Ropeginterferon Alfa-2b: Efficacy and Safety in Different Age Groups.
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ABSTRACT:
SUBMITTER: Gisslinger H
PROVIDER: S-EPMC7587416 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Ropeginterferon Alfa-2b: Efficacy and Safety in Different Age Groups.
Gisslinger Heinz H Klade Christoph C Georgiev Pencho P Krochmalczyk Dorota D Gercheva-Kyuchukova Liana L Egyed Miklos M Rossiev Viktor V Dulicek Petr P Illes Arpad A Pylypenko Halyna H Sivcheva Lylia L Mayer Jiri J Yablokova Vera V Krejcy Kurt K Hasselbalch Hans C HC Kralovics Robert R Kiladjian Jean-Jacques JJ
HemaSphere 20201020 6
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Project description:Background and aimRopeginterferon alfa-2b (P1101) is a novel long-acting mono-PEGylated recombinant proline interferon (IFN) conjugated to a 40 kDa branched polyethylene glycol (PEG) chain at its N-terminus, allowing every-two-week injection. It received European Medicines Agency and Taiwan marketing authorization for the treatment of polycythemia vera in 2019 and 2020, respectively. This phase 2 study aimed to evaluate the pharmacokinetics, safety, and preliminary efficacy of ropeginterferon alfa-2b as compared with PEG-IFN-α2a in patients with chronic hepatitis C virus genotype 1 infection.MethodsOne hundred six treatment naive patients were enrolled in this phase 2 study and randomized to four treatment groups: subcutaneous weekly PEG-IFN-α2a 180 μg (group 1), weekly ropeginterferon alfa-2b 180 μg (group 2), weekly ropeginterferon alfa-2b 270 μg (group 3), or biweekly ropeginterferon alfa-2b 450 μg (group 4) plus ribavirin for 48 weeks.ResultsAfter multiple weekly administration, serum exposure (AUC0-τ) in ropeginterferon alfa-2b 180 μg was approximately 41% greater and the accumulation ratio of 2-fold greater than PEG-IFN-α2a 180 μg. The incidences of flu-like symptoms were 66.7% (18/27), 53.3% (16/30), 55.0% (11/20), and 48.3% (14/29), anxiety were 14.8% (4/27), 6.7% (2/30), 0%, and 0%, and depression were 25.9% (7/27), 13.3% (4/30), 0%, and 3.4% (1/29), for groups 1-4, respectively. Two grade 2 of 3 depression were noted in PEG-IFN-α2a arm, but none in ropeginterferon arms. The SVR24 rates were 77.8% (21/27), 66.7% (20/30), 80% (16/20), and 69% (20/29), respectively.ConclusionsRopeginterferon alfa-2b showed longer effective half-life and superior safety profile than PEG-IFN-α2a. Biweekly injection of ropeginterferon alfa-2b will be studied in larger viral hepatitis patient population.
| S-EPMC8341194 | biostudies-literature
Project description: Not available
| S-EPMC9061291 | biostudies-literature
Project description:Myeloproliferative neoplasms (MPN) such as essential thrombocythemia (ET) and polycythemia vera (PV) are rare during pregnancy. However, they are harmful because they are associated with an increased risk of thromboembolic, hemorrhagic, or microcirculatory disturbances or placental dysfunction leading to fetal growth restriction or loss. Low-dose aspirin and low-molecular-weight heparin (LMWH) are recommended to reduce pregnancy complications, and interferon (IFN) is the only treatment option for cytoreductive therapy based on the likelihood of live birth in pregnant women with MPN. Since ropeginterferon alfa-2b is the only available IFN in South Korea, we present a case report of ropeginterferon alfa-2b use during pregnancy in an MPN patient. A 40-year-old woman who had been diagnosed with low-risk PV in 2017 and had been maintained on phlebotomy, hydroxyurea (HU), and anagrelide (ANA) for 4 years was confirmed as 5 weeks pregnant on 9 December 2021. After stopping treatment with HU and ANA, the patient showed a rapid increase in platelet count (1113 × 109/L to 2074 × 109/L, normal range, 150-450 × 109/L) and white blood cell count (21.93 × 109/L to 35.55 × 109/L, normal range, 4.0-10.0 × 109/L). Considering the high risk of complications, aggressive cytoreductive treatment was required, for which we chose ropeginterferon alfa-2b, as it is the only available IFN agent in South Korea. The patient underwent 8 cycles of ropeginterferon alfa-2b over 6 months during pregnancy and delivered without any neonatal or maternal complications. This case report highlights the importance of considering treatment options for MPN patients who are pregnant or planning a pregnancy, as well as the need for further investigation into the safety and efficacy of ropeginterferon alfa-2b in this population.
| S-EPMC10048098 | biostudies-literature
Project description:Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations. Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b. Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations. Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.
| S-EPMC8193675 | biostudies-literature
Project description:In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) ?-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-?. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.
| S-EPMC4608390 | biostudies-literature
Project description:Although ropeginterferon alfa-2b has recently been clinically applied to myeloproliferative neoplasms with promising results, its antitumor mechanism has not been thoroughly investigated. Using a leukemia model developed in immunocompetent mice, we evaluated the direct cytotoxic effects and indirect effects induced by ropeginterferon alfa-2b in tumor cells. Ropeginterferon alfa-2b therapy significantly prolonged the survival of mice bearing leukemia cells and led to long-term remission in some mice. Alternatively, conventional interferon-alpha treatment slightly extended the survival and all mice died. When ropeginterferon alfa-2b was administered to interferon-alpha receptor 1-knockout mice after the development of leukemia to verify the direct effect on the tumor, the survival of these mice was slightly prolonged; nevertheless, all of them died. In vivo CD4+ or CD8+ T-cell depletion resulted in a significant loss of therapeutic efficacy in mice. These results indicate that the host adoptive immunostimulatory effect of ropeginterferon alfa-2b is the dominant mechanism through which tumor cells are suppressed. Moreover, mice in long-term remission did not develop leukemia, even after tumor rechallenge. Rejection of rechallenge tumors was canceled only when both CD4+ and CD8+ T cells were removed in vivo, which indicates that each T-cell group functions independently in immunological memory. We show that ropeginterferon alfa-2b induces excellent antitumor immunomodulation in hosts. Our finding serves in devising therapeutic strategies with ropeginterferon alfa-2b.
| S-EPMC9277408 | biostudies-literature
Project description:BackgroundRopeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to 8-14 isomers of other on-market pegylated interferon, allowing injection every two or more weeks with higher tolerability. It received European Medicines Agency and Taiwan marketing authorization in 2019 and 2020, for treatment of polycythemia vera. This phase I/II study aimed to have preliminary evaluation of safety and efficacy in chronic hepatitis B.MethodsThirty-one HBeAg-positive and 31 HBeAg-negative were stratified by HBeAg status and randomized at 1:1:1 ratio to q2w ropeginterferon alfa-2b 350 μg (group 1), q2w 450 μg (group 2) or q1w PEG-IFN alfa-2a 180 μg (group 3). Each patient received 48-week treatment (TW48) and 24-week post-treatment follow-up (FW24).ResultsThe baseline demographics were comparable among the three groups, except for mean HBeAg in HBeAg-positive patients (2.90, 2.23, 2.99 log10 S/CO, respectively). Cumulative HBeAg seroconversion rate at follow-up period was 27.3% (3/11), 36.4% (4/11), and 11.1% (1/9) with time to HBeAg seroconversion starting from TW24, TW16, and TW48 in group 1, 2, and 3, respectively. The rate of HBV DNA < 2000 IU/mL and HBsAg levels < 1500 IU/mL at FW24 were comparable in all groups. Ropeginterferon alfa-2b (group 1 & 2) had numerically lower incidence of rash (9.5% and 4.5%) as compared to PEG-IFN alfa-2a (36.8%). Ropeginterferon alfa-2b 350 μg (group 1) had more ALT elevation (38.1%), however the rate was comparable in group 2 (9.1%) and group 3 (10.5%).ConclusionIn this preliminary study, ropeginterferon alfa-2b, although in only half the number of injections, is as safe and effective as pegylated interferon alfa-2a for chronic hepatitis B.
| S-EPMC7803873 | biostudies-literature
Project description:IntroductionThis study, for the first time to our knowledge, evaluated the efficacy of ropeginterferon alfa-2b, a long-acting pegylated interferon (IFN)-alfa, in the treatment of COVID-19.MethodsWe retrospectively evaluated ropeginterferon alfa-2b administered subcutaneously at a single dose of 250 µg for the treatment of mild and moderate COVID-19. Primary outcome was to compare the overall negative conversion time from the confirmed, last positive SARS-CoV-2 RT-PCR to the first RT-PCR negative conversion between patients receiving ropeginterferon alfa-2b plus standard of care (SOC) and those receiving SOC alone.ResultsThirty-five patients with mild COVID-19 and 37 patients with moderate disease were included. Of them, 19 patients received SOC plus ropeginterferon alfa-2b and 53 patients received SOC alone. All patients with moderate disease in the ropeginterferon alfa-2b group showed RT-PCR negative conversion within 8 days, while a significant portion of patients in the SOC alone group failed to do so. For patients with moderate disease and age ≤ 65 years old, the ropeginterferon alfa-2b group had statistically significant shorter median RT-PCR conversion time than the SOC alone group (7 vs. 11.5 days, p < 0.05).ConclusionsRopeginterferon alfa-2b showed the potential for the treatment of moderate COVID-19 patients. A randomized, controlled Phase III study is planned to further assess the effectiveness of ropeginterferon alfa-2b in COVID-19 patients.
| S-EPMC8672342 | biostudies-literature
Project description:PurposeWe tested the hypothesis that the combination of tremelimumab and interferon alfa-2b acting via different and possibly synergistic mechanisms would overcome tumor immune tolerance and lead to significant and durable clinical responses.Patients and methodsWe conducted a phase II study in which patients were administered tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) intravenously every 12 weeks. High-dose interferon alfa-2b (HDI) was administered concurrently, including intravenous induction at 20 MU/m2/d for 5 d/wk for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously.ResultsThirty-seven patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) were enrolled. Two patients had previously treated brain metastases. Grades 3 and 4 toxicities included neutropenia (six patients; 17%), diarrhea/colitis (four patients; 11%), liver enzyme increase (four patients; 11%), rash (four patients; 11%), fatigue (15 patients; 40%), and anxiety/depression (five patients; 14%). Response data were available for 35 patients. The best objective response rate (RR; Response Evaluation Criteria in Solid Tumors) by intention to treat was 24% (90% CI, 13% to 36%; four complete responses [CRs] and five partial responses [PRs] that lasted 6, 6, > 12, > 14, > 18, 20, > 28, 30, and > 37 months, respectively). Fourteen patients (38%) had stable disease (SD) that lasted 1.5 to 21 months. The median progression-free survival was 6.4 months (95% CI, 3.3 to 12.1 months). The median overall survival (OS) was 21 months (95% CI, 9.5 to not reached). There was a weak association between therapy-induced autoimmunity and clinical benefits (CR/PR/SD; P = .0059), baseline C-reactive protein (CRP) less than or equal to 2.7× the upper limit of normal and clinical benefits (P = .0494) and improved probability of survival (P = .0032), and baseline lymphocyte count of at least 1,000/μL and response (CR/PR; P = .0183) and clinical benefits (CR/PR/SD; P = .0255). Biomarker associations were not significant after adjustment for multiple comparisons.ConclusionHDI can be administered combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.
| S-EPMC3422533 | biostudies-literature
Project description:Interferon-?2b (IFN-?2b) is used to treat melanoma but there is a need to improve its efficacy. IFN-?2b signaling requires STAT1/STAT2 tyrosine phosphorylation and is subject to negative regulation by phosphatases. In this study, we determined whether inhibition of the protein tyrosine phosphatase Shp2 could enhance IFN-?2b responses in human melanoma cells. Shp2 knockdown increased IFN-?2b-stimulated STAT1 Tyr-701 phosphorylation and ISRE-luciferase activity even though it did not affect STAT2 Tyr-690 phosphorylation in A375 cells. In A375 tumor xenografts, Shp2 knockdown enhanced the anti-melanoma effect of IFN-?2b. Furthermore, the Shp2 inhibitor SPI-112Me increased the IFN-?2b-induced STAT1 activation and anti-proliferative response in A375 and SK-MEL-2 cells. These results demonstrate that inhibition of Shp2 can enhance the anti-melanoma activity of IFN-?2b.
| S-EPMC3319810 | biostudies-literature