Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction
Abstract Introduction Anemia is a prevalent complication of chronic kidney disease (CKD), primarily due to insufficient erythropoietin (EPO). Pegmolesatide (by Hansoh Pharma) is currently the only marketed long-acting EPO mimetic peptide (EMP) for the treatment of anemia in both dialysis and non-dia...
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2025-02-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06078-1 |
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| author | Xiaoying Ma Zhen Li Lu Zhang Hui Qian Qinkai Chen Ye Tao Yunfan Li Dandan Wang Zhizhen Hu Weili Luo Ping Li Hai Yu Changlin Mei Xueqing Yu Yuanfeng Zhou |
| author_facet | Xiaoying Ma Zhen Li Lu Zhang Hui Qian Qinkai Chen Ye Tao Yunfan Li Dandan Wang Zhizhen Hu Weili Luo Ping Li Hai Yu Changlin Mei Xueqing Yu Yuanfeng Zhou |
| author_sort | Xiaoying Ma |
| collection | DOAJ |
| description | Abstract Introduction Anemia is a prevalent complication of chronic kidney disease (CKD), primarily due to insufficient erythropoietin (EPO). Pegmolesatide (by Hansoh Pharma) is currently the only marketed long-acting EPO mimetic peptide (EMP) for the treatment of anemia in both dialysis and non-dialysis CKD patients. This paper aimed to explore the long-acting erythropoiesis stimulating molecular mechanism of Pegmolesatide. Methods In vitro assays were utilized to assess Pegmolesatide erythropoietin receptor (EPOR) affinity, competitive binding, cell proliferation/survival, apoptosis, cell surface receptor expression, and signal transduction. Pharmacokinetics (PK) and Pharmacodynamics (PD) parameters were evaluated in BALB/c mice following single administration. Furthermore, two Phase II clinical trials in dialysis and non-dialysis chronic kidney disease (CKD) patients with anemia, respectively CTR20140533 and CTR20140539, assessed PK-PD and safety following repeated administration. Results In vitro Pegmolesatide demonstrated enhanced binding stability and prolonged residency at EPOR, surpassing erythropoiesis-stimulating agents (ESAs) rHuEPO and Darbepoetin. This sustained EPOR binding facilitated heightened endogenous EPOR expression post-drug withdrawal, maintaining downstream signal transduction pathways (JAK2/STAT5, ERK1/2 MAPK) for erythropoiesis. Pegmolesatide promoted UT-7 cell proliferation & survival and suppressed apoptosis. Following a single 0.08 mg/kg dose of Pegmolesatide in BALB/c mice, reticulocyte count, red blood cells, hemoglobin, and hematocrit persisted at elevated levels 4-6 days after administration. In the two clinical Phase II studies dose-dependent increases in hemoglobin and prolonged response duration were independently observed. Pegmolesatide showed significant PK-PD dual prolongation effects and was well tolerated. Adverse events were mild and manageable, with no reports of severe anaphylaxis. Discussion Preclinical and clinical evidence signifies that Pegmolesatide is a unique, potent PEGylated EPO-memetic peptide (EMP) with a prolonged PD efficacy and PK half-life and a good safety-tolerability profile. To elucidate further, future studies will address the endocytosis, intracellular degradation, and ligand release of EPOR subsequent to Pegmolesatide binding, thereby supplementing our understanding of the molecular mechanism at play. Trial registration: Phase IIa clinical study of Pegmolesatide on renal anemia, CTR20140533. Initial Public Notice 14 Jan 2015, http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml . Phase II clinical study of Pegmolesatide on renal anemia, CTR20140539. Initial Public Notice 26 Jan 2015, http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml . |
| format | Article |
| id | doaj-art-a74b48509c874f5cb23e3189ba99fe87 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-a74b48509c874f5cb23e3189ba99fe872025-02-09T12:52:22ZengBMCJournal of Translational Medicine1479-58762025-02-0123111610.1186/s12967-025-06078-1Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transductionXiaoying Ma0Zhen Li1Lu Zhang2Hui Qian3Qinkai Chen4Ye Tao5Yunfan Li6Dandan Wang7Zhizhen Hu8Weili Luo9Ping Li10Hai Yu11Changlin Mei12Xueqing Yu13Yuanfeng Zhou14Translational Medicine Center, Shanghai Hansoh Biomedical Co., LtdTranslational Medicine Center, Shanghai Hansoh Biomedical Co., LtdTranslational Medicine Center, Shanghai Hansoh Biomedical Co., LtdTranslational Medicine Center, Shanghai Hansoh Biomedical Co., LtdThe First Affiliated Hospital of Nanchang UniversitySichuan University West China HospitalTranslational Medicine Center, Shanghai Hansoh Biomedical Co., LtdTranslational Medicine Center, Shanghai Hansoh Biomedical Co., LtdHansoh Pharmaceutical Group Co., LtdHansoh Pharmaceutical Group Co., LtdHansoh Pharmaceutical Group Co., LtdTranslational Medicine Center, Shanghai Hansoh Biomedical Co., LtdShanghai Changzheng Hospital, Navy Military Medical UniversityGuangdong Provincial People’s HospitalTranslational Medicine Center, Shanghai Hansoh Biomedical Co., LtdAbstract Introduction Anemia is a prevalent complication of chronic kidney disease (CKD), primarily due to insufficient erythropoietin (EPO). Pegmolesatide (by Hansoh Pharma) is currently the only marketed long-acting EPO mimetic peptide (EMP) for the treatment of anemia in both dialysis and non-dialysis CKD patients. This paper aimed to explore the long-acting erythropoiesis stimulating molecular mechanism of Pegmolesatide. Methods In vitro assays were utilized to assess Pegmolesatide erythropoietin receptor (EPOR) affinity, competitive binding, cell proliferation/survival, apoptosis, cell surface receptor expression, and signal transduction. Pharmacokinetics (PK) and Pharmacodynamics (PD) parameters were evaluated in BALB/c mice following single administration. Furthermore, two Phase II clinical trials in dialysis and non-dialysis chronic kidney disease (CKD) patients with anemia, respectively CTR20140533 and CTR20140539, assessed PK-PD and safety following repeated administration. Results In vitro Pegmolesatide demonstrated enhanced binding stability and prolonged residency at EPOR, surpassing erythropoiesis-stimulating agents (ESAs) rHuEPO and Darbepoetin. This sustained EPOR binding facilitated heightened endogenous EPOR expression post-drug withdrawal, maintaining downstream signal transduction pathways (JAK2/STAT5, ERK1/2 MAPK) for erythropoiesis. Pegmolesatide promoted UT-7 cell proliferation & survival and suppressed apoptosis. Following a single 0.08 mg/kg dose of Pegmolesatide in BALB/c mice, reticulocyte count, red blood cells, hemoglobin, and hematocrit persisted at elevated levels 4-6 days after administration. In the two clinical Phase II studies dose-dependent increases in hemoglobin and prolonged response duration were independently observed. Pegmolesatide showed significant PK-PD dual prolongation effects and was well tolerated. Adverse events were mild and manageable, with no reports of severe anaphylaxis. Discussion Preclinical and clinical evidence signifies that Pegmolesatide is a unique, potent PEGylated EPO-memetic peptide (EMP) with a prolonged PD efficacy and PK half-life and a good safety-tolerability profile. To elucidate further, future studies will address the endocytosis, intracellular degradation, and ligand release of EPOR subsequent to Pegmolesatide binding, thereby supplementing our understanding of the molecular mechanism at play. Trial registration: Phase IIa clinical study of Pegmolesatide on renal anemia, CTR20140533. Initial Public Notice 14 Jan 2015, http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml . Phase II clinical study of Pegmolesatide on renal anemia, CTR20140539. Initial Public Notice 26 Jan 2015, http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml .https://doi.org/10.1186/s12967-025-06078-1AnemiaCell signalingCell survivalChronic kidney disease |
| spellingShingle | Xiaoying Ma Zhen Li Lu Zhang Hui Qian Qinkai Chen Ye Tao Yunfan Li Dandan Wang Zhizhen Hu Weili Luo Ping Li Hai Yu Changlin Mei Xueqing Yu Yuanfeng Zhou Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction Journal of Translational Medicine Anemia Cell signaling Cell survival Chronic kidney disease |
| title | Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction |
| title_full | Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction |
| title_fullStr | Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction |
| title_full_unstemmed | Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction |
| title_short | Overview of preclinical and phase II clinical studies on Pegmolesatide’s long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction |
| title_sort | overview of preclinical and phase ii clinical studies on pegmolesatide s long term erythropoiesis stimulating effect via epor mediated signal transduction |
| topic | Anemia Cell signaling Cell survival Chronic kidney disease |
| url | https://doi.org/10.1186/s12967-025-06078-1 |
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