Aims to functionally cure hepatitis B!

January 20, 2022/eMedClub News/--On January 17, 2021, according to the announcement of the Center for Drug Evaluation (CDE) of the China National Medical Products Administration, the clinical trials of two hepatitis B gene therapies filed by Roche in China The trial application has been accepted
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▲ Image source: CDE official website ➤ RO7445482 injection RO7445482 (RG6346, DCR-HBVS) is a subcutaneous siRNA drug developed by Roche and Novo Nordisk subsidiary Dicerna Pharmaceuticals, which is delivered using Dicerna’s own GalXC™ A platform that targets the mRNA of hepatitis B surface antigen (HBsAg) and inhibits protein expression
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Currently, the drug is undergoing Phase 2 clinical research abroad
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▲ siRNA inhibits the expression of multiple hepatitis B virus genes (Image source: Roche’s official website) Previously published phase 1 data showed that after 4 months of subcutaneous injection in chronic hepatitis B patients, HBsAg continued to decrease for up to 1 year, and it was safe The performance was favorable, with no patients experiencing serious adverse events (SAEs), and there were no dose-limiting toxicities or safety-related discontinuations
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 Additionally, the researchers presented Phase 1 pharmacokinetic (PK) data for RO7445482 at the 2021 American Annual Meeting for the Study of Liver Diseases (AASLD 2021)
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Results showed similar PK parameter values ​​in Asians and non-Asians after a single subcutaneous injection of the drug
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The drug was well tolerated in both Asian and non-Asian populations
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There were no clinically significant differences in adverse event profiles, clinical laboratory results, or vital signs between the two groups
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Asian subjects did not appear to require dose adjustment compared to non-Asian subjects
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  ▲ The data of Asian and non-Asian populations are similar (Image source: Roche’s official website) In March 2021, the drug has been implicitly approved for clinical trials by the State Food and Drug Administration, and is intended to be used in combination with nucleoside (acid) (NUC) or with polyethylene The combination of glycol interferon (PEG-IFN) + NUC for the treatment of chronic hepatitis B has not yet started a clinical trial
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 ➤ RO7191863 Injection RO7191863 (RG6084) is a liver-targeted PD-L1 single-stranded oligonucleotide drug modified by locked nucleic acid (LNA) technology, which blocks the PD-1/PD-L1 pathway by blocking the PD-1/PD-L1 pathway.
to treat hepatitis
B.

PD-L1 is overexpressed in B cells of patients with chronic hepatitis B.
RO7191863 relieves T cell immunosuppression by targeting and inhibiting the PD-L1/PD-1 immune checkpoint pathway to achieve the effect of treating hepatitis B; targeted, is expected to reduce systemic toxicity
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  ▲ LNA targeting PD-L1 can inhibit the T cell immunosuppressive signal mediated by PD-1 signaling pathway (Image source: Roche official website) RO7191863 is currently in Phase 1 clinical development, and its preliminary data has been disclosed at AASLD 2021
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This clinical trial is the first-in-human trial of the drug in hepatitis B subjects and is designed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of different drug doses and regimens
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The trial included 25 subjects (4 women, 21 men), of whom 23 received RO7191863 and 2 received placebo
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 The results showed that at the highest dose of 3.
0 mg/kg Q2W, the HBsAg quantification of 6 patients decreased by an average maximum of 0.
3 log10 IU/mL from baseline
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The largest reduction, reaching 0.
6 log10 IU/mL, was observed in 1 patient in the treatment group with baseline HBsAg <2.
5 log10 IU/mL, accompanied by a rise in alanine aminotransferase (ALT) and a decrease in soluble PD-L1, demonstrating recovery of immune function
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In terms of safety, 7 patients experienced treatment-related adverse events (AEs), the most common being headache and injection site reactions
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No serious or immune-related AEs were observed
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 This preliminary data suggests that targeting the PD-1/PD-L1 pathway through liver-directed inhibition of PD-1/PD-L1 mRNA expression is feasible, and supports RO7191863 in combination with other therapies to achieve chronic Functional cure in hepatitis B patients
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 Other strategies that are expected to functionally cure hepatitis B.
After hepatitis B virus (HBV) enters the host, it will integrate its own genome into NDA in the nucleus of the host liver cell to form covalently closed circular DNA (cccDNA), and then use the host to synthesize mRNA and virus particles protein required for assembly
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Current HBV treatments slow disease progression but do not eliminate cccDNA, requiring patients to receive lifelong treatment
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 In recent years, a number of companies at home and abroad have developed novel therapies that have made progress, bringing a new dawn to the functional cure of hepatitis B: On December 9, 2021, Vir Biotechnology announced that its RNAi therapy VIR- The first patient has been dosed in a Phase 2 clinical trial of a novel therapeutic combination of 2218 for the treatment of patients with chronic hepatitis B virus (HBV) infection, aiming to achieve a functional cure
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It is worth mentioning that in December 2020, Tengsheng Biopharmaceutical has introduced VIR-2218 and started the clinical development of this RNAi therapy in China
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Recommended reading: RNAi combination therapy is expected to functionally cure hepatitis B, and phase 2 clinical trial is launchedYimai Meng broke the newsOn December 7, 2021, Precision BioSciences announced its gene editing project based on the ARCUS platform at the Hep Dart 2021 meeting of the hepatitis B conference Preclinical data on PBGENE-HBV
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In this preclinical study, ARCUS efficiently targeted and degraded HBV cccDNA, reducing the expression of hepatitis B surface antigen (HBsAg) by 77% in HBV-infected primary human hepatocytes (PHH)
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Recommended reading: Is hepatitis B treatment promising? On October 11, 2021, Aligos Therapeutics announced that ALG-020572 has completed the first patient dosing in the Phase 1 clinical trial
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This is an antisense oligonucleotide (ASO) therapy that reduces hepatitis B surface antigen (HBsAg) levels in chronic hepatitis B patients by interfering with the transfer of genetic information from nucleic acid to protein by complementary binding to mRNA
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 On June 26, 2021, Arbutus Biopharma announced the presentation of the latest results of its RNAi therapy AB-729 at the EASL International Liver Congress (ILC2021)
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Trial data showed that all dosing regimens resulted in a significant reduction in HBsAg, with 75% (15/20) of subjects HBsAg falling below 100 IU/mL
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At 20 weeks of dosing, the subjects' HBsAg levels showed a sustained and stable plateau in all dosing regimens
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Recommended reading: In the treatment of hepatitis B, RNAi therapy shows strong therapeutic potentialYimai Meng broke the news On May 18, 2021, Immunocore announced that its innovative bispecific immunotherapy IMC-I109V is in clinical trials for the treatment of chronic hepatitis B patients Completion of first patient dosing
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IMC-I109V is a bispecific T cell receptor (TCR) therapy developed by Immunocore
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It activates T cells and specifically eliminates HBV-infected, HBsAg-expressing hepatocytes to achieve functional cure for chronic HBV infection
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 Reference materials: 1.
https:// database "2 models on the same day! Roche's Hepatitis B Gene Therapy Reported Clinically in China, Antiviral siRNA, PD-L1 Targeting Oligonucleotide"