Category Archives: Polycythemia Vera

FORUS Therapeutics Inc. and PharmaEssentia Corporation Have Entered Into an Exclusive Licensing Agreement for The Registration and Distribution of BESREMi(R) (ropeginterferon alfa-2b) for The Treatment of polycythemia vera (PV), in Canada

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October 31, 2024 8:30 AM EDT | Source: FORUS Therapeutics Inc.

  • Under the terms of the agreement, FORUS is licensing BESREMi from PharmaEssentia for PV in Canada, with potential expansion to other investigational myeloproliferative neoplasms (MPN) indications.
  • FORUS will oversee the drug registration and commercialization of BESREMi in Canada, including securing approval of BESREMi in PV and meeting certain milestones.

Oakville, Ontario–(Newsfile Corp. – October 31, 2024) – FORUS Therapeutics Inc (“FORUS”) and PharmaEssentia Corporation (“PharmaEssentia”) have entered into an exclusive licensing agreement for the registration and distribution of BESREMi® (ropeginterferon alfa-2b) for the treatment of polycythemia vera (PV), in Canada.

“On behalf of the FORUS Therapeutics team, I am truly excited to announce this licensing agreement with PharmaEssentia and to commence the process of commercializing BESREMi in Canada. BESREMi represents the second novel therapeutic in the FORUS hematology-oncology pipeline and is another important step in fulfilling the organization’s mission and vision. We are committed to rapidly advancing BESREMi through the regulatory and reimbursement pathways to ensure that PV patients in Canada have broad access to this novel medication,” said Kevin Leshuk, President and CEO of FORUS. “We are making this announcement today to support the momentum created by the September 12th, Annual MPN Awareness Day and the International Congress on Myeloproliferative Neoplasms, recently held in Brooklyn, New York. We believe that continuing to elevate awareness with the goal of meeting the unmet needs of the MPN community is critical to making a difference in the lives of patients.”

“BESREMi is an important and significant development for clinicians who treat patients with PV. BESREMi as a potential future treatment option is particularly critical for Canada, where treatment options are notably limited for these patients,” says Dr. Shireen Sirhan, a founding member and the current President of the Canadian MPN group, and Vice-President for research in MPNs of the Groupe Québécois de recherche en LMC-NMP. “Canadian physicians have played a significant role in the clinical development program for BESREMi and we look forward to having this important treatment available in the clinic for our patients in need.”

“This is very exciting news for the PV community across Canada,” says Doug Chisholm and Patricia Saluk, the former and current Chair, Board of Directors of the Canadian MPN Network Patient Advocacy group. “Polycythemia vera is a rare blood cancer and the future commercialization of BESREMi in Canada offers highly anticipated new hope for patients, families, and their support networks. We hope the Canadian regulatory and payor systems will work as quickly as possible to ensure our patient community has access to this much needed new treatment regimen.”

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Update: Ruxolitinib Beats Best Available Therapy in Treating Polycythemia Vera

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October 14, 2024

Author(s): Mary Caffrey

An updated meta-analysis confirms that ruxolitinib, the Janus kinase (JAK) 1/JAK2 inhibitor sold as Jakafi, offers improvements in key measures of efficacy compared with best available therapy (BAT) for patients with polycythemia vera (PV),1 a rare, slow-progressing disorder that causes the blood to make too many red blood cells.

Caused by a genetic mutation, PV is not typically fatal on its own, but it can cause dangerous blood clots and damage to the spleen. In a small number of cases, it progresses to more aggressive forms of blood cancer.

The latest results were reported in the journal APMIS,1 formerly known as Acta Pathologica, Microbiologica, et Immunologica Scandinavica.

The analysis followed a 2020 meta-analysis involving 16 studies that appeared in Blood Advances.2 That analysis included evidence from 4 randomized controlled trials and included 663 patients; the authors estimated a thrombosis incidence of 3.09% per year for ruxolitinib vs 5.51% for BAT, but noted that globally, this did not reach significance (P = .098). “A clinical trial on selected patients at high risk of thrombosis would be warranted, but its feasibility is questionable,” the authors wrote.2

The current analysis examines ruxolitinib’s efficacy and safety compared BAT in 1061 patients with PV and in hydroxyurea-resistant and intolerant patients with PV across 6 studies, with a cutoff of November 2023. The patients included 620 on BAT and 441 on ruxolitinib. According to the investigators:

  • Those taking ruxolitinib showed higher hematocrit control (P = .015) and treatment response (P = .04) compared to BAT.
  • Patients taking ruxolitinib had significantly improved Myeloproliferative Neoplasms-Symptom Assessment Form scores (MPN-SAF), P < .01.

However, on the safety front, patients with PV treated with ruxolitinib had higher rates of nonmelanoma skin cancer (P < .01), as has been previously documented.

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High Rates of Polycythemia Vera Remission Seen With Ruxolitinib Plus Peg-IFN

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Andrea S. Blevins Primeau, PhD, MBA

Final results from the phase 2 COMBI II trial demonstrated high rates of remission of newly-diagnosed polycythemia vera (PV) after treatment with ruxolitinib plus pegylated-interferon-α2a (peg-IFN), according to a report published in Blood Advances.

The COMBI I trial previously demonstrated efficacy and safety of the combination of ruxolitinib with peg-IFN among patients who were refractory or intolerant to peg-IFN monotherapy and/or hydroxyurea.

“This study supports the previously described theory that combination therapy with ruxolitinib and peg-IFN may be one of the most promising treatment options in patients with myeloproliferative neoplasms,” the researchers wrote in their report.

In the investigator-initiated, single-center, phase 2 study, researchers treated 25 adult patients with newly-diagnosed PV with ruxolitinib and peg-IFN. All patients underwent pretreatment phlebotomies and patients who were high-risk, aged 60 or older, or who had a prior thrombosis also received hydroxyurea.

The primary endpoint was safety and secondary endpoints included complete remission (CR), peripheral blood count remission (PBCR), and bone marrow histologic remission (BMHR).

The median age of the patients was 70 years and 56% were male. The median number of phlebotomies from diagnosis to study entry was 3. There were 76% of patients who were considered high-risk, 20% had a prior thrombosis, and 12% had splenomegaly. The median hemoglobin was 13.8 g/dL and the median hematocrit was 0.44 IQR. The median variant allele fraction (VAF) of JAK2 V617F at baseline was 54 IQR.

Remission was achieved by 52% of patients by 12 months, with 12% of patients having achieved a CR. At 24 months, the overall remission rate was 56% and the CR rate remained at 12%.

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Dr Grunwald on the Patient Population and Limitations of the REVEAL Study in PV

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September 4, 2024

Author(s): Michael R. Grunwald, MD, FACP

Michael R. Grunwald, MD, FACP, hematologist/oncologist, chief, Leukemia Division; director, Transplantation and Cellular Therapy Program, Levine Cancer Institute, Atrium Health, discusses the key characteristics of patients with polycythemia vera (PV) enrolled onto the real-world, observational REVEAL study (NCT02252159), as well as thelimitations of the investigation.

This observational study represents the largest prospective cohort study of patients with PV conducted to date, Grunwald begins. Patients were not uniformly enrolled at the time of diagnosis; rather, they could be enrolled at any stage of their disease progression. A total of 2510 patients were included in the study, with 2023 having a confirmed diagnosis of PV, ensuring the accuracy of their inclusion in the study, he explains. The remaining patients may or may not have had PV, which introduces a level of uncertainty regarding their inclusion, Grunwald adds.

The analysis focused those who exhibited signs of progression to myelofibrosis, he continues. By comparing the characteristics of patients in the transformed group with those in the non-transformed group, it was observed that patients in the transformed group had a longer duration between their initial diagnosis and enrollment in the study, Grunwald elucidates.

Although the study offers valuable insights, it has limitations, according to Grunwald. Although its findings are effective in generating hypotheses, they do not provide definitive guidance on therapeutic interventions, he explains. Real-world data can offer insights into the outcomes of patients with low-risk disease treated with various therapies, Grunwald says. However, the true validation of a therapy’s effectiveness, particularly for low-risk disease, lies in clinical trials, Grunwald reports.

Looking ahead, there is a need for clinical trials that focus on early intervention in patients classified as low risk, who may harbor features indicating a higher risk of disease progression, he continues. Early intervention may alter the disease course, though this must be balanced against the risk of introducing toxicity prematurely or exhausting treatment options too early, Grunwald says. Fortunately, the treatment paradigm for myeloproliferative neoplasms is evolving, with a significant increase in drug development and approvals over the past decade, he notes. It is anticipated that concerns about exhausting treatment options prematurely will diminish as more therapies become available for patients, he concludes.

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What are the future prospects for polycythemia vera pharmacotherapies for patients with hydroxyurea resistance?

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August 26, 2024

Megan Metzger & John Mascarenhas

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis in the context of a somatic JAK2 mutation and a hypercellular marrow with an atypical megakaryocyte morphology. Virtually, all patients with PV harbor a point activating JAK2 mutation, including >95% with JAKV617F and the remainder with other activating JAK2 mutations, including exon 12 [Citation1]. Beyond the JAK2 driver mutation, acquired subclonal mutations have been described in PV involving epigenetic regulation (i.e. TET2 and ASXL1), splicing (i.e. SRSF2), and cellular metabolism (i.e. IDH2) [Citation2]. While clinically derived risk factors including advanced age, thrombosis history, and leukocyte count influence survival outcomes, clonal genomics have recently been integrated into prognostication with the mutation-enhanced international prognostic systems for PV (MIPSS-PV), which highlights the adverse prognostic role of non-driver mutations [Citation3].

Current management of PV is based on risk stratification, favoring cytoreductive treatment in patients with higher risk of thrombosis. The principal goal of PV management is to optimize patients in a way that improves the quality of life and decreases PV-related events, namely, thrombotic events, progression to myelofibrosis, and transformation to blast phase, which are ultimately associated with poor prognosis. While low-dose aspirin and therapeutic phlebotomy are standard management for all risk groups, patients with high-risk PV are recommended to be treated with the addition of a cytoreductive agent. Furthermore, cytoreductive therapy should be considered in certain subgroups of low-risk PV, including patients intolerant of venesection, those with progressive splenomegaly, individuals with persistent leukocytosis or thrombocytosis, or cases of high symptom burden such as intractable pruritus [Citation4]. Regardless of the risk group or treatment strategy, a target hematocrit (Hct) of <45% is required, as control of this hematologic parameter is associated with a lower rate of cardiovascular death and major thrombosis [Citation5].

First-line drugs of choice for PV currently include hydroxyurea (HU) and pegylated interferon alfa-2a (peg-IFN). HU was first introduced as cytoreductive therapy for PV in 1970 and has, therefore, accumulated a significant amount of data endorsing efficacy and tolerability. Despite a lack of randomized control trials and continued debate over potential leukemogenicity, there is general agreement on the net benefit of HU. Early non-randomized trials demonstrated a lower incidence of early thrombosis in HU-treated patients compared to phlebotomy-only historical controls [Citation6]. A recent reappraisal of over 1000 patients enrolled in the ECLAP study confirmed less frequent fatal and non-fatal cardiovascular events with HU treatment compared to phlebotomy alone [Citation7]. However, approximately 25% of PV patients are considered intolerant to HU because of emergent toxicities or are resistant to HU due to lack of effective cytoreduction.

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Ropeginterferon alfa-2b shows anti-polycythaemia vera activity without causing clinically significant anaemia

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Keita Kirito, Albert Qin, Shanshan Suo, Rongfeng Fu, Daoxiang Wu, Toshiaki Sato, Oleh Zagrijtschuk, Kazuya Shimoda, Norio Komatsu & Jie Jin

July 11, 2o24

Polycythaemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) that, in most cases, harbour the Janus kinase 2 gene (JAK2) driver mutation JAK2V617F [1]. PV is characterised by an over-production of blood cells with increased haematocrit levels, which is a risk factor for thrombotic events (TEs) and cardiovascular mortality [1, 2]. Low-dose aspirin and phlebotomy are usually recommended for patients with low-risk PV (i.e., no history of thrombosis and age ≤60 years). The National Comprehensive Cancer Network (NCCN) recommends ropeginterferon alfa-2b (BESREMi®) as a preferred cytoreductive treatment for patients with low- or high-risk PV [3].

Ropeginterferon alfa-2b is a novel polyethylene glycol (PEG)-conjugated recombinant proline-interferon alpha (IFN-a) with a favourable in vivo pharmacokinetic (PK) profile [4, 5]. Ropeginterferon alfa-2b has demonstrated substantial anti-PV clinical activity, including complete haematologic response (CHR; defined as a haematocrit <45% without phlebotomy, a platelet count ≤ 400 × 109/L, and a white blood cell count ≤10 × 109/L) and a reduction in the JAK2V617F allele burden [6,7,8,9]. Ropeginterferon alfa-2b injection is approved for adult patients with PV at an initial dose of 100 µg (or 50 µg for patients already receiving cytoreductive therapy) with 50 µg incremental intrapatient increases in the dose up to a maximum recommended dose of 500 µg every two weeks. It can take several months to reach the plateau dose level [6]. An alternative dosing regimen with a higher starting dose of 250 µg and simpler intrapatient dose escalation to 500 µg every two weeks with flexible dose adjustment according to tolerability was explored as a treatment option. This regimen controlled PV effectively, as defined by the CHR, and was associated with a shorter time to achieve a CHR [8, 9]. In this report, we aimed to examine the data from the approved slow-dose titration and exploratory higher starting dose regimens focusing on the dynamics of haemoglobin (Hgb) and the occurrence of anaemia. Anaemia is important in the context of PV treatment for several reasons. First, patients who undergo frequent phlebotomy may suffer from symptomatic iron deficiency, leading to anaemia [10]. Anaemia and symptoms can negatively affect the patient well-being and should be avoided in patients with PV and MPNs. The symptoms include headache, insomnia, concentration difficulties, dizziness, restless legs and may coincide and potentiate the disease-related symptoms of the underlying MPN [11,12,13]. Commonly used agents in the PV treatment cause anaemia in substantial numbers of cases ranging from 18% with hydroxyurea (HU) [14] to 72% with ruxolitinib [11, 15]. Anaemia is symptomatic in many cases and may limit the treatment dose or lead to treatment interruption if uncontrolled or severe cases are present. Association between venous thromboembolism and iron-deficiency anaemia has also been shown [16]. Thus, having an agent that can effectively control the elevated haematocrit without excessively suppressing the normal erythropoiesis is a major therapeutic advantage.

An important question regarding ropeginterferon alfa-2b in this context is whether the control of haematocrit is commonly accompanied by clinically significant anaemia, i.e., at the ≥grade 3 level or at the moderate, grade 2 level, but the anaemia is persistent and unmanageable. We therefore performed a retrospective analysis of the effect of ropeginterferon alfa-2b on Hgb levels at various time points or on the occurrence of anaemia with the data available from our two prospective clinical studies in patients with PV.

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Disease Duration, Elevated WBC Count, and VAF Predict Disease Progression in Polycythemia Vera

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June 14, 2024

Author(s): Megan Hollasch

Time from diagnosis to enrollment, elevated white blood cell (WBC) count, and variant allele frequency (VAF) were significantly associated with an increased risk of disease progression among patients with polycythemia vera (PV), according to data from the phase 4 prospective, observational REVEAL study (NCT02252159) presented at the 2024 EHA Congress by Michael R. Grunwald, MD.

“Five predictors of PV progression were identified: disease duration, thrombotic event [TE] history, WBC count of greater than 11 × 109/L, hematocrit [HCT] level of 0.45 L/L or lower, and VAF. However, HCT [level] of 0.45 L/L or lower may be confounded by disease duration and cytoreductive treatment covariates. These results provide additional support for the use of disease duration and elevated WBC and VAF as risk factors for disease progression, and identify history of TEs as a potential novel risk factor,” Grunwald and coauthors wrote in a poster presentation of the findings. Grunwald is chief of the Leukemia Division at Atrium Health’s Levine Cancer Institute and director of the Transplantation and Cellular Therapy Program at Levine Cancer Institute in Charlotte, North Carolina.

At a median follow-up of 3.7 years, findings from REVEAL, the largest prospective, observational clinical study in patients with PV to date (n = 2023), showed that 6.7% of patients progressed to myelofibrosis (MF). Results from a univariate analysis of patients with vs without progression revealed that significant covariates consisted of time from PV diagnosis to enrollment (OR, 1.065; 95% CI, 1.040-1.090; P < .0001), history of TEs (yes vs no; OR, 1.722; 95% CI, 1.170-2.534; P = .0059), HCT levels of 0.45 L/L or lower (>0.45 vs ≤0.45 L/L; OR, 0.593; 95% CI, 0.410-0.858; P = .0056), and white blood cell (WBC) count of greater than 11 × 109/L at enrollment (>11 vs ≤11 × 109/L; OR, 2.053; 95% CI, 1.445-2.918; P < .0001).

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Dr Raajit Rampal Discusses Disease Modification and Emerging Therapies in Polycythemia Vera

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Laura Joszt, MA

Achieving a disease-modifying therapy for polycythemia vera might require adjusting the end points in a study needed for a drug to be approved, said Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.

Transcript

Currently, there are no disease-modifying treatments in polycythemia vera, but it is being explored. What might such a therapy look like?

If we talk about disease modification, the first question is, what do you mean by disease modification? I think, what we would want is for our patients to live the longest and fullest life, free of the symptoms or burdens of their disease. To me, that is the sort of working definition of disease modification. From there, one can try to come up with biological definitions of things like depleting the stem cell, which are important things. But keeping this on a patient level, what we want for our patients [is a life free of disease burden]. How do we think about therapies that address those issues?

Part of it is a regulatory conundrum in the sense that studies have to meet certain end points for drugs to get approved, but the way we study the drugs is relative to the definitions of the end points that make the drugs successful. In many cases, [the end point is asking] are you controlling the hematocrit adequately? That’s one of the major things in polycythemia vera. But in order to really try to get at the question of disease modification, we’ve got to think about changing the end points of our studies to reflect that.

What are the things that are going to best correlate with the idea that you aren’t keeping patients free of the catastrophic consequences of their disease, like blood clots, like [disease] turning into leukemia or myelofibrosis? Are you controlling the patient’s symptoms to an adequate degree? Those are the things that I think are fundamental. But we’ve got to change the end points of our studies to really get at that.

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Younger Patients With PV May Benefit From Earlier Treatment With Cytoreductive Therapies

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Laura Joszt, MA

Although patients younger than age 60 with polycythemia vera (PV) are typically not treated with cytoreductive therapy due to treatment toxicity concerns, this may result in an undertreatment of patients as there is no clear evidence that the risk of toxicity exceeds the potential benefit of treatment, according to a study published in Blood Advances.1

PV causes an overproduction of blood cells in the bone marrow, which leads to high numbers of circulating red blood cells.2 This thickens the blood, which may not flow through smaller blood vessels properly. Although PV can be diagnosed at any age, it most often occurs in people over the age of 60 years.2

For most patients, phlebotomy is the standard treatment, and it may be the only treatment needed for years. However, additional treatment to suppress the formation of blood cells in the bone marrow may be needed. Cytoreductive therapies, such as interferons, hydroxyurea, ruxolitinib, and anagrelide, may be needed, particularly for high-risk patients.3

Currently, cytoreductive therapies are not routinely recommended by the European LeukemiaNet or National Comprehensive Cancer Network for patients with PV younger than 60 years who don’t have a history of thrombosis, a high symptom burden, or an intolerance to phlebotomy.

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Rusfertide Treatment Strengthens Response and Decreases Erythrocytosis Among Patients With Polycythemia Vera

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Jordan Kadish

03/22/2024

According to findings from the international phase 2 REVIVE trial published in The New England Journal of Medicine, treatment with rusfertide, a peptide mimetic of the master iron regulatory hormone hepcidin, strengthened responses and decreased erythrocytosis among patients with polycythemia vera (PV). Patients who received rusfertide demonstrated a mean hematocrit of less than 45% during the dose-finding period.

Marina Kremyanskaya, MD, PhD, Icahn School of Medicine at Mount Sinai, New York, New York, and coauthors stated, “Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis,” or a high concentration of red blood cells in the blood. “The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown,” they added.

To expand on the available research, the study authors aimed to assess the efficacy of rusfertide among patients with polycythemia vera. The primary end point was a response, which was characterized by the hematocrit control, absence of phlebotomy, and finishing the trial regimen during part 2. The modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary was utilized to assess patient-reported outcomes of symptoms.

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