Interferon-beta (IFN-β), an extracellular cytokine that initiates signaling pathways for gene regulation, has been demonstrated to function as a tumor suppressor protein through lentiviral gene ...transduction. In this article, I review the relevant previous works and propose a cell cycle-based, tumor suppressor protein-mediated mechanism of anti-cancer surveillance. IFN-β induces a tumor cell cycle alteration that leads to S phase accumulation, senescence entry, and a loss of tumorigenicity in solid tumor cells. IFN-β does not show a significant cell cycle effect in their normal counterparts. Retinoblastoma protein RB1, another tumor suppressor protein, tightly controls the cell cycle and differentiation of normal cells, preventing them from being significantly impacted by the IFN-β effect. The interplay between IFN-β and RB1 acts as a mechanism of cell cycle-based, tumor suppressor protein-mediated anti-cancer surveillance that can selectively suppress solid tumor or proliferating transformed cells from the loss of control leading to cancer. This mechanism has important implications for the treatment of solid tumors.
Ropeginterferon alfa-2b is a novel monopegylated recombinant interferon alfa-2b for the treatment of patients with polycythemia vera. The objectives of this study were to evaluate the ...pharmacokinetics, pharmacodynamics, safety, and tolerability of ropeginterferon alfa-2b in healthy Japanese subjects compared with Caucasian subjects.
In this multicenter, parallel-group phase I study, a cohort consisting of six Japanese and six Caucasian subjects was designated to receive a single subcutaneous dose of ropeginterferon alfa-2b (100, 200, 300, and 450 µg). Pharmacokinetic and pharmacodynamic parameters, and immunogenicity were evaluated. Safety was assessed throughout the study.
Cohort 4 (450-µg dose) was not initiated because the primary objective of this study was achieved based on the three completed cohorts. A total of 36 enrolled subjects (18 Japanese and 18 Caucasian) in three cohorts were included in the safety, pharmacokinetic, and pharmacodynamic analysis sets. Ropeginterferon alfa-2b exposure in terms of the area under the serum concentration-time curve (AUC) from time zero extrapolated to infinity and the AUC from time zero to the time of the last quantifiable concentration was approximately 1.7-fold and two-fold higher in Japanese subjects than in Caucasian subjects, respectively. Across the same dose range, the maximum serum concentration was approximately 1.25-fold higher in Japanese subjects than in Caucasian subjects. The time to reach the median maximum serum concentration was similar between ethnicities (approximately 96-111 h). The terminal half-life was 48-57 h in Japanese subjects and 31-75 h in Caucasian subjects. The slope of the relationship between dose and drug exposure was greater than 1 in both ethnicities. The dose-dependent induction of beta-2 microglobulin and neopterin expression was observed in both ethnicities, and the two groups showed similar pharmacodynamic parameters. At the end of the study, 22.2% of Japanese subjects and 11.1% of Caucasian subjects developed anti-ropeginterferon alfa-2b-binding antibodies. The neutralizing capacity of these antibodies was not tested. Ropeginterferon alfa-2b up to 300 µg was safe and well tolerated, with no unexpected safety findings based on previous experiences with ropeginterferon alfa-2b and other forms of interferon.
Ropeginterferon alfa-2b exposure was higher in Japanese subjects than in Caucasian subjects. The increase in ropeginterferon alfa-2b exposure was greater than the dose proportion in the dose range of 100-300 µg. Ropeginterferon alfa-2b was safe and well tolerated.
ClinicalTrials.gov identifier NCT03546465, registered on 6 June, 2018.
Ropeginterferon alfa-2b is a novel, long-acting mono-pegylated proline-IFN-alpha-2b approved for treatment of polycythemia vera in adults, regardless of thrombotic risk level or treatment history. ...Clinical trial data indicate the dose and titration of ropeginterferon alfa-2b is safe and effective. However, additional studies may provide rationale for an amended, higher initial dosage and rapid titration. This article is an overview of current and upcoming studies of ropeginterferon alfa-2b in myeloproliferative neoplasms that support the exploration of an amended dosing scheme in order to optimize patient tolerability and efficacy outcomes.
Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a ...favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D.
Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo ...effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC.
Ropeginterferon alfa-2b is a novel, site-selective, monopegylated recombinant human interferon alfa-2b. Safety and efficacy of ropeginterferon alfa-2b for the treatment of polycythemia vera were ...demonstrated in clinical studies conducted in European countries, but clinical studies in Japanese patients are lacking. This phase 2, open-label, multicenter, single-arm study investigated the safety and efficacy of ropeginterferon alfa-2b in 29 Japanese patients with polycythemia vera including young patients and patients with low thrombosis risk who are difficult to receive guideline-based standard treatments. The primary outcome of durable complete hematologic response without phlebotomy at months 9 and 12 was achieved by 8/29 (27.6%) patients. The fastest complete hematologic response was observed at week 12. A corresponding reduction in the
JAK2
V617F allele burden from baseline to 52 weeks was also observed (mean ± standard deviation = − 19.2% ± 22.6%). No new safety concerns were identified in Japanese patients when compared with previous studies of ropeginterferon alfa-2b in European populations; the most common treatment-related adverse events were alopecia (55.2%), fatigue (27.6%) and influenza-like illness (27.6%). Most treatment-related adverse events were mild or moderate, with none of grade ≥ 3. Ropeginterferon alfa-2b is a safe and efficacious treatment option in Japanese patients with polycythemia vera.
Ropeginterferon alfa-2b is a novel mono-pegylated proline-interferon. Its biweekly dosing schema has demonstrated tolerability and clinical efficacy for treating chronic hepatitis in previous ...clinical studies. This trial evaluates the pharmacokinetics of 400 μg ropeginterferon alfa-2b in patients with chronic hepatitis C virus (HCV) and provides the data to support the clinical utility of ropeginterferon alfa-2b at 400 μg.
Seventeen patients with chronic HCV genotype 2 were enrolled to receive a single injection of 400 μg ropeginterferon alfa-2b plus 14-day treatment of ribavirin. Pharmacokinetics, safety, and HCV RNA reduction/clearance were assessed.
Tmax was 154.003 h and T1/2 was 114.273 h. The Cmax was 29.823 ng mL−1. AUClast was 9364.292 h∗ng mL−1 and AUCinf was 11084.317 h∗ng mL−1. All adverse events were mild or moderate, and there were no serious adverse events. A 1000-fold reduction in the geometric mean of HCV RNA was observed 14 d after the single injection of ropeginterferon alfa-2b. Two patients achieved clearance of HCV RNA, and the other five patients had HCV RNA levels lower than 200 IU mL−1.
Ropeginterferon alfa-2b at 400 μg led to PK exposures associated with safety and notable clinical activity in patients with chronic HCV. This study suggests that ropeginterferon alfa-2b at 400 μg is an acceptable dosing regimen for treating chronic HCV and also provides supporting data for the clinical use of ropeginterferon alfa-2b at a higher starting dose for other indications.
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)”.
