Roche's CpAM (RO7049389) and TLR7 Agonist (RO7020531) Combination Therapy Receives IND Approval in China for Chronic Hepatitis B Treatment

Source: Medical Horizon

According to the public information from the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration, Roche’s RO7049389 tablets and RO7020531 tablets combination therapy has received multiple implied approvals for clinical trials in China, with the indication being combination treatment for chronic hepatitis B. RO7049389 is a hepatitis B virus (HBV) capsid protein assembly inhibitor that affects viral replication by inhibiting capsid protein assembly. RO7020531 is a toll-like receptor 7 (TLR7) agonist. Currently, both drugs are in Phase 2 clinical trials globally.

Chronic hepatitis B virus (HBV) infection is a common cause of liver disease worldwide, with a particularly high disease burden in Southeast Asia. According to World Health Organization (WHO) estimates, approximately 257 million people globally are living with HBV infection. Although vaccines and nucleos(t)ide analogues (NUCs) have already reduced the rate of new infections and slowed the progression of liver disease, the scientific and medical communities are not content with the status quo. They have begun to collaborate on developing innovative antiviral drugs and immunotherapies aimed at curing this infection.

RO7049389 and RO7020531 are two innovative investigational drugs developed by Roche for the curative treatment of chronic hepatitis B.

RO7049389: Capsid Assembly Inhibitor

The HBV capsid is assembled from core proteins. Prior to reverse transcription, the HBV reverse transcriptase and HBV pregenomic RNA (pgRNA) must be properly encapsidated by the capsid protein. Therefore, inhibiting capsid protein assembly or accelerating its degradation disrupts the capsid assembly process, thereby impairing viral replication. Furthermore, the N-terminal 149 amino acid residues, which constitute the dimerization motif and assembly domain of the core protein, lack homologous sequences in human proteins. Consequently, capsid assembly inhibitors are regarded as a novel target for the development of anti-hepatitis B drugs.

RO7049389 is a small-molecule Class I hepatitis B virus (HBV) core protein allosteric modulator (CpAM) developed by Roche. It inhibits HBV replication by inducing the formation of aberrant HBV core aggregates, leading to defective capsid assembly, and may restore host immune responses against HBV. In both cell-based in vitro assays and in vivo animal models, RO7049389 effectively suppressed HBV replication.

According to Phase 1 clinical data presented by Roche at the 54th Annual Meeting of the European Association for the Study of the Liver (EASL) in 2019, all cohorts demonstrated significant reductions in HBV DNA and RNA levels. RO7049389 exhibited favorable anti-HBV activity and was well tolerated after 28 days of administration in patients with chronic hepatitis B virus (HBV) infection.

The Chinese Drug Clinical Trial Registration and Information Publicity Platform indicates that Roche has completed a randomized, open-label Phase 1 clinical trial in healthy subjects in China to evaluate the safety and tolerability of RO7049389 monotherapy compared with placebo following single and multiple ascending oral doses. In addition, a non-randomized, international multicenter (including China) Phase 2 clinical trial of RO7049389 is ongoing, aiming to assess the safety and efficacy of RO7049389 in combination with nucleos(t)ide analogues (NUCs) and pegylated interferon (PEG-IFN) in patients with chronic hepatitis B.

RO7020531: TLR7 Agonist

RO7020531 is a dual prodrug of the TLR7 agonist RO7011785, developed by Roche, and belongs to the class of oral small-molecule compounds. TLR7 agonists can activate B cells and T cells and induce cytokine production, thereby enhancing host immune activity to clear all hepatitis B virus from the body.

RO7020531 can induce the production of IFNα and various cytokines and chemokines, such as TNFα, IL-6, and IP-10, by stimulating human peripheral blood mononuclear cells (PBMCs) ex vivo via RO7011785. Roche is currently developing this drug for the treatment of chronic hepatitis B.

Preclinical studies have demonstrated that the anti-HBV activity of RO7020531 in mouse models is dose-dependent, with the TLR7 agonist significantly reducing serum HBV DNA and hepatitis B surface antigen (HBsAg) levels in chronic hepatitis B. At the 2019 Asian Pacific Association for the Study of the Liver (APASL) Annual Conference, Roche presented the results of a Phase I clinical trial of RO7020531 conducted in healthy Chinese volunteers. The study showed that single-dose RO7020531 exhibited favorable safety and tolerability profiles in healthy Chinese volunteers, with no serious adverse events reported.

Currently, while exploring the use of RO7049389 and RO7020531 as monotherapies for chronic hepatitis B, Roche is also investigating the efficacy of combining these two agents. According to data previously released by the company, the combination of these investigational drugs has demonstrated the ability to suppress HBV DNA and HBsAg expression in an adeno-associated virus-hepatitis B virus (AAV-HBV) mouse model, with hepatitis B surface antibodies (anti-HBs) detected in some animals.

Information on the ClinicalTrials.gov website indicates that Roche is conducting a Phase 2 clinical study to evaluate the safety, tolerability, and efficacy of combination therapy with CpAM (RO7049389), a TLR7 agonist (RO7020531), and nucleos(t)ide analogs in patients with chronic hepatitis B who have normal liver function and no significant fibrosis or cirrhosis.

Congratulations on the approval of the clinical trial for Roche’s CpAM (RO7049389) in combination with the TLR7 agonist (RO7020531) in China. We hope these studies proceed smoothly and provide a new treatment option for patients with chronic hepatitis B as soon as possible.

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