Cited 15 times in
A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis
DC Field | Value | Language |
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dc.contributor.author | 이정일 | - |
dc.date.accessioned | 2024-03-22T05:42:43Z | - |
dc.date.available | 2024-03-22T05:42:43Z | - |
dc.date.issued | 2023-04 | - |
dc.identifier.issn | 0168-8278 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/198160 | - |
dc.description.abstract | Background & Aims: Loss-of-function HSD17613 mutations protect against the development of chronic liver disease. HSD17613 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17#13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically sus-pected NASH. Methods: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17#13 mRNA and protein. Results: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17#13 mRNA from baseline to Day 71 were:-56.9% (25 mg),-85.5% (100 mg), and-93.4% (200 mg). The mean HSD17#13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17613 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were-7.7% (25 mg),-39.3% (100 mg), and-42.3% (200 mg) (p <0.001 for pooled cohorts). Conclusions: ARO-HSD was well tolerated at doses <-200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17#13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. | - |
dc.description.statementOfResponsibility | restriction | - |
dc.language | English | - |
dc.publisher | Elsevier | - |
dc.relation.isPartOf | JOURNAL OF HEPATOLOGY | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.subject.MESH | Alanine Transaminase | - |
dc.subject.MESH | Double-Blind Method | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | Liver / pathology | - |
dc.subject.MESH | Liver Function Tests | - |
dc.subject.MESH | Non-alcoholic Fatty Liver Disease* / complications | - |
dc.subject.MESH | Non-alcoholic Fatty Liver Disease* / drug therapy | - |
dc.subject.MESH | Non-alcoholic Fatty Liver Disease* / genetics | - |
dc.subject.MESH | RNA Interference | - |
dc.subject.MESH | Treatment Outcome | - |
dc.title | A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine (의과대학) | - |
dc.contributor.department | Dept. of Internal Medicine (내과학교실) | - |
dc.contributor.googleauthor | Lung-Yi Mak | - |
dc.contributor.googleauthor | Ed Gane | - |
dc.contributor.googleauthor | Christian Schwabe | - |
dc.contributor.googleauthor | Ki Tae Yoon | - |
dc.contributor.googleauthor | Jeong Heo | - |
dc.contributor.googleauthor | Russell Scott | - |
dc.contributor.googleauthor | Jeong-Hoon Lee | - |
dc.contributor.googleauthor | Jung Il Lee | - |
dc.contributor.googleauthor | Young Oh Kweon | - |
dc.contributor.googleauthor | Martin Weltman | - |
dc.contributor.googleauthor | Stephen A Harrison | - |
dc.contributor.googleauthor | Brent A Neuschwander-Tetri | - |
dc.contributor.googleauthor | Kenneth Cusi | - |
dc.contributor.googleauthor | Rohit Loomba | - |
dc.contributor.googleauthor | Bruce D Given | - |
dc.contributor.googleauthor | Dawn R Christianson | - |
dc.contributor.googleauthor | Eric Garcia-Medel | - |
dc.contributor.googleauthor | Min Yi | - |
dc.contributor.googleauthor | James Hamilton | - |
dc.contributor.googleauthor | Man-Fung Yuen | - |
dc.identifier.doi | 10.1016/j.jhep.2022.11.025 | - |
dc.contributor.localId | A03122 | - |
dc.relation.journalcode | J01441 | - |
dc.identifier.eissn | 1600-0641 | - |
dc.identifier.pmid | 36513186 | - |
dc.identifier.url | https://www.sciencedirect.com/science/article/pii/S0168827822033207 | - |
dc.subject.keyword | ARO-HSD | - |
dc.subject.keyword | HSD17β13 | - |
dc.subject.keyword | HSD17β13 mRNA and protein | - |
dc.subject.keyword | NASH | - |
dc.subject.keyword | Non-alcoholic steatohepatitis | - |
dc.subject.keyword | RNA interference | - |
dc.subject.keyword | RNA-induced silencing complex | - |
dc.contributor.alternativeName | Lee, Jung Il | - |
dc.contributor.affiliatedAuthor | 이정일 | - |
dc.citation.volume | 78 | - |
dc.citation.number | 4 | - |
dc.citation.startPage | 684 | - |
dc.citation.endPage | 692 | - |
dc.identifier.bibliographicCitation | JOURNAL OF HEPATOLOGY, Vol.78(4) : 684-692, 2023-04 | - |
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