Roche Submits IND Application in China for RO7191863, a Liver-Targeted PD-L1 Antisense Oligonucleotide Therapy for Chronic Hepatitis B

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Today (January 17), the official website of the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) announced that Roche has submitted a clinical trial application in China for RO7191863 injection, which has been accepted. Public information indicates that RO7191863 is a liver-targeted, PD-L1-targeting N-acetylgalactosamine (GalNAc)-modified single-stranded oligonucleotide candidate drug, intended for the development of treatment for chronic hepatitis B.

Screenshot source: CDE official website

Hepatitis B is one of the major infectious disease threats worldwide. Hepatitis B virus (HBV) infection is a leading cause of liver diseases and is difficult to cure with current treatment methods. In chronic HBV infection, T-cell exhaustion is an important factor in immune tolerance. Studies have shown that blocking the PD-1/PD-L1 pathway can effectively enhance the function of specific cytotoxic T cells, offering hope for achieving clinical cure in patients with chronic hepatitis B.

Currently, targeting the PD-1/PD-L1 pathway has emerged as a novel strategy in the development of drugs for chronic hepatitis B. However, previous research has mainly focused on exploring the therapeutic effects of monoclonal antibodies on this disease. Publicly available data indicates that RO7191863, developed by Roche, is a liver-targeted N-acetylgalactosamine (GalNac)-conjugated single-stranded oligonucleotide capable of inducing RNAseH (ribonuclease H)-mediated degradation of PD-L1 mRNA. Preclinical proof-of-concept studies have shown that RO7191863 can effectively bind to its target, amplify levels of CD4+/CD8+ T cells, NK cells, and antigen-presenting cells in the liver, and induce a dose-dependent antiviral response.

At the American Association for the Study of Liver Diseases (AASLD 2021) annual meeting held in November 2021, Roche announced the Phase 1 clinical study results of RO7191863 for the first time. According to the abstract, this is the first clinical study of RO7191863 conducted in patients with chronic hepatitis B, aiming to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of different doses and regimens.

According to the introduction, the subjects enrolled in this study were virologically suppressed chronic hepatitis B patients who were receiving stable antiviral therapy and showed no significant evidence of liver fibrosis. They participated in a multiple ascending dose (MAD) study. A total of 25 patients were involved in the trial, receiving either RO7191863 or placebo via subcutaneous injection. The dose level, number of doses, and dosing frequency were gradually increased, with administration every two weeks (Q2W).

Screenshot source: Reference [2]

Research data show that: after each administration, RO7191863 appears in the plasma with a median Tmax of 2.0 hours, followed by a biphasic decline; seven patients who received treatment experienced adverse events (AEs) considered related to the study treatment, the most common being headache and injection site reactions; no serious or immune-related adverse events were observed, and no patients discontinued the drug due to adverse events.

At the highest dose of 3.0 mg/kg Q2W, researchers found that the mean maximum decline in HBsAg from baseline was 0.3 log10 IU/mL in six treated patients. In one patient with a baseline HBsAg level <2.5 log10 IU/mL, the maximum reduction in HBsAg (a decrease of 0.6 log10 IU/mL) was observed, accompanied by an increase in alanine aminotransferase (ALT) and a decrease in soluble PD-L1 levels, suggesting restoration of immune response.

Screenshot source: Reference [2]

The study suggests: These preliminary safety and efficacy data indicate that targeting the PD-1/PD-L1 pathway by liver-directed suppression of PD-1/PD-L1 mRNA expression is feasible, and support the combination of RO7191863 with other therapies to achieve functional cure in patients with chronic HBV infection.

References:

[1] Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Jan 17, 2022, from https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d

[2] The Liver Meeting 2021 Late-breaking Abstracts, from https://www.aasld.org/sites/default/files/2021-11/TLM%202021%20Late%20Breaking%20Abstracts%2011.01.21.pdf?pdf

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