Anaemia could develop in polycythemia vera (PV) due to phlebotomy-caused iron-deficiency and cytotoxic effect of cytoreductive therapy. Ropeginterferon alfa-2b treatment was not associated with ≥grade 3 anaemia in two recent clinical studies of 78 patients with PV. Only four cases of grade 2 anaemias occurred, the anaemia resolved. The mean haemoglobin levels were above 120.0 g/L. Therefore, ropeginterferon alfa-2b treatment does not lead to clinically significant anaemia and appears to manage PV without affecting normal erythropoiesis. “Both trials were registered at clinicaltrials.gov (A19-201: NCT04182100; A20-202: NCT05485948)”.

Ropeginterferon alfa-2b (Ropeg) is approved for the treatment of adults with polycythemia vera (PV). This report aims to analyze the ethnic sensitivity of Ropeg for the treatment of PV, comparing the pharmacokinetics (PK), efficacy, and safety profiles across diverse ethnic groups. We conducted a relevant review of PV and analysis of data obtained from clinical studies involving Ropeg. The PK behavior of ropeg showed no significant differences between Chinese and overseas populations. Their efficacy and safety profiles were similar across the ethnic groups. The analyses indicated that the dose-exposure-response profile of Ropeg was consistent irrespective of ethnic variations. The results suggest that Ropeg exhibits a consistent PK and pharmacodynamics profile and a similar therapeutic effect across different ethnic groups, confirming its efficacy and safety in the global treatment of PV. More generally, these findings support the broader application of Ropeg in diverse patient populations and emphasize the need for an inclusive clinical practice.

Introduction Polycythemia vera (PV) is a common type of BCR-ABL-negative myeloproliferative neoplasms. It appears that almost all patients with PV carry a mutation in the Janus kinase 2 gene with the JAK2V617F mutation being identified in more than 95% of the cases. The JAK2V617F allele burden is associated with thromboembolic events and disease progression. Ropeginterferon alfa-2b (ropeg) represents a novel, mono-polyethylene glycol-conjugated (PEGylated) interferon-based therapy and is approved for the PV treatment. It has been assessed in two different dose titration regimens: a starting dose of 100 μg [50 μg if receiving hydroxyurea (HU)] with 50 μg dose titrations every two weeks to a maximum dose of 500 μg; or alternatively, a starting dose of 250 μg titrating to 350 μg and then 500 μg every two weeks if tolerated. The study assessed the two-year treatment results regarding molecular response, complete hematologic response (CHR) and safety with ropeg therapy at the higher starting dose regimen. Objective The aim of the study is to assess the CHR rate, molecular response, and safety of ropeg at a higher starting dose regimen with simpler intra-patient dose titrations in Chinese patients with PV with HU resistance or intolerance. Methods Adult patients diagnosed with PV according to WHO 2016 diagnostic criteria from 15 major hospitals in China were enrolled in this single-arm, open-label study. Patients were scheduled to receive ropeg every 2 weeks, starting at a dose of 250 µg at Week 0, increasing to 350 µg at Week 2 and then 500 µg from Week 4 onwards if tolerated. Dose could be adjusted according to tolerability and safety. After 52 weeks, eligible patients without disease progression could continue to receive ropeg treatment for an extension phase. Results A total of 49 patients with a median age of 56 years were enrolled in this study. All patients had the JAK2V617F mutation and HU intolerance. The mean and median allelic burden of JAK2V617F at baseline was 58.5% and 61.2%, respectively. 46 patients completed the first-year study. A total of 44 patients joined the extension phase since two patients declined consent for personal reasons. One patient discontinued the study due to an adverse event (AE) not related to treatment. After 24 months of treatment, 33/44 patients (75.0%) achieved CHR. Almost all patients except one showed a reduction of JAK2V617F. The mean and median JAK2V617F allelic burden at 24 months was 15.6% and 7.8%, respectively. At Month 24, complete molecular response (CMR) was achieved in 11/43 patients (25.6%). Previously, CMR was observed in 18/92 (19.6%) in patients with PV at 5 years (Month 60) of ropeg treatment under the approved, slow dose titration regimen. Notably, JAK2V617F in one patient decreased from a high allele burden of 83.9% to undetectable at Month 24. Partial molecular response was observed in 25/43 patients (58.1%) and 20/43 patients (46.5%), respectively, according to the 2009 and 2013 ELN criteria. During the extension phase, 37/44 patients (84.1%) experienced treatment-emergent AEs (TEAEs), with the majority being mild or moderate. The most common TEAEs included increased alanine aminotransferase (ALT), decreased WBC count, decreased neutrophil count, and all these AEs could be effectively managed and were reversible. No drug-related serious AEs (SAEs) were reported. There were no thromboembolic events and disease progression to myelofibrosis, acute leukemia and deaths. Conclusion: The 24-month data of our study showed that ropeg at the higher starting dose regimen was very effective in inducing molecular remission, and maintaining high levels of CHR. It was generally well-tolerated. Further analysis of the relationship between molecular remission and progression free survival, overall survival will be explored in future.

AimsTo investigate the exposure-response (E-R) relationship, including exposure-efficacy and exposure-safety, of ropeginterferon alfa-2b treatment in patients with polycythaemia vera (PV).MethodsBased on the results of the phase II trial A20-202 regarding ropeginterferon alfa-2b in patients with PV, E-R analyses were performed to evaluate the efficacy and safety of the given dosing regimen. The E-R analyses were based on logistic and linear regression and the relationship between exposure to ropeginterferon alfa-2b and key efficacy and safety variables. The key efficacy variables included complete haematologic response (CHR) and reduction of the driver mutation JAK2V617F. The safety variable was treatment-related adverse events (TRAEs).ResultsA clear relationship between the exposure to ropeginterferon alfa-2b and CHR was observed, with an increase in drug exposure resulting in an increased probability of achieving CHR. Similar CHR probabilities were observed in the third and fourth quantiles of the average concentration at Week 24. The results from the exposure-JAK2V617F model indicated that the JAK2V617F allele burden decreased with increasing exposure to ropeginterferon alfa-2b and baseline body surface area. Exposure-safety analysis revealed a risk of AEs associated with transaminase abnormalities, which were not associated with clinical significance.ConclusionsOur analyses have shown that patients with PV treated with ropeginterferon alfa-2b had an increased probability of achieving CHR and a molecular response with acceptable safety risks at the 250-350-500 mu g titration dosing regimen. This study has provided the relevant data for the application of a biologics licence of ropeginterferon alfa-2b for PV treatment in China.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm. Ropeginterferon alfa-2b is a new -generation polyethylene glycol -conjugated proline-interferon. It is approved for the treatment of PV at a starting dose of 100 mu g (50 mu g for patients receiving hydroxyurea (HU)) and dose titrations up to 500 mu g by 50 mu g increments. The study was aimed at assessing its efficacy and safety at a higher starting dose and simpler intra-patient dose escalation. Methods: Forty-nine patients with PV having HU intolerance from major hospitals in China were treated biweekly with an initial dose of 250 mu g, followed by 350 mu g and 500 mu g thereafter if tolerated. Complete hematological response (CHR) was assessed every 12 weeks based on the European LeukemiaNet criteria. The primary endpoint was the CHR rate at week 24. The secondary endpoints included CHR rates at weeks 12, 36 and 52, changes of JAK2 V617F allelic burden, time to first CHR, and safety assessments. Results: The CHR rates were 61.2%, 69.4% and 71.4% at weeks 24, 36, and 52, respectively. Mean allele burden of the driver mutation JAK2 V617F declined from 58.5% at baseline to 30.1% at 52 weeks. Both CHR and JAK2 V617F allele burden reduction showed consistent increases over the 52 weeks of the treatment. Twentynine patients (63.0%) achieved partial molecular response (PMR) and two achieved complete molecular response (CMR). The time to CHR was rapid and median time was 5.6 months according to central lab results. The CHRs were durable and median CHR duration time was not reached at week 52. Mean spleen index reduced from 55.6 cm 2 at baseline to 50.2 cm 2 at week 52. Adverse events (AEs) were mostly mild or moderate. Most common AEs were reversible alanine aminotransferase and aspartate aminotransferase increases, which were not associated with significant elevations in bilirubin levels or jaundice. There were no grade 4 or 5 AEs. Grade 3 AEs were reversible and manageable. Only one AE led to discontinuation. No incidence of thromboembolic events was observed. Conclusion: The 250-350-500 mu g dosing regimen was well tolerated and effectively induced CHR and MR and managed spleen size increase. Our findings demonstrate that ropeginterferon alfa-2b at this dosing regimen can provide an effective management of PV and support using this dosing regimen as a treatment option.

Ropeginterferon alfa-2b represents a new-generation pegylated interferon-based therapy and is administered every 2–4 weeks. It is approved for polycythemia vera (PV) treatment in the United States and Europe with a starting dose of 100 µg (50 µg for patients receiving hydoxyurea) and intra-patient dose titrations up to 500 µg at 50 µg increments, which took approximately 20 or more weeks to reach a plateau dose level. This study aimed to assess ropeginterferon alfa-2b at an alternative dosing regimen with a higher starting dose and quicker intra-patient dose titrations, i.e., the 250–350–500 μg schema, in 49 Chinese patients with PV with resistance or intolerance to hydroxyurea. The primary endpoint of the complete hematologic response rate at treatment weak 24 was 61.2%, which was notably higher than 43.1% at 12 months with the approved dosing schema. The JAK2 V617F allele burden decreased from baseline to week 24 (17.8% ± 18.0%), with one patient achieving a complete molecular response. Ropeginterferon alfa-2b was well-tolerated and most adverse events (AEs) were mild or moderate. Common AEs included alanine aminotransferase and aspartate aminotransferase increases mostly at grade 1 or 2 levels. Patients did not present with jaundice or significant bilirubin level increase. No grade 4 or 5 AEs occurred. Seven patients (14.3%) experienced reversible, drug-related grade 3 AEs. No AEs led to treatment discontinuation. Ropeginterferon alfa-2b at the 250–350–500 μg regimen is highly effective and well-tolerated and can help patients achieve greater and rapid complete hematologic and molecular responses. Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (Identifier: NCT05485948) and in China (China National Medical Products Administration Registration Number: CTR20211664).

Ropeginterferon α-2b is a mono-PEGylated proline-interferon for the treatment of polycythemia vera. This drug is used biweekly with a starting dose of 100 μg (50 μg if patients receiving hydroxyurea) and 50 μg increments up to a maximum dose of 500 μg. Increasing evidence indicates that patients can tolerate higher starting doses of ropeginterferon α-2b. This phase II trial utilizes 250 μg as the starting dose, 350 μg at week 2 and 500 μg at week 4 as the target dose. Doses can be adjusted according to tolerability. This study assesses the safety, efficacy and molecular response of ropeginterferon α-2b in Chinese patients with PV utilizing the 250–350–500 μg dosing schema. This study will be used to support the application of a biologics license for polycythemia vera treatment in China.

Background: Polycythemia vera (PV) is a common type of BCR-ABL-negative myeloproliferative neoplasms. It often harbors a Janus kinase 2 (JAK2) gene mutation and is associated with elevated blood cell counts, symptoms that can be debilitating over time and risks of thrombosis and hemorrhage, and disease progression to myelofibrosis and acute myeloid leukemia. Ropeginterferon alfa-2b, a novel, site-selective, mono-pegylated proline-interferon alfa-2b, has improved pharmacokinetic properties, allowing dosing every 2 to 4 weeks, with improved tolerability and convenience. The safety and efficacy of ropeginterferon alfa-2b for the treatment of PV has been demonstrated in clinical studies conducted in Europe (PEGINVERA, PROUD-PV, CONTINUATION-PV) and Japan. The approved dosing scheme of ropeginterferon alfa-2b is 100 μg (or 50 μg in patients under another cytoreductive therapy) as a starting dose, with dose increment of 50 μg to the maximum recommended dose of 500 μg. Faster dose escalation may help patients achieve control of hematologic parameters quicker. Aims: The aim of this phase Ⅱ, single-arm study (A20-202) was to assess the safety and efficacy of ropeginterferon alfa-2b in Chinese PV patients utilizing an accelerated dose titration schedule. Methods: Chinese patients 18 years or older with a PV diagnosis according to World Health Organization 2016 criteria and were resistant or intolerant to hydroxyurea (HU) were enrolled. Ropeginterferon alfa-2b was administered subcutaneously every 2 weeks for 52 Weeks at a starting dose of 250 μg, followed by 350 µg at Week 2, and a target dose of 500 μg at Week 4. Patients received the target dose, if tolerated, for the remainder of the 52-week treatment. The primary endpoint was the proportion of patients who reach a complete hematologic response (CHR) at Week 24 (CHR: hematocrit <45% without phlebotomy or erythrocyte apheresis in the preceding 12 weeks, platelet≤400×109/L, leukocyte <10×109/L). Secondary endpoints included changes in hematologic parameters and JAK2V617F allele burden, time to first complete hematologic response, and duration of response. Safety endpoints included the incidence of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Results: As of the data cut-off date of 01 July 2022, a-total of 49 patients, 31 males and 18 females, with a median age of 56 years, were enrolled in this study. Mean baseline values were hematocrit 45.95%, leukocyte count 11.35×109/L, and platelet count 478.5×109/L. All patients had the JAK2V617F mutation (mean allele burden: 58.49%). One patient withdrew consent and discontinued the study. The data of 27 patients were available to evaluate the CHR at Week 24. Fourteen out of the 27 (51.85%) patients achieved a CHR at Week 24 of the treatment. This was comparable to the CHR rate of 43.1% at Week 52 observed in the PROUD-PV study. Hematocrit, leukocyte and platelet levels decreased over time with mean change ± SD from baseline to Week 24: -3.63± 6.14%, -5.77± 12.22×109/L, and -254.0± 177.23×109/L, respectively. JAK2V617F allele burden decreased over time with mean change ± SD from baseline to week 24: -13.95±16.74% (n=26); consistent with an increase in molecular response. The JAK2V617F allele burden in two patients became undetectable after the treatment, as measured by Next-Generation Sequencing with a lower limit of quantitation at 3% by the central laboratory. TEAEs occurred in 47 patients (95.9%). Grade≥3 AEs occurred in 8 of the patients (16.3%) and among them, possibly treatment-related Grade ≥ 3 AEs occurred in five patients (10.2%). Serious adverse events (SAE) occurred in 4 of the patients (8.2%), and possibly treatment-related SAE occurred in two patients (4.1%). The most common TEAEs were alanine aminotransferase increase (38.8%), leukopenia (36.7%) and aspartate aminotransferase increase (36.7%). Preliminary result did not show significant AESIs (e.g., cardiovascular and psychiatric events) in all the patients who received the treatment. Summary/Conclusion: The interim results of our study demonstrate that Ropeginterferon alfa-2b using a 250-350-500 μg dosing scheme was safe, well tolerated, and efficacious in Chinese patients with PV. The data suggest that using an accelerated dosing scheme helps patients achieve a CHR earlier.