HOPE-PMF: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study to Assess Efficacy and Safety of Ropeginterferon Alfa-2b in Patients with Early/Lower-Risk Primary Myelofibrosis

Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms (MPNs) and patients require greater attention and likely require earlier therapeutic intervention. Progressive anemia, splenomegaly, and systemic symptoms accompanied by bone marrow myeloproliferation and fibrosis characterize the clinical burden of myelofibrosis (MF). The 2016 WHO revised diagnostic criteria for PMF to include overt PMF and pre-fibrotic PMF. JAK inhibitors are approved for symptomatic patients with higher-risk PMF. In addition, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF, i.e., pre-fibrotic PMF/overt PMF at low or intermediate-1, is not well-defined and requires randomized clinical trial evaluations. Interferon alfa therapy has demonstrated meaningful clinical activity including bone marrow response and fibrosis reversion in patients with early PMF or low or intermediate-1 risk MF, in small, non-randomized Phase 2 studies.1,2 Ropeginterferon alfa-2b (ropeg) is a long-acting, monopegylated proline-interferon that is approved by the FDA for the treatment of adults with polycythemia vera and currently in phase 3 investigation for essential thrombocythemia. This biologic was evaluated in patients with pre-fibrotic PMF, DIPSS+ low/intermediate-1 risk PMF or secondary MF in a single arm Phase 2 clinical study and was found to be well-tolerated with durable hematologic responses and evidence of disease modification.3 This randomized, double-blind, placebo-controlled, multicenter Phase 3 trial will assess its efficacy and safety in patients with pre-fibrotic PMF or PMF at low or intermediate-1 risk according to DIPSS+. Co-primary endpoints include clinically relevant complete hematologic response (CrCHR) and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. 150 eligible patients will be randomized in a 2:1 ratio to receive ropeg or placebo. Ropeg and placebo are planned to be administered subcutaneously every two weeks at the starting dose of 250 µg (Week 0), 350 µg (Week 2), and 500 µg (Week 4) thereafter in a double blinded manner until week 56, followed by a 4-week safety follow up. Treating physicians have the flexibility to adjust dose according to tolerability. Patients of both groups who have completed the safety follow up will enter an extended 56-week treatment. The dosing schedule modifications based on response are allowed in the extension phase. Major eligibility criteria include age ≥18 years with a diagnosis of pre-fibrotic PMF/overt PMF at low/intermediate-1 DIPSS+, white blood cells >10x109/L or platelets ≥450x109/L, hemoglobin ≥10 g/dL, and neutrophils ≥1x109/L. Key exclusion criteria include patients with prior interferon therapy having poor tolerability or lack of efficacy, spleen size > 5cm below the left costal margin on palpation, Myelofibrosis Symptom Assessment Form (MFSAF) v. 4.0 scores >20, use of any investigational drug <4 weeks prior to the first dose of study drug, or not recovered from effects of prior administration of any investigational drug, and eligibility for JAK inhibitor therapy at screening. Adequate bone marrow specimen and central review are mandatory. Blinded sample size re-estimation is designed for the study. Cochran-Mantel-Haenszel (CMH) test will be used for analyzing the two co-primary efficacy endpoints. The regions or pre-defined pooled regions will be the blocks for the CMH test. General statistical summaries are applied to primary and secondary endpoints. This study is sponsored by PharmaEssentia Corporation. ClinicalTrials.gov Identifier: NCT06468033. References: 1. Silver RT, Vandris K, Goldman JJ. 2011;117(24):6669-6672. 2. Pizzi M, Silver RT, Barel A et al. Mod Pathol. 2015;28(10):1315-1323. 3. Gill H, Au L, Leung GMK et al. Blood. 2023;142 (Supplement 1): 4562.

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