Ropeginterferon Alfa-2b versus Standard Therapy for Polycythaemia Vera; a Randomised, Controlled, Phase III Trial

Abstract

Background: Ropeginterferon alfa-2b (ropeg) is a novel, mono-pegylated interferon (IFN) for treatment of polycythemia vera (PV). The PROUD-PV/CONTINUATION-PV trial compared ropeg with hydroxyurea (HU), the standard therapy for PV, over three years of treatment. Methods: This phase III, randomised, controlled, open-label trial was conducted in 48 clinics in Europe in patients aged =18 years, with early-stage PV (cytoreduction-naive or less than three years of prior HU treatment), diagnosed by WHO 2008 criteria. In the PROUD-PV part, patients were randomised 1:1 with block-stratification by prior HU treatment, age (=60 or >60 years) and history of thromboembolic events to receive ropeg (subcutaneously every two weeks, starting at 100 µg) or HU (orally starting at 500 mg/day). After one year, patients rolled over to the CONTINUATION-PV part. The primary endpoint was disease response rate at 3 monthly assessment visits from 12 months onwards. Composite evaluation criteria were applied: complete haematological response (CHR) with normalisation of spleen size (PROUD-PV/CONTINUATION-PV), and CHR with improved disease burden (signs and symptoms) (CONTINUATION-PV only). The trial was registered on EudraCT (2012-005259-18; 2014-001357-17). Findings: Recruitment took place from October 2013 to March 2015; 257 patients were randomised, three withdrew consent and 127 per arm were treated. Overall, 171 patients rolled over to the ongoing CONTINUATION-PV part. All patients treated were analysed for safety; the intent-to-treat population was analysed for efficacy. After three years of treatment, response rates were significantly higher in the ropeg arm compared to control for CHR (67/95 [70·5%] versus 38/74 [51·4%]; p=0·01) and CHR with improved disease burden (50/95 [52·6%] versus 28/74 [37·8%]; p=0·04). Only 27/254 patients had splenomegaly at baseline precluding meaningful assessment of spleen size normalisation. JAK2V617F allele burden at three years showed a sustained decline in the ropeg arm only (molecular response in ropeg arm: 62/94 [66·0%]; control: 20/74 [27·0%]; p<0·0001). Comparable numbers of patients experienced treatment-related adverse events (ropeg: 95/127 [74·8%]; control: 100/127 [78·7%]). One treatment-related death occurred in the control arm (acute leukaemia attributed to HU). Interpretation: These data demonstrate high and durable haematological and molecular responses with good tolerability under ropeginterferon alfa-2b, offering a valuable and safe long-term treatment option with features distinct from hydroxyurea. Trial Registration Number: The trial was registered on EudraCT (2012-005259-18; 2014-001357-17). Funding: AOP Orphan Pharmaceuticals AG. Declaration of Interest: HG reports grants and personal fees from AOP Orphan during the conduct of the study; grants and personal fees from Novartis and personal fees from PharmaEssentia, MyeloPro Diagnostics and Research, Janssen-Cilag, Roche, and Celgene, outside the submitted work. CK, KK, and BGI report that they were employees of AOP Orphan during the conduct of the study. JM reports grants from AOP Orphan during the conduct of the study. RK reports personal fees from AOP Orphan Pharmaceuticals and PharmaEssentia, during the conduct of the study; personal fees from Qiagen and Novartis and stock ownership in MyeloPro Diagnostics and Research, outside the submitted work. HH reports Data Monitoring Board honoraria from AOP Orphan during the conduct of the study; grants from Novartis outside the submitted work. JJK reports grants and personal fees from AOP Orphan during the conduct of the study; grants and personal fees from Novartis and personal fees from Celgene, outside the submitted work. The remaining authors have nothing to disclose. Ethical Approval: The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. The protocol was approved by the institutional review board or independent ethics committees at each participating site.