Suzhou Xingyao Kunze Biopharma Advances in siRNA-Based Functional Cure for Hepatitis B with Innovative Combination Therapy

The performance of small nucleic acid drugs in the past two years can be described as "showing great potential." In 2022, Sarepta, a small nucleic acid drug company, reported net product revenue of $843.3 million for the entire year, representing a 38% increase year-over-year; Alnylam's total net product revenue for the year was $894 million, marking a 43% year-over-year growth. Multinational corporations (MNCs) have also been highly competitive, with Novartis’ Inclisiran — the first small nucleic acid drug targeting the common condition of hyperlipidemia — seeing its revenue skyrocket by 833% to $112 million in the U.S. market in 2022. Earlier this year, GSK announced its full commitment to small nucleic acid drugs, and recently, Alnylam and Roche’s RNAi therapeutic, zilebesiran, has drawn significant attention for its potential to revolutionize the treatment model for hypertension.

Since the approval of the world's first small nucleic acid drug in 2016, 11 new drugs have been approved in the past seven years. The indications for small nucleic acid drugs are expanding from rare diseases to chronic diseases and other fields. Among them, the functional cure of hepatitis B is a key focus area for innovative small nucleic acid drugs. In this field, multiple small nucleic acid drugs are under development worldwide. One of the fastest progressing pipelines is VIR-2218, jointly developed by Vir Biotechnology and Alnylam. Existing Phase I/II clinical trial data shows that 71% of patients experienced a reduction in HBsAg levels by more than 1 log, and some patients may achieve clearance of HBsAg through this drug, potentially reaching a functional cure.

In China, one of the companies with the most notable progress is Suzhou Hepa Thera Biotech Co., Ltd., incubated by Fosun Health Capital's new drug innovation fund.This innovative drug company, which focuses on the field of liver disease treatment, announced in March this year that it had completed a Pre-A round of financing exceeding 100 million yuan. With RNA interference technology at its core, combined with technologies such as antibodies, fusion proteins, and cell therapy, the company is committed to addressing unmet treatment needs in areas like hepatitis B and NASH. Recently, VCBeat interviewed Ma Yanqin, the executive president of Suzhou Hepa Thera Biotech Co., Ltd.

China is a country with a high prevalence of hepatitis B. According to the statistics from the Chinese Center for Disease Control and Prevention (CDC) in 2021, the prevalence rates of hepatitis B surface antigen (HBsAg) among the age groups of 1-4 years, 5-14 years, and 15-29 years were 0.32%, 0.94%, and 4.38%, respectively. Currently, the overall prevalence rate of HBsAg positivity in China is 5-6%, with 70 million chronic HBV carriers, of which 20-30 million are patients with active chronic hepatitis B. Moreover, 90% of liver cancer patients in China develop the disease from hepatitis B, indicating a significant burden of liver disease.

The treatment of hepatitis B is an ongoing exploratory process. Existing treatment options (nucleoside analogs, interferon) can achieve a 20% e-antigen seroclearance rate, suppress viral replication, but cannot yet achieve functional cure, which refers to HBsAg seroclearance or the production of HBsAb — the current clinical goal and also the target for the development of small nucleic acid drugs. Hepatitis B virus enters liver cells for infection and replication by binding to the NTCP receptor, with cccDNA being the core of viral replication in the liver. Commonly used nucleoside analogs can only inhibit HBV DNA replication and are unable to eliminate HBsAg and cccDNA. However, small nucleic acid drugs have shown significant potential in reducing HBsAg levels during preclinical and clinical studies, offering hope for achieving a functional cure for hepatitis B.

Fosun Health Capital's New Drug Innovation Fund, as an innovative incubation fund under Fosun Pharma, noticed the significant demand and market potential in the field of liver diseases and the expansion of the small nucleic acid technology track in this area at an early stage. Among these, siRNA drugs are considered to have the potential to become the next generation of revolutionary products. Fosun Health Capital has set its sights on this blue ocean and chose to enter the siRNA space by introducing its first siRNA hepatitis B drug in 2021 and establishing Suzhou Hepa Thera Biotech Co., Ltd.

Ma Yanqin, the current Executive President, joined the company in 2022. Prior to this, she had over two decades of experience in corporate management and product development within the healthcare industry, leading multiple cross-border licensing deals for new drugs as well as their subsequent research and development.

Ma Yanqin, Executive President of Hepa Thera, Source: Provided by the interviewee

Hepa Thera’s First HBV Pipeline siRNA Product, Code Name HT-101, Completed Enrollment of All Subjects in Phase Ia Clinical Trial in March This Year and Administered the First Patient Dose in May, Officially Entering Phase Ib Clinical Research. HT-101 Inhibits Hepatitis B Virus Particle Formation by Efficiently Degrading mRNAs Transcribed from cccDNA, Disrupting Their Translation Function and Preventing the Synthesis of Related Viral Proteins, for the Treatment of Chronic Hepatitis B Virus Infection.

According to reports, HT-101 injection is the first domestically produced GalNAc-conjugated siRNA hepatitis B product in China to enter the clinical stage, with existing Phase Ia clinical data showing promising results. In terms of safety, the overall incidence of treatment-related adverse reactions is low and mostly mild, classified as Grade 1. Currently, this product has entered Phase Ib clinical trials for hepatitis B patients. Notably, from the submission of the pre-IND application for HT-101 in March 2022 to entering Phase Ib clinical trials, it took just over a year, demonstrating Suzhou Hepa Thera Biotech Co., Ltd's outstanding R&D capabilities.

"Preparation ensures success; lack of it leads to failure. In the early stage of R&D, we need to plan every step of subsequent development to ensure seamless integration at each stage. Before the IND application, we had already completed the preparations for Phase I clinical trials." On the efficiency of advancing pipelines, Ma Yanqin summarized, "The research and development of small nucleic acid drugs in China is still an emerging technology. Currently, regulatory authorities have not yet formulated corresponding technical guidelines for such drugs. We referred to relevant guidelines from Europe and the United States, combined with related research on small nucleic acid drugs, conducted relatively comprehensive preclinical studies, ensuring the smooth approval of the IND."

According to the company, the Phase Ib clinical study of HT-101 will be completed in the first half of 2024.

After the launch of the "Hepatitis B Everest Project" in 2018, it promoted a wave of clinical cures for chronic hepatitis B in China. As of May 2023, nearly 30,000 patients have been enrolled, achieving clinical cures for 5,258 patients with chronic hepatitis B. However, multiple issues still exist, such as "low response rate," "narrow treatment window," and "high heterogeneity in efficacy." Taking the data as of July 2020 as an example, among over 8,000 enrolled patients, 1,400 patients achieved S antigen clearance (1,500 IU/ml), and the clearance efficiency varied significantly, with HBsAg levels ranging from 10% to 85%.

Interim data shows that the lower the patient's HBsAg level, the higher the probability of achieving functional cure. Therefore, in the pursuit of functional cure, there are two main challenges: one is how to convert non-advantaged patients into advantaged patients, and the other is how to improve the quality of advantaged patients to make them deeply advantaged patients, enabling them to reach the level of functional cure.

To this end, Hepa Thera is actively exploring the combination of "siRNA + neutralizing antibodies." This combination therapy can lower HBsAg levels to a plateau by using siRNA to interfere with viral replication in liver cells. Afterward, neutralizing antibodies are applied to neutralize peripheral free viruses and S antigens, which are then phagocytosed by antigen-presenting cells, thereby further reducing HBsAg levels. This opens a "window" for the body's immune response and increases the proportion of patients achieving functional cure.

HT-102, a neutralizing antibody jointly developed by Hepa Thera and Suzhou BioRay Biotech Co., Ltd., is a fully human monoclonal antibody targeting HBV through multiple mechanisms by specifically binding to and targeting the small (S) envelope protein. According to Hepa Thera, preclinical studies have shown that the combination of HT-102 with HT-101 injection demonstrates stronger and more sustained antiviral activity.

The combination of "siRNA + neutralizing antibody" was first clinically tested by VIR Company. In 2021, VIR announced the latest clinical results of VIR-2218 and the neutralizing antibody therapy VIR-3434 for hepatitis B, showing potential in reducing hepatitis B surface antigen levels. However, there are no other independently developed combination therapies in China, with Hepa Thera being the first domestically developed option. The combined use of both therapies can cover a broader population of hepatitis B patients with higher viral loads, bringing functional cure for hepatitis B one step closer.

Hepa Thera is rapidly advancing the clinical progress of multiple pipelines. Ma Yanqin stated: "In the next two to three years, we expect HT-101 and HT-102 to advance to Phase II clinical trials and collaborate with pharmaceutical companies. In the longer term, the company is also considering a gene therapy pipeline for hepatitis B. Meanwhile, our bispecific fusion protein for NASH indication, as well as the pipeline for liver fibrosis indications, are also progressing, with preclinical evaluations expected to be completed in the second half of this year."