A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis
Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed t...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Mak, Lung-Yi [verfasserIn] Gane, Ed [verfasserIn] Schwabe, Christian [verfasserIn] Yoon, Ki Tae [verfasserIn] Heo, Jeong [verfasserIn] Scott, Russell [verfasserIn] Lee, Jeong-Hoon [verfasserIn] Lee, Jung Il [verfasserIn] Kweon, Young Oh [verfasserIn] Weltman, Martin [verfasserIn] Harrison, Stephen A. [verfasserIn] Neuschwander-Tetri, Brent A. [verfasserIn] Cusi, Kenneth [verfasserIn] Loomba, Rohit [verfasserIn] Given, Bruce D. [verfasserIn] Christianson, Dawn R. [verfasserIn] Garcia-Medel, Eric [verfasserIn] Yi, Min [verfasserIn] Hamilton, James [verfasserIn] Yuen, Man-Fung [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Journal of hepatology - Amsterdam [u.a.] : Elsevier Science, 1985, 78 |
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| Übergeordnetes Werk: |
volume:78 |
| DOI / URN: |
10.1016/j.jhep.2022.11.025 |
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| Katalog-ID: |
ELV009425454 |
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| 024 | 7 | |a 10.1016/j.jhep.2022.11.025 |2 doi | |
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| 100 | 1 | |a Mak, Lung-Yi |e verfasserin |0 (orcid)0000-0002-2266-3935 |4 aut | |
| 245 | 1 | 0 | |a A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis |
| 264 | 1 | |c 2022 | |
| 336 | |a nicht spezifiziert |b zzz |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. | ||
| 650 | 4 | |a Non-alcoholic steatohepatitis | |
| 650 | 4 | |a NASH | |
| 650 | 4 | |a ARO-HSD | |
| 650 | 4 | |a HSD17β13 | |
| 650 | 4 | |a RNA interference | |
| 650 | 4 | |a RNA-induced silencing complex | |
| 650 | 4 | |a HSD17β13 mRNA and protein | |
| 700 | 1 | |a Gane, Ed |e verfasserin |4 aut | |
| 700 | 1 | |a Schwabe, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Yoon, Ki Tae |e verfasserin |4 aut | |
| 700 | 1 | |a Heo, Jeong |e verfasserin |4 aut | |
| 700 | 1 | |a Scott, Russell |e verfasserin |0 (orcid)0000-0002-2107-6480 |4 aut | |
| 700 | 1 | |a Lee, Jeong-Hoon |e verfasserin |0 (orcid)0000-0002-0315-2080 |4 aut | |
| 700 | 1 | |a Lee, Jung Il |e verfasserin |0 (orcid)0000-0002-0142-1398 |4 aut | |
| 700 | 1 | |a Kweon, Young Oh |e verfasserin |0 (orcid)0000-0001-5708-7985 |4 aut | |
| 700 | 1 | |a Weltman, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, Stephen A. |e verfasserin |4 aut | |
| 700 | 1 | |a Neuschwander-Tetri, Brent A. |e verfasserin |0 (orcid)0000-0002-8520-7398 |4 aut | |
| 700 | 1 | |a Cusi, Kenneth |e verfasserin |0 (orcid)0000-0002-8629-418X |4 aut | |
| 700 | 1 | |a Loomba, Rohit |e verfasserin |0 (orcid)0000-0002-4845-9991 |4 aut | |
| 700 | 1 | |a Given, Bruce D. |e verfasserin |4 aut | |
| 700 | 1 | |a Christianson, Dawn R. |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia-Medel, Eric |e verfasserin |0 (orcid)0000-0002-7537-0992 |4 aut | |
| 700 | 1 | |a Yi, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Hamilton, James |e verfasserin |0 (orcid)0000-0002-5494-2744 |4 aut | |
| 700 | 1 | |a Yuen, Man-Fung |e verfasserin |0 (orcid)0000-0001-7985-7725 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of hepatology |d Amsterdam [u.a.] : Elsevier Science, 1985 |g 78 |h Online-Ressource |w (DE-627)320984486 |w (DE-600)2027112-8 |w (DE-576)093888856 |x 1600-0641 |7 nnns |
| 773 | 1 | 8 | |g volume:78 |
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| 912 | |a GBV_ILN_224 | ||
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| 912 | |a GBV_ILN_602 | ||
| 912 | |a GBV_ILN_702 | ||
| 912 | |a GBV_ILN_2003 | ||
| 912 | |a GBV_ILN_2004 | ||
| 912 | |a GBV_ILN_2005 | ||
| 912 | |a GBV_ILN_2011 | ||
| 912 | |a GBV_ILN_2014 | ||
| 912 | |a GBV_ILN_2015 | ||
| 912 | |a GBV_ILN_2020 | ||
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| 912 | |a GBV_ILN_4251 | ||
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2022 |
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44.87 |
| publishDate |
2022 |
| allfields |
10.1016/j.jhep.2022.11.025 doi (DE-627)ELV009425454 (ELSEVIER)S0168-8278(22)03320-7 DE-627 ger DE-627 rda eng 610 DE-600 44.87 bkl Mak, Lung-Yi verfasserin (orcid)0000-0002-2266-3935 aut A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. Non-alcoholic steatohepatitis NASH ARO-HSD HSD17β13 RNA interference RNA-induced silencing complex HSD17β13 mRNA and protein Gane, Ed verfasserin aut Schwabe, Christian verfasserin aut Yoon, Ki Tae verfasserin aut Heo, Jeong verfasserin aut Scott, Russell verfasserin (orcid)0000-0002-2107-6480 aut Lee, Jeong-Hoon verfasserin (orcid)0000-0002-0315-2080 aut Lee, Jung Il verfasserin (orcid)0000-0002-0142-1398 aut Kweon, Young Oh verfasserin (orcid)0000-0001-5708-7985 aut Weltman, Martin verfasserin aut Harrison, Stephen A. verfasserin aut Neuschwander-Tetri, Brent A. verfasserin (orcid)0000-0002-8520-7398 aut Cusi, Kenneth verfasserin (orcid)0000-0002-8629-418X aut Loomba, Rohit verfasserin (orcid)0000-0002-4845-9991 aut Given, Bruce D. verfasserin aut Christianson, Dawn R. verfasserin aut Garcia-Medel, Eric verfasserin (orcid)0000-0002-7537-0992 aut Yi, Min verfasserin aut Hamilton, James verfasserin (orcid)0000-0002-5494-2744 aut Yuen, Man-Fung verfasserin (orcid)0000-0001-7985-7725 aut Enthalten in Journal of hepatology Amsterdam [u.a.] : Elsevier Science, 1985 78 Online-Ressource (DE-627)320984486 (DE-600)2027112-8 (DE-576)093888856 1600-0641 nnns volume:78 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.87 Gastroenterologie AR 78 |
| spelling |
10.1016/j.jhep.2022.11.025 doi (DE-627)ELV009425454 (ELSEVIER)S0168-8278(22)03320-7 DE-627 ger DE-627 rda eng 610 DE-600 44.87 bkl Mak, Lung-Yi verfasserin (orcid)0000-0002-2266-3935 aut A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. Non-alcoholic steatohepatitis NASH ARO-HSD HSD17β13 RNA interference RNA-induced silencing complex HSD17β13 mRNA and protein Gane, Ed verfasserin aut Schwabe, Christian verfasserin aut Yoon, Ki Tae verfasserin aut Heo, Jeong verfasserin aut Scott, Russell verfasserin (orcid)0000-0002-2107-6480 aut Lee, Jeong-Hoon verfasserin (orcid)0000-0002-0315-2080 aut Lee, Jung Il verfasserin (orcid)0000-0002-0142-1398 aut Kweon, Young Oh verfasserin (orcid)0000-0001-5708-7985 aut Weltman, Martin verfasserin aut Harrison, Stephen A. verfasserin aut Neuschwander-Tetri, Brent A. verfasserin (orcid)0000-0002-8520-7398 aut Cusi, Kenneth verfasserin (orcid)0000-0002-8629-418X aut Loomba, Rohit verfasserin (orcid)0000-0002-4845-9991 aut Given, Bruce D. verfasserin aut Christianson, Dawn R. verfasserin aut Garcia-Medel, Eric verfasserin (orcid)0000-0002-7537-0992 aut Yi, Min verfasserin aut Hamilton, James verfasserin (orcid)0000-0002-5494-2744 aut Yuen, Man-Fung verfasserin (orcid)0000-0001-7985-7725 aut Enthalten in Journal of hepatology Amsterdam [u.a.] : Elsevier Science, 1985 78 Online-Ressource (DE-627)320984486 (DE-600)2027112-8 (DE-576)093888856 1600-0641 nnns volume:78 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.87 Gastroenterologie AR 78 |
| allfields_unstemmed |
10.1016/j.jhep.2022.11.025 doi (DE-627)ELV009425454 (ELSEVIER)S0168-8278(22)03320-7 DE-627 ger DE-627 rda eng 610 DE-600 44.87 bkl Mak, Lung-Yi verfasserin (orcid)0000-0002-2266-3935 aut A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. Non-alcoholic steatohepatitis NASH ARO-HSD HSD17β13 RNA interference RNA-induced silencing complex HSD17β13 mRNA and protein Gane, Ed verfasserin aut Schwabe, Christian verfasserin aut Yoon, Ki Tae verfasserin aut Heo, Jeong verfasserin aut Scott, Russell verfasserin (orcid)0000-0002-2107-6480 aut Lee, Jeong-Hoon verfasserin (orcid)0000-0002-0315-2080 aut Lee, Jung Il verfasserin (orcid)0000-0002-0142-1398 aut Kweon, Young Oh verfasserin (orcid)0000-0001-5708-7985 aut Weltman, Martin verfasserin aut Harrison, Stephen A. verfasserin aut Neuschwander-Tetri, Brent A. verfasserin (orcid)0000-0002-8520-7398 aut Cusi, Kenneth verfasserin (orcid)0000-0002-8629-418X aut Loomba, Rohit verfasserin (orcid)0000-0002-4845-9991 aut Given, Bruce D. verfasserin aut Christianson, Dawn R. verfasserin aut Garcia-Medel, Eric verfasserin (orcid)0000-0002-7537-0992 aut Yi, Min verfasserin aut Hamilton, James verfasserin (orcid)0000-0002-5494-2744 aut Yuen, Man-Fung verfasserin (orcid)0000-0001-7985-7725 aut Enthalten in Journal of hepatology Amsterdam [u.a.] : Elsevier Science, 1985 78 Online-Ressource (DE-627)320984486 (DE-600)2027112-8 (DE-576)093888856 1600-0641 nnns volume:78 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.87 Gastroenterologie AR 78 |
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10.1016/j.jhep.2022.11.025 doi (DE-627)ELV009425454 (ELSEVIER)S0168-8278(22)03320-7 DE-627 ger DE-627 rda eng 610 DE-600 44.87 bkl Mak, Lung-Yi verfasserin (orcid)0000-0002-2266-3935 aut A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. Non-alcoholic steatohepatitis NASH ARO-HSD HSD17β13 RNA interference RNA-induced silencing complex HSD17β13 mRNA and protein Gane, Ed verfasserin aut Schwabe, Christian verfasserin aut Yoon, Ki Tae verfasserin aut Heo, Jeong verfasserin aut Scott, Russell verfasserin (orcid)0000-0002-2107-6480 aut Lee, Jeong-Hoon verfasserin (orcid)0000-0002-0315-2080 aut Lee, Jung Il verfasserin (orcid)0000-0002-0142-1398 aut Kweon, Young Oh verfasserin (orcid)0000-0001-5708-7985 aut Weltman, Martin verfasserin aut Harrison, Stephen A. verfasserin aut Neuschwander-Tetri, Brent A. verfasserin (orcid)0000-0002-8520-7398 aut Cusi, Kenneth verfasserin (orcid)0000-0002-8629-418X aut Loomba, Rohit verfasserin (orcid)0000-0002-4845-9991 aut Given, Bruce D. verfasserin aut Christianson, Dawn R. verfasserin aut Garcia-Medel, Eric verfasserin (orcid)0000-0002-7537-0992 aut Yi, Min verfasserin aut Hamilton, James verfasserin (orcid)0000-0002-5494-2744 aut Yuen, Man-Fung verfasserin (orcid)0000-0001-7985-7725 aut Enthalten in Journal of hepatology Amsterdam [u.a.] : Elsevier Science, 1985 78 Online-Ressource (DE-627)320984486 (DE-600)2027112-8 (DE-576)093888856 1600-0641 nnns volume:78 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.87 Gastroenterologie AR 78 |
| allfieldsSound |
10.1016/j.jhep.2022.11.025 doi (DE-627)ELV009425454 (ELSEVIER)S0168-8278(22)03320-7 DE-627 ger DE-627 rda eng 610 DE-600 44.87 bkl Mak, Lung-Yi verfasserin (orcid)0000-0002-2266-3935 aut A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. Non-alcoholic steatohepatitis NASH ARO-HSD HSD17β13 RNA interference RNA-induced silencing complex HSD17β13 mRNA and protein Gane, Ed verfasserin aut Schwabe, Christian verfasserin aut Yoon, Ki Tae verfasserin aut Heo, Jeong verfasserin aut Scott, Russell verfasserin (orcid)0000-0002-2107-6480 aut Lee, Jeong-Hoon verfasserin (orcid)0000-0002-0315-2080 aut Lee, Jung Il verfasserin (orcid)0000-0002-0142-1398 aut Kweon, Young Oh verfasserin (orcid)0000-0001-5708-7985 aut Weltman, Martin verfasserin aut Harrison, Stephen A. verfasserin aut Neuschwander-Tetri, Brent A. verfasserin (orcid)0000-0002-8520-7398 aut Cusi, Kenneth verfasserin (orcid)0000-0002-8629-418X aut Loomba, Rohit verfasserin (orcid)0000-0002-4845-9991 aut Given, Bruce D. verfasserin aut Christianson, Dawn R. verfasserin aut Garcia-Medel, Eric verfasserin (orcid)0000-0002-7537-0992 aut Yi, Min verfasserin aut Hamilton, James verfasserin (orcid)0000-0002-5494-2744 aut Yuen, Man-Fung verfasserin (orcid)0000-0001-7985-7725 aut Enthalten in Journal of hepatology Amsterdam [u.a.] : Elsevier Science, 1985 78 Online-Ressource (DE-627)320984486 (DE-600)2027112-8 (DE-576)093888856 1600-0641 nnns volume:78 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.87 Gastroenterologie AR 78 |
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Enthalten in Journal of hepatology 78 volume:78 |
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Non-alcoholic steatohepatitis NASH ARO-HSD HSD17β13 RNA interference RNA-induced silencing complex HSD17β13 mRNA and protein |
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Mak, Lung-Yi @@aut@@ Gane, Ed @@aut@@ Schwabe, Christian @@aut@@ Yoon, Ki Tae @@aut@@ Heo, Jeong @@aut@@ Scott, Russell @@aut@@ Lee, Jeong-Hoon @@aut@@ Lee, Jung Il @@aut@@ Kweon, Young Oh @@aut@@ Weltman, Martin @@aut@@ Harrison, Stephen A. @@aut@@ Neuschwander-Tetri, Brent A. @@aut@@ Cusi, Kenneth @@aut@@ Loomba, Rohit @@aut@@ Given, Bruce D. @@aut@@ Christianson, Dawn R. @@aut@@ Garcia-Medel, Eric @@aut@@ Yi, Min @@aut@@ Hamilton, James @@aut@@ Yuen, Man-Fung @@aut@@ |
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2022-01-01T00:00:00Z |
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Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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. 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Mak, Lung-Yi |
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Mak, Lung-Yi ddc 610 bkl 44.87 misc Non-alcoholic steatohepatitis misc NASH misc ARO-HSD misc HSD17β13 misc RNA interference misc RNA-induced silencing complex misc HSD17β13 mRNA and protein A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis |
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610 DE-600 44.87 bkl A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis Non-alcoholic steatohepatitis NASH ARO-HSD HSD17β13 RNA interference RNA-induced silencing complex HSD17β13 mRNA and protein |
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A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis |
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A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis |
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Mak, Lung-Yi Gane, Ed Schwabe, Christian Yoon, Ki Tae Heo, Jeong Scott, Russell Lee, Jeong-Hoon Lee, Jung Il Kweon, Young Oh Weltman, Martin Harrison, Stephen A. Neuschwander-Tetri, Brent A. Cusi, Kenneth Loomba, Rohit Given, Bruce D. Christianson, Dawn R. Garcia-Medel, Eric Yi, Min Hamilton, James Yuen, Man-Fung |
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Mak, Lung-Yi |
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10.1016/j.jhep.2022.11.025 |
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(ORCID)0000-0002-2266-3935 (ORCID)0000-0002-2107-6480 (ORCID)0000-0002-0315-2080 (ORCID)0000-0002-0142-1398 (ORCID)0000-0001-5708-7985 (ORCID)0000-0002-8520-7398 (ORCID)0000-0002-8629-418X (ORCID)0000-0002-4845-9991 (ORCID)0000-0002-7537-0992 (ORCID)0000-0002-5494-2744 (ORCID)0000-0001-7985-7725 |
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a phase i/ii study of aro-hsd, an rna interference therapeutic, for the treatment of non-alcoholic steatohepatitis |
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A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis |
| abstract |
Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. |
| abstractGer |
Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. |
| abstract_unstemmed |
Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 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 HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected 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 HSD17β13 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 HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 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 HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.ClinicalTrials.gov number: NCT04202354.Impacts and implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease. |
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| title_short |
A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis |
| remote_bool |
true |
| author2 |
Gane, Ed Schwabe, Christian Yoon, Ki Tae Heo, Jeong Scott, Russell Lee, Jeong-Hoon Lee, Jung Il Kweon, Young Oh Weltman, Martin Harrison, Stephen A. Neuschwander-Tetri, Brent A. Cusi, Kenneth Loomba, Rohit Given, Bruce D. Christianson, Dawn R. Garcia-Medel, Eric Yi, Min Hamilton, James Yuen, Man-Fung |
| author2Str |
Gane, Ed Schwabe, Christian Yoon, Ki Tae Heo, Jeong Scott, Russell Lee, Jeong-Hoon Lee, Jung Il Kweon, Young Oh Weltman, Martin Harrison, Stephen A. Neuschwander-Tetri, Brent A. Cusi, Kenneth Loomba, Rohit Given, Bruce D. Christianson, Dawn R. Garcia-Medel, Eric Yi, Min Hamilton, James Yuen, Man-Fung |
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320984486 |
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c |
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| doi_str |
10.1016/j.jhep.2022.11.025 |
| up_date |
2024-07-06T23:06:54.545Z |
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1803872857801883648 |
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| score |
7.400981 |