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Summary Background The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. Methods PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). Findings Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). Interpretation In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. Funding AOP Orphan Pharmaceuticals AG.

Introduction: Ropeginterferon alfa-2b (BESREMi®), a novel pegylated interferon with an extended half-life, was approved in Europe for treatment of patients with PV based on results from the phase 3 PROUD-PV and CONTINUATION-PV trials. Ropeginterferon alfa-2b treatment is recommended in hydroxyurea (HU) naïve patients as well as in those who have previously received HU. Therefore, treatment response was analyzed by prior HU treatment status, and the influence of baseline JAK2V617F allele burden and additional mutations - which may increase over time during non-disease modifying treatment - was explored. Methods: In PROUD-PV, patients aged ≥18 years, diagnosed with PV according to WHO 2008 criteria, and either cytoreduction-naïve or HU-pre-treated (for 50%), and in patients with available data (N=159), by the presence of non-driver mutations (TruSight™ Myeloid Panel, Illumina) or chromosomal aberrations (Affymetrix SNP6.0 array) at baseline. Results: After 5 years of treatment with ropeginterferon alfa-2b, high rates of CHR were sustained in both HU-naïve and HU pre-treated patients (53.1% and 61.3%, respectively), whereas in the control arm, the CHR rate was lower among HU pre-treated patients (36.0% compared to 48.0% for HU-naïve patients). Molecular response rates at 5 years in HU naïve and pre-treated patients were 71.4% and 64.5% respectively in the ropeginterferon alfa-2b arm and 26.0% versus 12.5% respectively in the control arm. Rates of adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to discontinuation were similar between the subgroups regardless of HU pre-treatment. Similar CHR rates were observed at 5 years irrespective of baseline JAK2V617F allele burden category (ropeginterferon alfa-2b arm: 57.1% versus 53.1% for allele burden ≤50% or >50%, respectively; control: 46.9% versus 38.5%, respectively). The molecular response rate in the ropeginterferon alfa-2b arm was higher among patients with baseline allele burden >50% (84.4% versus 61.3% for allele burden ≤50%); in the control arm there was no difference in molecular response rates between the allele burden subgroups (23.1% versus 20.8%, respectively). Of interest, the presence of non-driver mutations or chromosomal aberrations at baseline had no apparent influence on molecular response rates to ropeginterferon alfa-2b (64.5% compared with 70.7% in patients without these genetic abnormalities). Conclusion: High hematologic and molecular response rates in both HU-pretreated and HU-naïve patients and in those with more advanced JAK2V617F burden suggest that ropeginterferon alfa-2b is also a suitable treatment option in patients switching from HU. Disclosures Gisslinger: AOP Orphan Pharmaceuticals GmbH: Other: Personal fees, Research Funding; Novartis: Other: Personal fees, Research Funding; PharmaEssentia: Other: Personal fees; MyeloPro Diagnostics and Research: Other: Personal fees; Janssen-Cilag: Other: Personal fees; Roche: Other: Personal fees; Celgene: Other: Personal fees. Klade: AOP Orphan Pharmaceuticals GmbH: Current Employment. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Mayer: AOP Orphan Pharmaceuticals GmbH: Research Funding. Krejcy: AOP Orphan Pharmaceuticals GmbH: Current Employment. Empson: AOP Orphan Pharmaceuticals GmbH: Current Employment. Hasselbalch: Novartis, AOP Orphan: Consultancy, Other: Advisory Board. Kralovics: AOP Orphan Pharmaceuticals GmbH: Other: Personal fees; PharmaEssentia: Other: Personal fees; Qiagen: Other: Personal fees; Novartis: Other: Personal fees; MyeloPro Diagnostics and Research: Current holder of individual stocks in a privately-held company. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; Taiho Oncology, Inc.: Research Funding.

Introduction: Patients with polycythemia vera (PV) require life-long treatment to prevent thromboembolic events and minimize the risk of progression. Ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) may ultimately modify the natural history of PV by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV studies, long-term treatment with ropeg was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as evolution of hematologic and molecular parameters over five years. Methods: Patients aged ≥18 years and diagnosed with PV according to WHO 2008 criteria who were either cytoreduction-naïve or hydroxyurea (HU)-pre-treated for < 3 years were enrolled. A total of 257 patients were randomized 1:1 (stratified by age > 60 years, prior thromboembolic events, and HU pre-treatment) to receive ropeg or HU at individualized doses for 12 months in the initial study (PROUD-PV). In the extension study (CONTINUATION-PV), patients in the HU arm were permitted to switch to best available treatment. Efficacy assessments included hematologic parameters, phlebotomy need, JAK2V617F allele burden, and molecular response defined by modified ELN criteria. An interim analysis was conducted once all patients reached 5 years of treatment; efficacy data for patients enrolled in the extension study and all available safety data were analyzed. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension study. Most patients in the control arm continued to receive HU (88% at month 60). At the time of this 5-year analysis, 70 patients in the ropeg arm and 57 in the control arm remained on study; discontinuation rates were balanced between the treatment arms (ropeg: 26.3%; control: 25.0%). Hematocrit With respect to the causative JAK2V617F mutation, the median allele burden declined from 37.3% at baseline to 7.3% over 5 years of treatment in the ropeg arm, whereas in the control arm the median allele burden increased from 38.1% to 42.6% in the same period (p A further analysis of combined hematologic and molecular parameters was performed, these being known to influence the risk of thrombosis and of progression in PV. At the 5 year visit, 58.5% of patients receiving ropeg had well-controlled hematocrit ( Regarding safety and tolerability, no new signals were detected in the fifth year. Treatment related adverse events were reported in 25.6% and 24.2% of patients in the ropeg and control arms, respectively, and one patient in each arm withdrew due to drug-related toxicity. Three patients (3.8%) in the ropeg arm reported grade ≥3 treatment-related adverse events in the fifth year; over the entire treatment period, the rate of grade ≥3 drug-related adverse events was the same in each study arm (16.5%). Conclusions: In a randomized controlled setting, ropeg treatment effectively controlled hematocrit and minimized the occurrence of thromboembolic events in patients with PV. Disease progression was very rare during long-term treatment with ropeg and this possible change in the disease natural history appears to be related to deep and durable molecular responses selectively achieved with ropeg. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; PharmaEssentia: Honoraria; MyeloPro Diagnostics and Research: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Celgene: Honoraria. Klade:AOP Orphan Pharmaceuticals AG: Current Employment. Illés:Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy. Mayer:Celgene: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Current Employment. Empson:AOP Orphan Pharmaceuticals AG: Current Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals AG: Honoraria. Kralovics:AOP Orphan Pharmaceuticals AG: Honoraria; Qiagen: Honoraria; Novartis: Honoraria; MyeloPro Diagnostics and Research: Current equity holder in private company; PharmaEssentia: Honoraria. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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

Introduction: The key treatment goals for polycythemia vera (PV) are to prevent thromboembolic events and minimize the risk of progression, ultimately modifying the natural history of the disease by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV study, long-term treatment with ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as hematological and molecular parameters over a four-year period. Methods: Cytoreduction-naïve or HU-pre-treated patients aged ≥18 years diagnosed with PV according to WHO 2008 criteria were eligible. A total of 257 patients were randomly allocated to ropeg or hydroxyurea at individualized doses for 12 months in the initial study phase (PROUD-PV). In the ongoing extension phase (CONTINUATION-PV), patients in the hydroxyurea arm were permitted to switch to best available treatment. Efficacy assessments included a longitudinal analysis of complete hematological response (CHR) and complete molecular response (CMR; JAK2V617F was determined using real-time PCR [ipsogen® JAK2 MutaQuant® kit; QIAGEN GmbH]), defined by modified ELN criteria. Discontinued patients were considered non-responders. A data snapshot was performed once all patients reached 48 months of treatment; all available safety data were included. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension phase. At the time of analysis 139 patients remained on study: 74/95 in the ropeg arm and 65/76 in the control arm. Almost all patients in the control arm (>97% at the last available assessment) continued on HU. The rate of patients in CHR was significantly higher in the ropeg arm than in the control arm in the 4th year (60.6% versus 43.4%; p=0.02), as seen after 2 and 3 years of treatment. In line with this effective control of hematologic parameters by ropeg, a very low rate of major thromboembolic adverse events was observed in the ropeg arm: 0.0%, 0.0% and 1.1% of patients in the 2nd, 3rd and 4th years, respectively. In the control arm, rates of major thromboembolic adverse events in the 2nd, 3rd and 4th year were 0.9%, 1.4% and 0.0%, respectively. The median JAK2V617F allele burden declined from 37.3% at baseline to 9.8% over 4 years in the ropeg arm, whereas in the control group, the median allele burden increased from 38.1% to 43.1% in the same period (p In terms of safety, no new signals were detected in the 4th year. Rates of patients with treatment-related adverse events remained similar in the ropeg and control arms in the 4th year (ropeg: 28.7% of patients; control: 22.9%). Disease or treatment-related secondary malignancies reported in the entire study period comprised 2 cases of acute leukemia, 2 cases of basal cell carcinoma and 1 case of malignant melanoma, all in the control group; 1 case of disease-related transformation to myelofibrosis occurred in each treatment arm. Conclusions: Ropeg minimizes the occurrence of thromboembolic events in patients with PV over long-term treatment, without leukemogenic risk. In addition, we show for the first time in a randomized study that, in contrast to hydroxyurea, long-term ropeg treatment is capable of inducing deep molecular responses including CMR, which underscores its disease modifying potential. These results also suggest that selected patients could achieve operational cure (with both CHR and CMR) with ropeg, opening the way for treatment discontinuation. Disclosures Kiladjian: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Klade:AOP Orphan Pharmaceuticals AG: Employment. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. Kralovics:Pharma Essentia: Honoraria; MyeloPro Diagnostics and Research: Equity Ownership; AOP Orphan Pharmaceuticals AG: Honoraria, Other: Advisory board; Qiagen: Honoraria; Novartis: Honoraria. Gisslinger:Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Roche Austria GmbH: Consultancy; Janssen-Cilag: Honoraria; Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding; Myelopro GmbH: Consultancy.

Background: Interferon-alpha (IFN) is being used in myeloproliferative neoplasms (MPNs) since years and remains the only known treatment with disease-modifying potential. Ropeginterferon alfa-2b (Ropeg) is a novel mono-pegylated IFN, with reduced dosing frequency and improved tolerability. Here, we report 3 years clinical data from the phase III PROUD/CONTI-PV trials with an additional emphasis on the first comprehensive, prospective, randomized, controlled genomic profiling including not only JAK2V617F, but longitudinal targeted sequencing to identify non-JAK somatic mutations and chromosomal aberrations. Study design: 254 PV patients (WHO 2008 criteria, naïve to cytoreduction or HU pretreated but not resistant) were randomized to receive Ropeg or hydroxyurea (HU) in the PROUD-PV study and were rolled over to CONTI-PV study after 12 months, with the option to switch from HU to best-available-therapy (BAT). Efficacy assessment included complete hematological response (CHR, by ELN criteria), and CHR plus symptom improvement (PV-related symptoms and signs including clinically significant splenomegaly). Secondary endpoints included JAK2V617F molecular response (MR, modified ELN criteria). Next-generation-sequencing (NGS, TruSight Myeloid Panel, Illumina) and genome-wide analysis (SNP 6.0, Affymetrix) was applied comprehensively as exploratory genetic work-up. Results: 83 (Ropeg) and 70 (HU/BAT) patients completed the 36-month efficacy analysis time point, mean treatment duration for safety analysis was 3.8 years. Median doses in the third year remained constant: 425 µg Ropeg every 2 weeks and 1,000 mg HU per day. In the HU/BAT arm over 97% of patients remained treated with HU. After 36 months of treatment, maintenance of higher responder rates (full analysis set) was shown in the Ropeg arm compared to HU/BAT for CHR (70.5% vs. 51.4%; p=0.0122; RR [95% CI]: 1.38 [1.07-1.79]) and for CHR plus symptom improvement (52.6% vs. 37.8%; p=0.0437; RR [95% CI]: 1.42 [1.01-2.00]). In contrast to HU/BAT, response rates were steadily increasing in the Ropeg arm throughout 24 months of treatment and remained constant after 36 months. Regarding safety, comparable numbers of patients experienced adverse events (89.8% for Ropeg, 90.6% for HU) and treatment-related adverse events (74.8% for Ropeg, 78.7% for HU). The most common (>10%) treatment-related adverse events anemia, thrombocytopenia and leukopenia occurred more frequently under HU, whereas GGT increase was mainly observed under Ropeg. No new safety signals appeared in the third year of treatment. Regarding JAK2V617F, after 36 months 66.0% of patients in the Ropeg arm but only 27.0% in the HU/BAT arm had achieved MR (p In line with these molecular findings, disease or treatment related secondary malignancies occurred only in the HU cohort, including 2 cases of acute myeloid leukemia, 1 melanoma and 2 basaliomas, whereas in the Ropeg cohort 3 malignancies (glioblastoma, seminoma, adrenal neoplasm) most likely unrelated to IFNa treatment were reported. For one case of AML detailed longitudinal analysis revealed loss of JAK2V617F followed by rapid acquisition of DNMT3A and U2AF1 mutations shortly prior onset of leukemia. Conclusions: These data demonstrate high and durable hematologic responses and symptom control with good tolerability under Ropeg. The effect not only on JAK2V617F but other mutations involved in MPNs and on cytogentic aberrations confirm the concept of disease modification capability of IFNa. Ropeginterferon alfa-2b will provide a valuable and safe new long-term treatment option with features distinct from other treatment modalities including HU. Disclosures Gisslinger: Janssen Cilag: Consultancy, Honoraria; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Klade:AOP Orphan Pharmaceuticals AG: Employment. Georgiev:Alnylam: Consultancy. Mayer:Roche: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Eisai: Research Funding; Affimed: Research Funding. Krejcy:AOP Orphan Pharmaceuticals: Employment. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Hasselbalch:Novartis: Research Funding. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding.