV,” said John Mascarenhas, MD, professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, in a statement.1

PV, a rare hematological malignancy and the most common chronic myeloproliferative neoplasm, is characterized by overproduction of red blood cells in bone marrow that can lead to elevated white blood cell and platelet counts. Ropeginterferon alfa-2b is a monopegylated, long-acting interferon that blocks the signals that cause malignant cells to multiply.

The FDA approval of ropeginterferon alfa-2b was based on safety data from the PEGINVERA (NCT01193699) trial; PROUD-PV (NCT01949805) and its open-label extension portion, CONTINUATION-PV (NCT02218047); and efficacy data from the PEGINVERA clinical study program, according to a press release following the 2021 approval.3

Efficacy results showed that 61% of patients experienced complete hematological response—defined as hematocrit less than 45% without phlebotomy for at least 2 months since the patient’s last phlebotomy, platelet counts of 400 x 109/L or less, leukocytes of 10 x 109/L or less, and normal spleen size—following 7.5 years of treatment with ropeginterferon alfa-2b. Based on objective laboratory parameters, 80% of patients achieved a hematological response in the study.

As far as safety, ropeginterferon alfa-2b was shown tolerable in a pooled safety population, with the most common adverse reactions with incidence of 40% or higher being influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain. Serious adverse reactions occurring in less than 4% of cases were urinary tract infection, transient ischemic attack, and depression.

New data from the PROUD-PV and CONTINUATION-PV studies were presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition last December, adding to evidence in support of ropeginterferon alfa-2b for PV. In one abstract, the majority of both low- and high-risk patients with PV (85.7% and 75.0%, respectively) in the CONTINUATION-PV trial did not require phlebotomy for the entire sixth year of treatment.4

“This recent update to treatment guidelines by NCCN represents the community’s recognition of the value of [ropeginterferon alfa-2b] as a therapeutic option for all adults with PV, regardless of their treatment history,” said Raymond Urbanski, MD, PhD, US. Head of Clinical Development and Medical Affairs at PharmEssentia. “Given its deep, durable control over the disease beyond the symptoms, we’re continuing to study [ropeginterferon alfa-2b] in PV, as well as other myeloproliferative neoplasms (MPNs) and hematologic malignancies.”

References

1. NCCN Clinical Practice Guidelines in Oncology updated to recommend Besremi (ropeginterferon alfa-2b-njft) as a preferred intervention for polycythemia vera. News release. PharmaEssentia USA Corporation. May 23, 2023. Accessed May 24, 2023. https://us.pharmaessentia.com/wp-content/uploads/2023/05/NCCN_Guidelines_Update_Press_Release_May-23-2023.pdf

2. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed July 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-rare-blood-disease

3. US FDA approves Besremi (ropeginterferon alfa-2b-njft) as the only interferon for adults with polycythemia vera. News release. PharmaEssentia Corporation. November 12, 2021. Accessed July 6, 2023. https://us.pharmaessentia.com/wp-content/uploads/2021/11/BESREMi-FDA-Approval-November-12-2021.pdf

4. Caffrey M, Shaw ML, Klein H. ASH 2022: rare diseases & blood disorders. Am J Manag Care. 2023;29(SP1):SP42-SP46.

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Dr Kremyanskaya on the Efficacy of Rusfertide in Phlebotomy-Dependent Polycythemia Vera

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June 16, 2023

Marina Kremyanskaya, MD, PhD

Marina Kremyanskaya, MD, PhD, assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses key efficacy data for rusfertide (PTG-300) in the phase 2 REVIVE trial (NCT04057040) of phlebotomy-dependent polycythemia vera.

Polycythemia vera is a specific type of erythrocytosis that also features systemic symptoms and a high risk of thromboembolic and/or cardiovascular (CV) complications. High levels of the iron-regulator hepcidin have been implicated in uncontrolled red blood cell formation.

The REVIVE trial compared the ability of the first-in-class hepcidin mimetic rusfertide vs placebo to control erythrocytosis in patients with polycythemia vera who had previously received 3 or more phlebotomies in 28 weeks with or without concurrent cytoreductive therapy. The trial was composed of a dose-finding stage (part 1), blinded randomized withdrawal (part 2), and an open-label extension portion (part 3).

Patients in part 1 received a weekly subcutaneous dose of rusfertide that was individually adjusted to achieve a hematocrit level below 45% (range, 10 mg-120 mg). In part 2, patients were randomized to continue rusfertide or to receive placebo. The study’s primary end point was efficacy as characterized by the proportion of responders in part 2, Kremyanskaya says. Responses were achieved if patients had a hematocrit level below 45% without phlebotomy eligibility, did not receive therapeutic phlebotomy, and had completed 12 weeks of treatment, she explains.

Results from the randomized withdrawal phase were presented at the 2023 EHA Congress and demonstrated that rusfertide produced a significantly higher percentage of responders vs placebo, Kremyanskaya reports. These percentages were 69.2% (n = 18/26) with rusfertide vs 18.5% (n = 5/27) with placebo. Additionally, most patients on the study had low ferretin levels at baseline, indicating iron deficiency, Kremyanskaya states. After treatment with rusfertide, ferretin levels were normalized and maintained for many of these patients, she says.

Analysis of symptom improvement was based on data from part 1, as the majority of patients in the placebo arm of part 2 discontinued treatment prior to the 12-week mark, Kremyanskaya continues. Rusfertide treatment significantly improved the rate and severity of problems with concentration, itching, fatigue, and inactivity, which tend to be moderate or severe at baseline. Regarding safety, the agent was generally well tolerated, Kremyanskaya concludes.

Disclosures: Dr Kremyanskaya reported receiving honoraria and being on the advisory board for Protagonist Therapeutics, Inc.

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Rusfertide Offers Durable Hematocrit Control in Phlebotomy-Dependent Polycythemia Vera

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June 11, 2023

Caroline Seymour

Rusfertide (PTG-300) demonstrated freedom from phlebotomy, sustained hematocrit control, and 12-week treatment completion in 69.2% (n = 18/26) vs 18.5% (n = 5/27) of patients with phlebotomy-dependent polycythemia vera who received placebo (P = .0003), meeting the primary end point of the phase 2 REVIVE trial (NCT04057040). Findings were presented at the 2023 EHA Congress.

“The REVIVE study demonstrated significantly higher efficacy with rusfertide compared with placebo in subjects with polycythemia vera,” said Marina Kremyanskaya, MD, PhD, lead study author and assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, New York, in a presentation of the data. “Current standard-of-care therapy in polycythemia vera does not consistently maintain hematocrit below 45%, thereby potentially increasing the risk of thromboembolic events. Rusfertide has the potential to consistently maintain hematocrit [levels] below 45%.”

Polycythemia vera is a myeloproliferative neoplasm (MPN) that produces red blood cells in excess and is often marked by elevated hematocrit. Hematocrit, when uncontrolled, can lead to higher fatality from cardiovascular causes or thrombotic events. Although guidelines from the National Comprehensive Cancer Network and European LeukemiaNet state that hematocrit should be maintained below 45%, current standard-of-care therapy fails to do so in most patients.

Hepcidin is a peptide hormone that controls iron availability for red blood cell formation. Rusfertide is a novel hepcidin mimetic that mirrors the effects of hepcidin on erythropoiesis, representing a potential add-on therapy to standard therapy with improved activity. This hypothesis was tested in the phase 2 REVIVE trial.

To be eligible for enrollment in the study, patients had to have phlebotomy-dependent polycythemia vera per 2016 World Health Organization criteria, having received at least 3 phlebotomies in 28 weeks with or without concurrent cytoreductive therapy. Additionally, all patients had to be phlebotomized to hematocrit levels below 45% prior to the first dose of rusfertide to standardize the starting hematocrit.

The study consisted of 3 parts: dose finding, blinded randomized withdrawal, and open-label extension. Rusfertide was administered subcutaneously in doses ranging from 10 mg to 120 mg weekly. In part 1, rusfertide was titrated for the first 16 weeks to determine the clinically effective dose. Efficacy was evaluated in weeks 17 to 28. In part 2, patients were randomly assigned 1:1 to receive active or placebo doses of rusfertide in weeks 29 to 41. Study treatment continued in part 3 for up to 3 years.

Safety and efficacy served as key end points of the trial. Efficacy was characterized by the proportion of responders in part 2, defined by the proportion of patients who maintained hematocrit below 45% and the percentage reduction in phlebotomies. Patient outcomes were evaluated with the MPN Symptoms Assessment Form Total Symptom Score.

A total of 70 patients were included in the dose-finding portion of the research. Fifty-nine patients were treated in part 2, 53 of which were included in the primary efficacy analysis set. Fifty-two patients are ongoing treatment in part 3

Regarding baseline characteristics of those included in part 2, most patients were male, above the age of 50 years at diagnosis, had polycythemia vera for approximately 5 years, and received hydroxyurea as the primary means of cytoreductive therapy. Across the arms, 52.7% of patients were high risk and 47.4% were low risk. Body mass index was 30.1 ± 5.76 kg/m2 and 28.7 ± 4.55 kg/m2 in the placebo and rusfertide arms, respectively.

Additional findings demonstrated similar benefit in time to treatment failure with rusfertide in responders (P < .0001), patients ineligible for phlebotomy plus hydroxyurea (P < .0001), and those with hematocrit under 45% (P < .0001).

Kremyanskaya also explained that rusfertide led to meaningful reductions in the need for phlebotomy, both with phlebotomy only (n = 37) and phlebotomy plus cytoreductive therapy (n = 33).

Although the focus of the presentation centered around outcomes in part 2, investigators also evaluated symptom improvement in part 1. Notably, moderate or severe symptoms of problems with concentration (P =.0018), itching (P = .0054), fatigue (P =.0074), and inactivity (P =.0005) were all improved following treatment with rusfertide. Kremyanskaya noted that meaningful comparison of symptom improvement was not possible in part 2 because most patients who were randomized to placebo discontinued prior to the 12-week symptom assessment.

In terms of safety, Kremyanskaya stated that rusfertide was “generally well tolerated.” Treatment-emergent adverse effects (TEAEs) included injection site erythema (64.3%), injection site pain (41.4%), injection site pruritus (40.4%), fatigue (31.4%), injection site mass (25.7%), pruritus (25.7%), arthralgia (24.3%), injection site swelling (24.3%), dizziness (22.9%), headache (22.9%), nausea (22.9%), anemia (20.0%), COVID-19 (20.0%), injection site irritation (18.6%), and injection site bruising (15.7%). Most events were grade 1/2 (83%), and 17% of patients experienced grade 3 events. No grade 5 events occurred.

“Most common TEAEs were injection site reactions, which decreased in incidence with continued treatment,” Kremyanskaya noted. “Additionally, events were localized, grade 1 or 2 in severity, and generally did not lead to treatment discontinuation,”

Two treatment-related events of mild thrombocytosis and recurrent grade 1 injection site erythema led to treatment discontinuation.

Patients who completed the REVIVE study will be eligible to enroll in PTG-300-21, a separate, 2-year follow-on extension trial. The agent is also under evaluation in the phase 3 VERIFY trial (NCT05210790), where it is being compared with placebo in patients with polycythemia vera maintaining hematocrit control and in improving symptoms of disease.

Disclosures: Dr Kremyanskaya reported receiving honoraria and being on the advisory board for Protagonist Therapeutics, Inc.

Reference

Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: – blinded randomized withdrawal results of the REVIVE study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2710.

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