Paradigm-PV: A Global, Randomized, Multicenter, Two-Arm Phase IV Study to Assess the Efficacy and Safety of Ropeginterferon Alfa-2b in Low- and High-Risk Patients with Polycythemia Vera
Authors: Yacoub Abdulraheem , Abu-Zeinah Ghaith , Qin Albert , Shih Weichung Joe , Da'na Waleed , Tashi Tsewang , Zagrijtschuk Oleh , Geller Robert , Gill Harinder 
Published: December 2024

Polycythemia vera (PV) is the most common classical myeloproliferative neoplasm (MPN) and is characterized by the excessive production of erythrocytes, panmyelosis, increased thrombohemorrhagic risk, and carries a risk of progression to myelofibrosis (MF) and acute leukemia. The risk stratification for thrombotic events in PV is based on age &gt;60 years or a history of thrombosis; high-risk patients meet either of these criteria while low-risk patients do not meet either. The cornerstone of treatment for high-risk patients includes pharmacological cytoreductive therapy, low dose aspirin, and therapeutic phlebotomy (PHL) as needed. The first-line treatments for most patients with low-risk PV are PHL and aspirin, but some are candidates for cytoreductive therapy. While there is robust evidence of reduction in thrombotic risk in high-risk PV patients with modern therapy, similar evidence for low-risk PV is lacking. Studies have also shown that frequent PHL worsens quality of life and work productivity.

Ropeginterferon alfa-2b (ROPEG) is a long-acting mono-pegylated proline interferon (IFN) approved for the treatment of adults with PV by the FDA in 2021. ROPEG was evaluated in patients with PV in several clinical studies at a starting dose of 100 mcg Q 2 weeks (or 50 mcg Q 2 weeks if on hydroxyurea [HU]), and titration of 50 mcg Q 2 weeks until a maximum dose of 500 mcg. A phase 2 clinical trial that evaluated an accelerated dosing scheme of 250/350/500 mcg of ROPEG showed a complete hematologic response (CHR) of 61.2% at 6 months of treatment in HU-intolerant patients with PV, which is higher than the CHR of 43.1% at 12 months observed in the PROUD-PV study. The Low-PV study evaluated ROPEG in low-risk PV patients at a 100 mcg Q 2 week fixed-dose compared to PHL alone; the results showed a significant reduction in PHL and progression and was stopped early due to superiority of the ROPEG arm.

This will be the first study to evaluate the efficacy of an accelerated dosing scheme of ROPEG in low- and high-risk PV patients compared to standard of care therapy with PHL alone or PHL with other cytoreductive agents.

The efficacy and safety of an accelerated dosing scheme of ROPEG will be evaluated in this international, randomized, open-label, multicenter, two-arm study compared to PHL alone or PHL with other cytoreductive agents (control group) as it relates to maintaining a safe hematocrit (HCT) value without PHL in PHL-requiring PV. The primary endpoint for this trial is the proportion of patients whose HCT is maintained without PHL eligibility in Weeks 20-32 as defined previously by others. PHL eligibility is defined as any of the following: a confirmed HCT ≥45% and that is at least 3% higher than the baseline HCT or a confirmed ≥HCT 48%. Key secondary endpoints include a change in JAK2V617F allele burden, molecular response, symptom assessments, proportion of patients with CHR, proportion of patients with HCT ≤45%, the average number of PHLs at Week 32, and the proportion of patients maintaining the median Hct values &lt;45% without disease progression. The 60-week study is divided into a 32-week treatment phase, a 24-week extension treatment phase, and a 4-week safety follow-up phase. ROPEG will be administered subcutaneously every 2 weeks at the starting dose of 250 mcg (Week 0), 350 mcg (Week 2), and target dose of 500 mcg (Week 4) and remain fixed for the treatment period and can be adjusted for tolerability. Patients will be randomized in a 1:1 manner to the control group or ROPEG during the treatment phase. Patients in the control group may cross over in the extension phase if certain criteria are met.

Key eligibility criteria include the following: adults with PV (diagnosed according to the WHO 2016 or 2022 criteria) with a JAK2V617F or JAK2 exon 12 mutation, poor HCT control requiring a frequency of 3 PHL in 6 months or 5 PHL within 1 year of randomization, HCT &lt;45%, WBC levels of 4-20 x10^3/mL, and platelet count of 100-1,000 x10^3/mL. Key exclusion criteria include the following: patients who require PHL when HCT &lt;45%, contraindication to pegylated IFN, or a known non-responder/resistant to IFN or other cytoreductive therapy.

The primary endpoint will be compared between groups using the Chi-square test. AEs will be graded according to CTCAE v5.0.

This study is sponsored by PharmaEssentia Corporation. ClinicalTrials.gov Identifier: NCT06290765.