Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET)

Background Ropeginterferon alfa-2b-njft (ropeg), a mono-PEGylated interferon-α, showed efficacy and safety in patients with hydroxyurea-intolerant/resistant essential thrombocythemia (ET) in the phase 3 SURPASS-ET largely conducted in Asia. Here we report the results from the EXCEED-ET study, which evaluated ropeg in both treatment-naïve and hydroxyurea pre-treated ET in North America. Methods The single-arm, multicentre, phase 2b trial EXCEED-ET was conducted at 28 centers in the United States and Canada. Patients with ET enrolled were required to have a platelet count >450 × 10 9 /L at screening. Patients were eligible regardless of prior cytoreductive therapy status and included both treatment-naïve and hydroxyurea-pretreated patients. Ropeg was subcutaneously administered in an accelerated titration schedule at 250 μg at Week 0, 350 μg at Week 2, and 500 μg from Week 4 and beyond. The primary endpoint was durable, modified European LeukemiaNet (ELN) response at both Months 10 and 13 (ClinicalTrials.gov identifier: NCT05482971). Findings Between January 17, 2023, and May 15, 2025, 106 patients were screened and 91 were enrolled. At baseline, participant median age was 57 years (range, 22–84) with 57/91 (62.6%) being female and 71/91 (78.0%) being White. Among 91 patients enrolled, durable modified ELN response rate was 60.2% (95% CI, 49.0–71.4). The median time to hematologic response was only 8.4 weeks (95% CI: 8.1–11.9). Splenomegaly and symptom improvement or non progression occurred in 90/91 (98.9%) and 71/91 (78.0%), respectively. Seven of 91 (7.7%) patients with palpable spleen at baseline and all had an improvement in disease-related signs. The rates of molecular response for driver mutations at Month 13 as defined by ELN2009 criteria were 35.0% (7/20) for patients with JAK2 V617F, 16.0% (4/25) for CALR , and 25.0% (2/8) for MPL mutations. One (1/1) TP53 mutation-positive patient showed a complete molecular response. Thrombosis and progression occurred in 3.4% (3/91) and 1.1% (1/91), respectively. Most treatment-emergent adverse events were mild, including fatigue (60%) and reversible transaminase elevations (58%). There was no grade 5 TEAE and one (1.1%) grade 4 TEAE (hepatitis toxic) which recovered without sequelae. Grade ≥3 TEAEs occurred in 27.5% (25/91) of the participants, most commonly with alanine aminotransferase and aspartate aminotransferase increases (4.4%; 4/91), neutrophil count decrease (4.4%; 4/91), fatigue (3.3%; 3/91) and lymphocyte count decrease (3.3%; 3/91). Treatment-related serious adverse events occurred in 5.5% (5/91) of patients. Pneumonia was the most common SAE, occurring in 2/91 (2.2%) patients. Ropeg-related discontinuations occurred in 9/91 (9.9%) patients. Interpretation Ropeg showed efficacy and substantial molecular responses with good overall tolerability across a broad ET population. Funding PharmaEssentia