HEBABIZ Biopharma: Can Multi-Molecule, Multi-Target TCM Be the Answer to Complex Chronic Diseases?
Recently, Huibaoyuan Biologics announced externally,Its investigational multi-molecule, multi-target innovative traditional Chinese medicine, Z018B capsules, has received approval for its Investigational New Drug (IND) application in China.Approval to conduct clinical trials for nonalcoholic steatohepatitis (NASH).
NASH is one of the few common diseases for which no standard therapy exists. Since the second half of 2022, there has been a steady stream of positive news regarding breakthroughs by biotech companies in the NASH field; however, as of the end of June this year, no FDA-approved drug had yet emerged. Nevertheless, enthusiasm for NASH drug research and development has been ignited both domestically and internationally. According to incomplete statistics, there are more than 20 NASH drug candidates in the pipeline in China, with the majority in Phase I clinical trials.
The pathogenesis of non-alcoholic steatohepatitis (NASH) is complex, typically involving multiple aspects such as glucose and lipid metabolism. Most pharmaceutical companies select therapeutic targets primarily from three areas: metabolism, inflammation, or fibrosis. However, targeting a single mechanism is insufficient to improve all clinical endpoints simultaneously. To date, only Saroglitazar, a dual PPARα/γ agonist developed by Zydus Cadila, has been approved in India.
"We believe that,"Targeting a single pathway is insufficient for treating complex chronic diseases such as NASH,New opportunities may be found from the perspective of developing traditional Chinese medicines with multi-molecular and multi-target mechanisms.“Dr. Zhou Hua, Founder, Chairman, and Chief Scientist of Huibaoyuan Bio,” said Dr. Zhou Hua.
For Dr. Zhou Hua, embarking on entrepreneurship was a natural progression.
In the 1980s, as one of the first scholars in molecular biology after China’s reform and opening-up, Zhou Hua engaged with and dedicated himself to research in genetic engineering within the fields of plant and biological sciences at China Agricultural University. “In China, virtually no one is untouched by Traditional Chinese Medicine (TCM); it is merely a matter of degree, and I have been profoundly influenced.” Drawing on his microscopic studies of plants and the TCM influences from his childhood, Zhou Hua developed a strong interest in innovative drugs derived from botanical sources.
In the early 1990s, Zhou Hua studied under Professor Henry Bronson, a pharmacology professor at Yale University in the United States, and Academician Zheng Yongqi, a renowned pharmacologist. He primarily conducted pharmacological research on small-molecule chemical drugs and developed therapeutic agents for liver diseases, tumors, and other conditions. During his studies, Zhou Hua participated in the development of lamivudine, the first-generation anti-hepatitis B virus drug led by his mentor, Academician Zheng Yongqi. He was mainly responsible for researching the pathogenesis of hepatitis B and the pharmacological mechanisms of anti-hepatitis B drugs.
During the drug development process, Academician Zheng Yongqi and Zhou Hua simultaneously recognized the limitations of small-molecule chemical drugs, namely their propensity for off-target effects due to single-target mechanisms and their inability to easily cure multi-target chronic diseases. Subsequently, Academician Zheng developed a strong interest in developing innovative traditional Chinese medicine (TCM) with multi-component and multi-target profiles. He established a TCM research team and founded the Global Alliance for Traditional Chinese Medicine, proposing that “ancient traditional Chinese medicine holds new potential for unlocking cancer treatments.” Nevertheless, there remains a long road ahead for the further development of TCM.
In Zhou Hua's view,Traditional Chinese Medicine (TCM) faces three major challenges in its development,“First, in terms of conceptual framework, the holistic perspective of Traditional Chinese Medicine (TCM) differs from Western medicine’s molecular-level understanding. Therefore, translating TCM into a language comprehensible to Western medicine and acceptable globally has become the primary challenge in developing modern TCM. Second, regarding the sourcing of Chinese herbal medicines, the vast variety of herbs and the difficulty in strictly differentiating and identifying them according to standardized criteria pose significant issues. From botanical and genetic perspectives, as well as due to variations in ecological environments, medicinal materials are bound to undergo certain changes; thus, directly prescribing based on ancient formulas warrants careful consideration. Finally, there is the pharmacological challenge: whether for single-ingredient or multi-ingredient formulations, it remains difficult to elucidate at the pharmacological level the specific molecules responsible for their therapeutic effects.”
To overcome the three major challenges of thinking, sourcing, and pharmacology,Academician Zheng Yongqi spearheaded the development of “Phytomics QC” technology. This technology integrates chemical fingerprint analysis with biological response profiling, leveraging omics technologies to implement quality control for herbal medicines or genus-specific products. Currently, the U.S. Food and Drug Administration (FDA) recognizes this approach as a critical technique for the quality control of oral herbal drugs, addressing the long-standing concern among mainstream scientists that traditional Chinese medicine formulations lack consistency.
In 2013, after founding Huibaoyuan Biotechnology, Zhou Hua began leveraging this technology to process samples from"Shennong Ben Cao Jing's"oneResearch and Development of Single-Ingredient Traditional Chinese Medicines That Are Both Food and Medicine, after nearly a decade of effort, successfully launched the innovative traditional Chinese medicine pipeline Z018B with multi-molecule and multi-target properties。
From the perspective of the three major challenges that traditional Chinese medicine (TCM) must overcome, the development of Z018B is based on “Phytomics QC” technology. This technology enables the identification of drug sources and discovery of active ingredients, as well as the precise determination of indications and related pathways to clearly elucidate pharmacological mechanisms. “Z018B is an innovative multi-component, multi-target TCM drug, which is more suitable for chronic diseases with complex pathogenesis. Its development difficulty is far greater than that of single-molecule chemical drugs,” added Zhou Hua. According to the introduction, the development of Z018B requires first identifying and confirming one or a few key molecules, then exploring combinations of multiple molecules and their associations with the key molecules, followed by validation to determine the efficacy of the drug across various pathways in disease treatment.
Z018B is positioned as a multi-molecule, multi-target regulator of glucose and lipid metabolism. It achieves therapeutic effects by modulating inflammation, oxidative stress, and hepatic fibrosis through multiple targets. As a Class I innovative traditional Chinese medicine (TCM) drug, it is part of Huibaoyuan Biopharma’s development pipeline focused on the “multi-molecule, multi-target precision therapy track for innovative TCM.”
After the know-how for the Z018B pipeline was determined,HuiBaoyuan Biotech has entrusted the CRO company Saifu Pharma to complete critical development stages, including preclinical pharmacokinetics, safety evaluation, and support for IND filing.As an industry-leading, one-stop CRO platform for innovative drugs, Saifu Pharma boasts a core R&D team composed of experts with many years of industry experience, covering the entire industrial chain of innovative drug development. Saifu Pharma’s seasoned core R&D team and its extensive preclinical trial experience have provided strong support for Z018B’s successful Investigational New Drug (IND) application in China.
From Zhou Hua’s perspective, the NASH patient population is enormous, with a clear and unmet clinical need; moreover, NASH is just one of several liver diseases characterized by such clearly unmet needs.
According to a previously released bulletin by the World Health Organization (WHO), China bears the heaviest global burden of liver disease. Rough estimates indicate that more than 400 million people in China are affected by chronic liver diseases. With the exception of most hepatitis C cases, which are curable, other liver diseases remain difficult to cure, creating an urgent need for highly effective clinical therapies. Consequently, Huibaoyuan Biotechnology has also directed its focus toward developing drugs for conditions with unmet clinical needs, such as hepatitis B and liver cancer.
With unmet clinical needs as the horizontal axis and innovative traditional Chinese medicines as the vertical axis.Huibaoyuan Biologics currently has seven innovative pipeline candidates in development, including four small-molecule drugs and three innovative traditional Chinese medicines., covering areas such as liver cancer, chronic hepatitis B, NASH, and alcoholic liver disease, while also seeking breakthroughs in the fields of glioblastoma, pancreatic cancer, and renal cell carcinoma.Among them, three innovative drugs from Huibaoyuan Biologics have entered Phase III clinical trials.
“As we advance our various innovative pipelines, we must still conduct studies on druggability assessment and clinical positioning to ensure more precise new drug development and a higher probability of success,” said Zhou Hua. The advancement of multiple pipelines requires robust technical and hardware support. To this end, Huibaoyuan Biopharma has established a national-level R&D center—the National-Local Joint Engineering Research Center for Anti-Tumor Drug Development—three provincial-level technology centers, systematic technology platforms for small-molecule drugs and innovative traditional Chinese medicines, and one postdoctoral research workstation, thereby pursuing new drug development with “product druggability as the core strategy.”
The research and development of innovative traditional Chinese medicines (TCMs) is inherently distinct from that of chemical drugs. “TCMs contain multiple constituents, and their quality and efficacy are influenced by factors such as cultivation region, harvest timing, quality of raw herbal materials, processing techniques, production control, as well as the stability and uniformity of the final product.” Therefore, Huibaoyuan Biotechnology established its production base and pilot-scale platform at an early stage to accelerate Chemistry, Manufacturing, and Controls (CMC) studies and regulatory submissions, laying a solid foundation for the R&D, registration, manufacturing, and commercialization of innovative TCMs.
Leveraging a technical team led by Dr. Zhou Hua, Huibaoyuan Biopharma has established comprehensive capabilities in single-ingredient formulations, small-complex formulas, large-complex formulas, and classic traditional Chinese medicine (TCM) prescriptions. By focusing on innovative TCM approaches that address chronic diseases through multi-molecule, multi-target mechanisms, the company is advancing the globalization of TCM.
From the removal of restrictions on certain traditional Chinese medicine (TCM) products in the 2021 National Reimbursement Drug List, the conclusion of the pilot program for TCM formula granules, and the issuance of guidelines on leveraging medical insurance to support the inheritance, innovation, and development of TCM, to the renewed emphasis on advancing TCM modernization in China’s 14th Five-Year Plan, state support for the TCM industry has been continuously strengthened. With implementation details becoming increasingly clear, the future development of TCM is poised for robust growth.
Amid favorable national policies, how to promote and accelerate the global expansion of Traditional Chinese Medicine (TCM) has become a defining issue of our time. In Zhou Hua’s view, there are currently two main directions for the modern development of TCM: “The most mainstream approach follows Western medical paradigms, focusing on the research and development of single-molecule drugs, which has already yielded many successful cases. However, we believe that for TCM to achieve further in-depth development and globalization, it is essential to narrow the gap between single-molecule and multi-molecule drug development. Therefore,”The second approach is more suitable for the R&D direction of multi-molecule, multi-target therapies for chronic diseases.“, is the R&D direction we are more optimistic about,” said Zhou Hua.
Innovative traditional Chinese medicine (TCM) cannot be achieved overnight; therefore, Huibaoyuan Biopharma is simultaneously advancing the secondary development of classic TCM formulas. “First, we derive new formulations from classic prescriptions; second, we identify new indications. In other words, we translate the relatively vague clinical applications of TCM into indications that are more readily understood in modern hospital settings, thereby refining their therapeutic use.” One of Huibaoyuan Biopharma’s innovative drug pipelines—Yigan Mingmu Oral Liquid—is the first candidate in its multi-component, multi-target innovative TCM track. Through systematic research and secondary development, this product has been elevated from a regulatory TCM formulation to a modern TCM agent for precision therapy.
The “multi-molecule, multi-target” characteristics of traditional Chinese medicine (TCM) confer unique advantages in blocking or even reversing liver fibrosis, particularly in chronic diseases with complex pathogenesis. Although some proprietary Chinese medicines are currently used in China to treat chronic liver fibrosis and cirrhosis, no drug has yet been approved specifically for non-alcoholic steatohepatitis (NASH). Can Z018B, an innovative TCM developed along the “multi-molecule, multi-target” technological pathway, become a “breakthrough solution” for NASH treatment? VCBeat New Medicine will continue to monitor this development.