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- Publisher Website: 10.1016/j.jhep.2023.07.026
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- PMID: 37524230
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Article: First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection
Title | First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection |
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Authors | |
Keywords | Gene expression Hepatitis B virus Immune clearance Pharmacology Therapeutic use |
Issue Date | 29-Jul-2023 |
Publisher | Elsevier |
Citation | Journal of Hepatology, 2023, v. 79, n. 5, p. 1139-1149 How to Cite? |
Abstract | Background & Aims: RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). Methods: This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). Results: RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. Conclusions: These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. Clinical Trial Number: ClinicalTrials.gov NCT03772249. Impact and implications: Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians. |
Persistent Identifier | http://hdl.handle.net/10722/348115 |
ISSN | 2023 Impact Factor: 26.8 2023 SCImago Journal Rankings: 9.857 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Gane, Edward J | - |
dc.contributor.author | Kim, Won | - |
dc.contributor.author | Lim, Tien Huey | - |
dc.contributor.author | Tangkijvanich, Pisit | - |
dc.contributor.author | Yoon, Jung Hwan | - |
dc.contributor.author | Sievert, William | - |
dc.contributor.author | Sukeepaisarnjaroen, Wattana | - |
dc.contributor.author | Thompson, Alexander J | - |
dc.contributor.author | Pavlovic, Vedran | - |
dc.contributor.author | Surujbally, Bernadette | - |
dc.contributor.author | Wat, Cynthia | - |
dc.contributor.author | Brown, Bob D | - |
dc.contributor.author | Achneck, Hardean E | - |
dc.contributor.author | Yuen, Man Fung | - |
dc.date.accessioned | 2024-10-05T00:30:37Z | - |
dc.date.available | 2024-10-05T00:30:37Z | - |
dc.date.issued | 2023-07-29 | - |
dc.identifier.citation | Journal of Hepatology, 2023, v. 79, n. 5, p. 1139-1149 | - |
dc.identifier.issn | 0168-8278 | - |
dc.identifier.uri | http://hdl.handle.net/10722/348115 | - |
dc.description.abstract | Background & Aims: RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). Methods: This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). Results: RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. Conclusions: These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. Clinical Trial Number: ClinicalTrials.gov NCT03772249. Impact and implications: Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians. | - |
dc.language | eng | - |
dc.publisher | Elsevier | - |
dc.relation.ispartof | Journal of Hepatology | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | Gene expression | - |
dc.subject | Hepatitis B virus | - |
dc.subject | Immune clearance | - |
dc.subject | Pharmacology | - |
dc.subject | Therapeutic use | - |
dc.title | First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection | - |
dc.type | Article | - |
dc.identifier.doi | 10.1016/j.jhep.2023.07.026 | - |
dc.identifier.pmid | 37524230 | - |
dc.identifier.scopus | eid_2-s2.0-85169509907 | - |
dc.identifier.volume | 79 | - |
dc.identifier.issue | 5 | - |
dc.identifier.spage | 1139 | - |
dc.identifier.epage | 1149 | - |
dc.identifier.isi | WOS:001107584000001 | - |
dc.identifier.issnl | 0168-8278 | - |