Ropeginterferon alfa-2b 250micrograms/0.5ml solution for injection pre-filled disposable devices

Abstract Ropeginterferon alfa-2b is an interferon used in the treatment of myeloproliferative neoplasms, particularly polycythemia vera. Its efficacy in achieving hematologic and molecular responses has been demonstrated in clinical trials, but pooled data on long-term outcomes and sustained response remain limited. This systematic review and meta-analysis aimed to evaluate the hematologic and molecular response over 36 months. PubMed, Scopus, Science Direct, and Google Scholar databases were searched to identify studies reporting hematologic and molecular responses to ropeginterferon alfa-2b. Studies were included if they provided data on complete hematologic response (CHR) and JAK2V617F variant allele frequency (VAF) reduction. Pooled proportions and mean reductions were calculated using random-effects models. The pooled proportion of CHR increased progressively from 0.19 (95% CI: 0.04–0.57) at 3 months to 0.73 (95% CI: 0.17–0.97) at 36 months. Molecular response, measured by VAF reduction, deepened over time from − 7.33 (95% CI: -9.85 to -4.81) at 3 months to -54.90 (95% CI: -65.61 to -43.99) at 36 months. Subgroup analyses revealed significant variability in response rates, particularly in early follow-up periods. Ropeginterferon alfa-2b achieves significant and sustained hematologic and molecular responses over 36 months. This makes it a promising treatment for polycythemia vera. While variability in early responses needs further investigation, the sustained long-term efficacy compared to hydroxyurea supports its use in clinical practice. Future studies should focus on identifying predictors of response and optimizing treatment protocols to maximize patient outcomes.

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BackgroundPolycythemia vera (PV) is a myeloproliferative neoplasm characterized by excessive blood cell production, which increases the risk of thrombosis. Ropeginterferon alfa-2b (RI) offers potential advantages over standard therapy (ST; including phlebotomy, hydroxyurea, and aspirin) by achieving hematologic and molecular responses. However, its comparative efficacy and safety remain understudied. We hypothesized that RI would improve hematologic and molecular outcomes but may differ in safety profiles compared to ST.AimTo evaluate the efficacy and safety of RI vs ST in patients with PV, focusing on hematologic response, molecular response, adverse events (AEs), and thrombotic risk.MethodsThis Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant meta-analysis included randomized controlled trials comparing RI to ST in adult PV patients. PubMed, EMBASE, ClinicalTrials.gov, and ScienceDirect were searched from inception to July 2025. Outcomes included complete hematological response (CHR), molecular response, AEs leading to discontinuation, JAK2V617F allele burden, thrombotic events, and phlebotomy frequency. Pooled odds ratios (ORs) and MD with 95% confidence intervals (95%CIs) were calculated using random-effects models. Risk of bias was assessed with Cochrane RoB 2; evidence certainty was evaluated via GRADE.ResultsFive studies involving 477 RI and 456 ST patients were included. RI significantly improved CHR (OR = 2.14, 95%CI: 1.18-3.88, P = 0.002) and molecular response (OR = 4.37, 95%CI: 0.99-19.38, P = 0.05), with substantial heterogeneity (I² = 76% and I² = 93%, respectively). AEs leading to discontinuation were higher with RI (OR = 3.89, 95%CI: 1.90-7.97, P = 0.0002; I² = 0%). No significant differences were observed in JAK2V617F allele burden (MD = -7.46, 95%CI: -21.12 to 6.20, P = 0.28; I² = 90%) or thrombotic events (OR = 0.93, 95%CI: 0.45-1.90, P = 0.83; I² = 0%). RI reduced phlebotomy frequency (MD = -1.52, 95%CI: -2.37 to -0.67, P = 0.0005; I² = 0%). Most studies had low to moderate risk of bias; evidence certainty was moderate for CHR and AEs, low for molecular response and thrombotic events, and very low for allele burden.ConclusionRI offers superior hematologic and molecular responses compared to ST in PV but is associated with higher discontinuation rates due to AEs. Comparable thrombotic risk and reduced phlebotomy needs highlight its potential, though tolerability requires careful management. The high heterogeneity in certain outcomes and potential for publication bias warrant cautious interpretation of these findings. Further long-term studies are needed to optimize dosing and patient selection.

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BackgroundThere is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone.MethodsIn 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325.FindingsBetween Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred.InterpretationSupplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera.FundingAOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.

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Aim: Polycythemia vera (PV), a rare, chronic myeloproliferative neoplasm, that negatively impacts patient outcomes, and optimal therapy remains unclear due to a lack of head-to-head trials. A targeted literature review and feasibility assessment for an indirect comparison of ropeginterferon alfa-2b-njft versus peginterferon alfa-2a or ruxolitinib, using standard of care comprising hydroxyurea (HU) as a common comparator was conducted. Materials & methods: A targeted literature review evaluated clinical comparative evidence for PV treatments published between January 2014 and May 2024 in PubMed and relevant conference abstracts. End points of interest included complete hematologic response, molecular response, allele burden, event-free survival and safety. The feasibility of a network metaanalysis (NMA) was evaluated based on homogeneity of patient populations, treatment regimens and end point definitions. Results: Of 193 PubMed records and 460 conference abstracts screened, 40 records were included, representing evidence from 11 randomized controlled trials and 10 observational studies. Among these, 20 studies formed connected evidence networks for the end points of interest. Substantial heterogeneity across studies precluded a robust NMA: patient populations varied (newly diagnosed, highrisk, low-risk, HU-refractory or -intolerant), complete hematologic response definitions differed (e.g., requirement for absence of disease-related symptoms), molecular response thresholds were inconsistent, follow-up durations varied and definitions of standard of care ranged from almost exclusive use of HU to mixed regimens. Conclusion: An NMA for PV treatments was not feasible due to significant clinical and methodological heterogeneity across studies, including differences in patient characteristics, treatments, outcome definitions and follow-up times. These findings highlight the importance of standardized clinical trial designs and outcome definitions to enable robust comparative evidence generation for rare conditions like PV.

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