Higher Ropeginterferon Alfa-2b Exposure Liked to JAK2 Reductions in ET

Higher exposure to ropeginterferon alfa-2b-njft (Besremi; PharmaEssentia) was associated with greater reductions in JAK2V617F allele burden among patients with essential thrombocythemia (ET), but it also was linked to a higher risk of anemia, according to a population pharmacokinetic-pharmacodynamic and exposure-response analysis published in The Journal of Clinical Pharmacology.¹ The exposure relationship for allele burden reached statistical significance at 6 or 7 months of treatment but not in the final model at 12 or 13 months.

Model-based simulations also showed no significant differences in drug exposure or overall hematologic response between Asian and Caucasian patients, the authors reported.

ET is a myeloproliferative neoplasm characterized by elevated platelet counts and risks of thrombosis and transformation to myelofibrosis or acute myeloid leukemia. The JAK2V617F driver mutation is present in 50% to 60% of patients, and 20% to 30% of patients develop resistance or intolerance to hydroxyurea, the usual off-label first-line cytoreductive therapy.

“Current treatment options for ET are limited and lack newer therapies that not only manage the thrombotic risk and symptom burden but also inhibit disease progression,” the authors wrote.

On August 31, 2026, the FDA approved ropeginterferon alfa-2b for adults with ET based on the phase 3 SURPASS ET trial (NCT04285086), in which 37.4% of patients treated with the drug vs 3.6% of those treated with anagrelide achieved a durable response at months 9 and 12.^2,3 The drug was previously approved for polycythemia vera.¹

The current analysis pooled data from 3 single-dose studies in healthy Caucasian, Chinese, and Japanese volunteers and 2 studies in patients with ET: SURPASS ET and the phase 2, single-arm EXCEED-ET study conducted in the United States and Canada. The pharmacokinetic model included 94 healthy volunteers and 179 patients with ET. Across all 273 participants, 51% were Asian and 42% were Caucasian. Patients with ET received the drug subcutaneously at a starting dose of 250 μg, titrated to 350 μg at week 2 and 500 μg from week 4. Researchers derived each patient’s average serum concentration from actual dosing records and linked it to changes in variant allele frequency (VAF) and adverse events.

JAK2V617F Allele Burden Reductions Tracked With Exposure

JAK2V617F VAF was measured in 87 patients at month 6 or 7 and 80 patients at month 12 or 13. Exploratory scatterplots showed significant positive linear trends between exposure and VAF reduction at both time points (P = .008 and P = .035, respectively), and no efficacy plateau was observed. In the final linear regression models, which included baseline JAK2V617F VAF as a covariate, the exposure effect was significant at month 6 or 7 (estimate, –0.127; SE, 0.054; P = .021) but not at month 12 or 13 (estimate, –0.147; SE, 0.082; P = .077).

No positive correlation was found between exposure and CALR VAF, which was measured in 22 and 18 patients at the 2 time points.

“Our findings highlight the requirement for maintaining a higher [pharmacokinetic] exposure to support the disease-modifying action of ropeginterferon alfa-2b,” the authors wrote.

For hematologic markers, the model estimated maximum reductions in platelet and white blood cell production of 65% and 57%, respectively. Simulated median exposures for different racial groups all fell within 80% to 125% of the population median. White blood cell counts fell below the target of 9.5 × 10⁹/L in a simulated median of 3.1 days in Caucasian patients and 11.8 days in Asian patients, a difference the authors said might not be clinically significant and might reflect higher baseline counts in Asian patients.

In the exposure-safety analysis, the incidence of anemia increased with average exposure (estimate, 0.024; SE, 0.0106; P = .022), and lower baseline hemoglobin was associated with a higher rate of anemia (P < .001). Only 5 cases of grade 3 anemia occurred, with none more severe, and most cases were reversible and manageable, the authors noted. Elevations in alanine aminotransferase and aspartate aminotransferase were not significantly associated with exposure.

The study was limited by the small number of patients with CALR mutations, which the authors said likely explained the lack of an exposure relationship for CALR VAF, and most of those patients were Caucasian, which prevented an evaluation of ethnic differences. In addition, blood counts were not monitored after treatment discontinuation or interruption, so the analysis could not capture the duration of efficacy or posttreatment rebound. Further analyses of CALR VAF with more patients or longer treatment are planned.

“Although the exposure-related anemia risk does not appear to significantly impact the benefit-to-risk ratio, our finding supports close monitoring of anemia at high doses of ropeginterferon alfa-2b treatment in patients with ET,” the authors concluded.

The analysis was funded by PharmaEssentia, and several authors are company employees.

References

1. Qin A, Masarova L, Chen H, et al. Exposure-response analyses of ropeginterferon alfa-2b in essential thrombocythemia. J Clin Pharmacol. 2026;66(10):e70258. doi:10.1002/jcph.70258

2. FDA approves treatment for essential thrombocythemia. News release. FDA. August 31, 2026. Accessed October 23, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-essential-thrombocythemia

3. Shaw ML. FDA approves ropeginterferon alfa-2b in essential thrombocythemia. AJMC®. September 1, 2026. Accessed October 23, 2026. https://www.ajmc.com/view/fda-approves-ropeginterferon-alfa-2b-in-essential-thrombocythemia

4. Mesa R, Gill H, Zhang L, et al. Ropeginterferon alfa-2b in hydroxyurea-intolerant or hydroxyurea-refractory essential thrombocythaemia (SURPASS ET): a multicentre, open-label, randomised, active-controlled, phase 3 study. Lancet Haematol. 2025;12(11):e862-e875. doi:10.1016/S2352-3026(25)00264-9