Targeting PV source with ropeginterferon alfa-2b revolutionizes treatment

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by overproduction of red blood cells, which poses a significant risk of thrombohaemorrhagic complications and impaired survival. Traditionally, treatment approaches have focused on managing the symptoms and reducing haematocrit levels, but these do not address the underlying cause of the disease.

Ropeginterferon alfa-2b (BESREMi, PharmaEssentia), an innovative monopegylated long-acting interferon, offers a novel approach by directly targeting and depleting JAK2-mutated hematopoietic stem cells (HSCs) in the bone marrow, which is the source of the disease. This article focuses on the role of ropeginterferon alfa-2b in transforming the treatment landscape for PV, its mechanisms, clinical benefits, and potential to significantly improve patient outcomes.

Causes and clinical consequences of PV
In nearly all patients with PV, the disease originates from an HSC carrying a JAK2 mutation. The mutated JAK2 gene provides a selective advantage over normal cells, leading to expansion of the malignant clone in the bone marrow. [Blood 2017;129:1607-1616] This expansion results in abnormal haematopoiesis, thrombosis, and other cardiovascular events. [Am J Hematol Oneal 2017;13:23-31]. Additionally, there is a risk of progression to myelofibrosis (MF) or transformation to acute myeloid leukaemia (AML) [Figure 1]. [J Clin Oneal 2015;33:3953-3960; Blood Cancer J 2015;5:e366; Mayo Clin Proc 2015;90: 1283-1293]

PV treatment landscape
Therapy for PV aims to control the clinical symptoms and lower the risk of thromboembolism, bleeding, and progression to myelofibrosis or AML. To improve the patients' quality of life, therapy should address the most clinically important symptoms while reducing phlebotomies to avoid adverse effects associated with iron deficiency.

In early disease and in patients with low-disease burden, therapy typically involves phlebotomy and low-dose aspirin. Additional cytoreductive therapy is required for high-risk patients (≥60 years old or with a history of thrombosis) and for low-risk patients experiencing new thrombosis, major bleeding, intolerance to phlebotomy, splenomegaly, progressive thrombocytosis/leukocytosis, or disease-related symptoms.

In the latest NCCN guidelines, cytoreductive therapy options for PV include ropeginterferon alfa-2b, hydroxyurea, and peginterferon alfa-2a (Table 1). [NCCN Guidelines Version 1. 2024 Myeloproliferative Neoplasms] Notably, ropeginterferon alfa-2b is recommended as a preferred first-line cytoreductive therapy for both low- and high-risk PV.

While hydroxyurea has been shown effective in reducing the risk of thrombosis, response to it may be limited by the occurrence of resistance and intolerance, potentially failing to prevent disease progression. [Turk J Haematol 2023;40:266-268]

Interferons induce a selective decrease in malignant stem cells and are disease-modifying. However, traditional IFN-a is poorly tolerated as it requires daily injections. To improve tolerability, pegylated (PEG) forms of IFN-a that can be administered less frequently have been developed. [Blood 2015;126:1762-1769]

The only PEG-IFN-a specifically Iicensed for the treatment of PV is ropeginterferon alfa-2b.

Introducing ropeginterferon alfa-2b
Ropeginterferon alfa-2b has distinct pharmacokinetic properties and extended half-life that allows dosing once every 2 weeks. After achieving haematologic stability for at least a year, the dosing interval can be prolonged to once every 4 weeks. [Besremi Pl. PharmaEssentia Corporation]

Ropeginterferon alfa-2b contains a single positional isomer of interferon alfa (Figure 2), unlike other pegylated interferon compounds that contain multiple isomers, which may affect the pharmacologic, toxicologic, and immunogenic activity.

Mechanism of action
Ropeginterferon alfa-2b targets and depletes JAK2-mutated HSCs, leading to a continuous and sustained reduction in mutant JAK2 allele burden. It also inhibits myeloproliferation, achieving significant and sustained control across all key blood counts, including the haematocrit, white blood cell, and platelet. [Clin Ther 2024;46:439-440]

Ropeginterferon alfa-2b is the first US FDA-approved medication for PV that patients can take regardless of their treatment history. [US FDA/Press Announcements (2021)] It is indicated as a monotherapy in adults for the treatment of PV and is now approved for use in Singapore. [HSA lnfosearch therapeutic products. https://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=getProductDetails]

Clinical efficacy and safety
In the pivotal phase Ill PROUD-PV study, patients with high-risk PV, who were cytoreduction-naive or pretreated with hydroxyurea, were randomly assigned to receive ropeginterferon alfa-2b or hydroxyurea (n=127 in each arm) for 1 year. [Lancet Haematol 2020;7:e196-e208] After 1 year, patients rolled over into the extension study CONTINUATION-PV for an additional 5 years of treatment. Patients could switch from hydroxyurea to best available treatment (BAT). Those in the ropeginterferon alfa-2b arm could extend the dosing interval to 3 or 4 weeks. The final efficacy analysis was conducted after all patients completed 6 years of treatment, with the maximum treatment duration of 7.3 years. [Leukemia 2023;37:2129-2132]

Higher haematologic and molecular responses with ropeginterferon alfa-2b
The results were consistent with previous interim analyses, showing higher rates of complete haematologic and molecular responses in patients who continued with ropeginterferon alfa-2b compared with the control group [Table 2].

Effects on patient-specific treatment goals
At 6 years, 81.4 percent of patients treated with ropeginterferon alfa-2b maintained a haematocrit level of <45 percent without the need for phlebotomy compared with 60 percent in the control group (p=0.005). Long-term treatment with ropeginterferon alfa-2b resulted in low occurrence of symptoms defined in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). [Figure 3]. Only 15.7 percent of patients in the ropeginterferon alfa-2b arm reported symptoms vs 20.7 percent in the control arm. [HemaSphere 2022;6, abstract S196]

Better event-free survival
Event-free survival (considering risk events such as disease progression, death, and thromboembolic episodes) over ≥6 years of treatment was significantly higher in the ropeginterferon alfa-2b arm than in the control arm. Specifically, risk events were reported in 5 out of 95 patients vs 12 out of 74 patients, respectively (p=0.04).

A higher mutant JAK2 allele burden is associated with an increased risk of thrombosis and haemorrhage as well as progression to MF. [Am J Hematol Oneal 2017;13:23-31; Ann Hematol 2017;96:1297-1302]

In the PROUD-PV/CONTINUATION-PV studies, treatment with ropeginterferon alfa-2b significantly reduced the JAK2V617F allele burden. At 6 years, JAK2V617F allele burden <1 percent was achieved in 20.7 percent of patients in the ropeginterferon alfa-2b arm (baseline allele burden >10 percent) and in 1.4 percent of patients in the control arm (p=0.0001) [Figure 4]. [HemaSphere 2022;6, abstract S196]

Safety profile
Final safety data from up to 7.3 years of treatment in PROUD-PV and CONTINUATION-PV confirmed the established positive safety profile of ropeginterferon alfa-2b [Haematol 2020;7:e196-208; Leukemia 2022;36:1408-1411]. Only 11 percent of patients in the ropeginterferon alfa-2b arm and 2.4 percent in the control arm discontinued treatment due to drug-related toxicity. The higher discontinuation rate in the ropeginterferon alfa-2b arm may reflect the intensive monitoring of certain interferon-alfa class effects, which mandated withdrawal according to the protocol.

Adverse events (AEs) were mostly mild or moderate, with similar rates of grade ≥3 treatment-related AEs between groups (15.7 percent with ropeginterferon alfa-2b; 16.5 percent with control). PV-associated AEs declined during ropeginterferon alfa-2b treatment, occurring in 7.1 percent of patients vs 12.1 percent in the control group. [Leukemia 2023;37:2129-2132]