Clinical Review of Pegylated Interferons Suggests Formulation and Mechanism of Action May Improve Outcomes for MPN Patients

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Business Wire
BURLINGTON, Mass., February 21, 2024–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TWSE: 6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology, oncology and immunology, announced the publication of a manuscript reviewing the clinical safety, efficacy and practical management of treatment with two pegylated interferons – peginterferon alfa-2a and ropeginterferon alfa-2b-njft (marketed as BESREMi®). The manuscript, “Interferons in the Treatment of Myeloproliferative Neoplasms” was co-authored by 12 renowned myeloproliferative neoplasm (MPN) specialists and published in Therapeutic Advances in Hematology. Writing and editorial support were funded by PharmaEssentia, however authors retained full editorial control and provided final approval on all content.
“Interferons are immune modulators that have been used to treat MPNs for more than 35 years. Pegylated interferons are an important therapeutic option and have shown much promise across diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF),” said Pankit Vachhani, M.D., study author and Associate Professor of Medicine in Hematology/Oncology at University of Alabama at Birmingham. “The manuscript serves as a tool for clinical practice by highlighting the advantages of pegylated interferons, as well as areas where more research is needed to further refine interferon therapies.”

Interferons in the treatment of myeloproliferative neoplasms

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Pankit Vachhani, John Mascarenhas , Prithviraj Bose , Gabriela Hobbs, Abdulraheem Yacoub, Jeanne M. Palmer , Aaron T. Gerds, Lucia Masarova, Andrew T. Kuykendall, Raajit K. Rampal, Ruben Mesa and Srdan Verstovsek

Abstract: Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferonbased therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.

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Navigating Cytoreduction in MPNs: Benefits, Risks, and Considerations

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Jordyn Sava

In an interview with Targeted Oncology, Douglas Tremblay, MD, discussed the significance of cytoreductive therapy in mitigating thrombotic risk in myeloproliferative neoplasms.

According to Douglas Tremblay, MD, cytoreductive therapy has emerged with a pivotal role in mitigating thrombotic risk in the treatment landscape of myeloproliferative neoplasms (MPNs), specifically essential thrombocytopenia (ET) and polycythemia vera (PV).

Despite the evident benefits, each therapy carries unique adverse effects, requiring the careful consideration of patient-specific factors in treatment administration. Deciding when to initiate cytoreductive therapy in patients with chronic MPNs relies on accurate risk assessment, with parameters such as age and prior thrombotic events often guiding treatment decisions.

Frontline therapies, such as hydroxyurea and interferon, manage blood counts for patients with ET and PV, and newer options are emerging, according to Tremblay, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai. However, the long-term implications focus on thrombosis prevention and disease progression.

Ongoing research endeavors aim to delve deeper into surrogate end points and novel therapeutic avenues, promising to further refine and revolutionize the management of MPNs.

In an interview with Targeted OncologyTM, Tremblay discussed the significance of cytoreductive therapy in mitigating thrombotic risk in MPNs, specifically ET and PV.

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JAK-STAT Pathway–Targeting Approaches in Myelofibrosis Are Evolving

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Raajit K. Rampal, MD, gave an overview of the classification, risk assessment, and current therapy options for patients with myelofibrosis.

Targeted Oncology: What is the latest understanding of the classification and pathogenesis of myeloproliferative neoplasms (MPNs)?

RAAJIT K. RAMPAL, MD, PHD: Nothing has changed in terms of the 2022 [World Health Organization] classification, unlike what has happened with myelodysplastic syndrome.1 JAK-STAT signaling is a hallmark of MPN pathogenesis, and all of the mutations that we’re aware of at the moment—JAK2, CALR [calreticulin], and MPL—function in the JAK-STAT pathway. MPL is the thrombopoietin receptor which complexes with JAK [Janus kinase].

CALR is interesting, because CALR was discovered in 2013 but we think at the moment CALR complexes with MPL and results in the aberrant activation of MPL, but CALR does traffic to the cell surface.2,3 That makes it a target for immunotherapy. That is the target of a couple of clinical trials; one is open [LIMBER (NCT06034002)] and the other is about to open, which is really interesting [and] could change everything in MPNs.

All that being said, there are still at least 8% to 15% of myelofibrosis cases that are “triple negative.”2,3 If you look at those cases by gene expression profiling, they have the JAK-STAT signature. The issue with those cases is that we haven’t identified the particular lesion that occurs there, but it is a JAK-STAT–activated lesion, regardless of what the actual driver is. Those are the important things to think about with regards to how the disease is driven.

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JNJ-88549968 by Johnson & Johnson for Essential Thrombocythemia: Likelihood of Approval

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JNJ-88549968 is under clinical development by Johnson & Johnson and currently in Phase I for Essential Thrombocythemia. According to GlobalData, Phase I drugs for Essential Thrombocythemia does not have sufficient historical data to build an indication benchmark PTSR for Phase I. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the JNJ-88549968 LoA Report. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

JNJ-88549968 overview

JNJ-88549968 is under development for the treatment of calreticulin (CALR)-mutated myeloproliferative neoplasms, essential thrombocythemia, neoplasms, leukemia and myelofibrosis. The therapeutic candidate is a bispecific antibody acts by targeting calreticulin and CD3.

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Identification of Novel Risk Variants of Inflammatory Factors Related to Myeloproliferative Neoplasm: A Bidirectional Mendelian Randomization Study

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Yang Li, Ting Sun, Jia Chen, Lei Zhang

Abstract

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427–0.964; p = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006–1.883; p = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002–0.084; p = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001–0.060; p = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

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Depression in patients with hematologic malignancies: The current landscape and future directions

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Thomas M. Kuczmarski, Lizabeth Roemer, Oreofe O. Odejide

February 13, 2024

Abstract

Patients with hematologic malignancies experience high rates of depression. These patients are vulnerable to depression throughout the disease trajectory, from diagnosis to survivorship, and at the end of life. In addition to the distressing nature of depression, it has substantial downstream effects including poor quality of life, increased risk of treatment complications, and worse survival. Therefore, systematic screening for depression and integration of robust psychological interventions for affected patients is crucial. Although depression has been historically studied mostly in patients with solid malignancies, research focusing on patients with hematologic malignancies is growing. In this article, we describe what is known about depression in patients with hematologic malignancies, including its assessment, prevalence, risk factors, and implications. We also describe interventions to ameliorate depression in this population. Future research is needed to test effective and scalable interventions to reduce the burden of depression among patients with blood cancers.

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MPN Symptoms Mimic Other Conditions, Open Communication Is Key

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Brielle Benyon

Myeloproliferative neoplasm (MPN) symptoms can often appear as another condition, making it essential that patients find a cancer care team that they trust and can have open communication with, according to Patrick Buxton.

Buxton, who is a clinical nurse manager at Fred Hutchinson Cancer Center in Seattle and a 2023 MPN Hero, explained that certain side effects like constant fatigue could mimic conditions such as depression. That is why it is important for patients to work with their oncology team to establish a baseline of lab results and symptoms and keep them up to date on how they are feeling.

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Significant Steps Forward in the Understanding and Treatment of MPNs

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Raajit Rampal, MD, PhD

February 13, 2024

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses some of the key takeaways from the 2023 American Society of Hematology (ASH) Annual Meeting and what he believes holds promise for the space in 2024.

This past year marked significant progress in the field of myeloproliferative neoplasms (MPNs) and highlights were presented at ASH 2023. Notably, 2 phase 3 trials were completed and 2 combination agents showed promising results. Additionally, several new non-JAK inhibitor drugs were highlighted, along with advancements in mastocytosis research.

Rampal explains that there is now excitement surrounding the emergence of small molecule inhibitors in clinical trials, which may offer potential insights. Moreover, the introduction of the first antibodies, particularly calreticulin antibodies from various companies, into clinical trials is anticipated to have a major impact, with insights expected to emerge soon.

These developments represent a significant step forward in the understanding and treatment of MPNs, offering hope for improved outcomes for patients in the near future.

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Gut Microbiota Differs in Patients With MPNs

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Ashley Chan

he gut microbiota in patients with myeloproliferative neoplasms (MPNs) showed a significant difference compared with healthy controls (HCs), according to a study published in the European Journal of Haematology, although patients with MPNs who have a specific driver mutation had a similar bacterial composition compared with HCs.

In particular, MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), pre-fibrotic myelofibrosis (pre-PMF) and primary myelofibrosis, have driver mutations, such as JAK2V617F, JAK2 exon, MPL or Calreticulin (CALR). Researchers found that patients with MPNs who are CALR-positive had the highest resemblance to HCs.

The study demonstrated that patients with MPNs have changes in the gut microbiota, which may be caused by their disease, which may include inflammation. This change in the microbiota has been shown to initiate and progress the disease, according to the study. Researchers also noted that the gut microbiota also affects the immune system, infection control and steady production of blood cells.

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