Frost & Sullivan Exclusive Interview with Haichang Biotech —— Innovative Nucleic Acid Drug R&D, Accelerating Clinical Trials for AKT-1 Targeted Drugs

01

Currently, many tracks are facing fierce competition, and Haichang Biotech needs to leverage its strengths to pursue a differentiated R&D path. In response to the difficulty of developing drugs targeting AKT, Haichang's independently developed QTsome™ delivery system and nucleic acid platform provide an effective solution.

The choice of AKT-1 as the target is due to the fact that inhibiting AKT-2 tends to cause metabolic adverse reactions, while AKT-3 is a rather contradictory target in terms of cancer suppression. Inhibiting the AKT-1 target with nucleic acid drugs is relatively more precise than traditional platforms. At the same time, pan-targets such as AKT and TP53 have great potential, but developing first-in-class drugs still requires overcoming many technical and integration challenges. Based on these considerations, Haichang has chosen AKT-1 as the target for innovative drug research and development. In addition to AKT, Haichang has also made arrangements for other targets such as Toll-like receptors.

Small nucleic acid (SNNA) drugs are susceptible to metabolism by non-specific enzymes, which is a major challenge for SNNA-based pharmaceuticals. Haichang's QTsome™ patented technology encapsulates SNNA drugs into liposomes (LNP), allowing for precise delivery to the liver and effectively solving the problems of short safety periods and easy degradation of SNNA drugs. The treatment regimen for the ongoing HC0201 product involves intravenous injections for two consecutive weeks, which can be inconvenient for patients and may lead to suboptimal compliance. Therefore, Haichang has optimized HC0201 by developing an upgraded product HC0301 by outsourcing LNP on top of HC0201. Although both products contain the same active pharmaceutical ingredient (API), HC0301 with LNP encapsulation performs better in terms of pharmacokinetics and tissue distribution, enabling a weekly dosing regimen and significantly improving patient compliance.

The reactive nucleic acid of HC0201 is modified with thio-phosphate, which gives it certain resistance to nucleases. However, it is cleared when passing through the kidneys, leading to a rapid decrease in blood drug concentration. To maintain the target blood drug concentration, continuous intravenous infusion is required. The reactive nucleic acid of HC0301 is encapsulated in LNP, avoiding rapid metabolic clearance and significantly improving stability. It also has a significant improvement in tumor cell intracellular escape, increasing the efficiency of targeted delivery to tumor tissue.

Currently, HC0301 is the main product of Haichang. In 2024, HC0301 plans to expand into four therapeutic areas, with advanced liver cancer and kidney cancer being the initial disease areas for the product. Among them, the clinical trial application for HC0301 targeting advanced liver cancer has been approved by the FDA for Phase II clinical trials and has received orphan drug designation. HC0301 is mainly used for second-line treatment of clear cell renal cancer and first-line treatment of non-clear cell renal cancer in the kidney cancer disease area. In addition, Haichang has also made arrangements for non-small cell lung cancer.

For liver cancer, the current first-line treatment is centered around immunotherapy, such as the combination of atezolizumab (PD-L1) and bevacizumab (VEGF antagonist). Existing first-line treatment drugs have made significant breakthroughs in patients with advanced liver cancer, extending overall survival and significantly improving quality of life. However, there are still many patients with liver cancer who fail or are intolerant to first-line treatment, and the subsequent clinical treatment needs are not met, with insufficient clinical evidence guiding the selection of treatment drugs. Therefore, Haichang aims at second-line treatment for liver cancer, focusing on developing differentiated therapeutic products based on small nucleic acids. Our Phase II and III clinical trials of HC0301 will focus on patients who are intolerant or have failed first-line immunotherapy combinations, hoping to bring longer survival and better quality of life to these patients through different drug mechanisms of action.

The combination of HC0201 with other drugs has shown certain efficacy in the treatment of tumors in the liver, kidneys, pancreas, and other organs, providing important supportive data for the expansion of subsequent indications. The advantage is even more significant due to the LNP coated on HC0301 based on the QTsome™ technology platform. The Phase II clinical trial of HC0301 has been approved by the FDA, and Haimang will soon initiate a Phase II clinical study of this product. For patients with advanced liver cancer who are receiving second-line treatment, they urgently need a new drug that can be combined with other drugs to overcome resistance issues and meet their clinical needs. This has prompted us to choose this time point to advance research on the combination of AKT-1 inhibitor HC0301 with tyrosine kinase inhibitor (TKI), aiming to fill the gap in second-line treatment for liver cancer.

In recent years, the first-line treatment pattern centered on immune-oncology therapy has just been established in the field of advanced unresectable liver cancer, with the overall survival period for liver cancer patients having reached 30 months or more. Compared to the past reliance on small molecule drugs such as sorafenib and lenvatinib, the significant progress brought about by immunotherapy is self-evident. However, guidelines are not yet clear regarding sequential therapy after the failure of immunotherapy or immunotherapy combinations, and clinical treatment plans need further optimization. Haichang's HC0301 combined with small molecule TKIs is expected to become the preferred drug regimen for second-line liver cancer treatment.

In 2023, we compiled the preclinical combination drug study data for HC0301 and wrote two abstracts, both of which were included in the annual meeting of the American Association for Cancer Research (AACR). At that meeting, we delivered a presentation on the therapeutic effects of HC0301 combined with other drugs and its vascular inhibitory properties. At the end of 2023, Haichang submitted a new abstract to AACR and it was accepted. A presentation will be given at the conference in April 2024. The preclinical study results of the combination of HC0301 with these drugs provide important support for the formulation of clinical trial protocols and are expected to be validated in clinical trials.

02

Innovatively built our own delivery system,

There are two technical platforms for delivering antisense oligonucleotides (ASOs) or small interfering nucleic acids (siRNAs): one is GalNAc chemical cross-linking technology, and the other is lipid nanoparticle technology. The GalNAc technique relies on the expression of non-sialylated glycoprotein (ASGPR) receptors, which are low expressed in liver cancer cells. Therefore, this technique has a better delivery effect only on liver parenchymal cells, and even normal liver parenchymal cells.

Haichang's QTsome™ belongs to the lipid nanoparticle platform. Traditional lipid nanoparticle technology usually requires the use of ionizable lipids, which have very limited ability to regulate surface charge, resulting in unsatisfactory stability. Haichang's QTsome&trade's composition consists of five components, with the fifth component being permanent positively charged tetravalent and trivalent lipid components added to the ionizable lipids. By optimizing the ratio of these components, the stability of lipid nanoparticles is improved. In addition, these components have tumor endothelial selectivity and can target tumor cells. The QTsome&trade' technology has diverse applications; it can deliver oligonucleotide drugs as well as mRNA drugs, achieving optimization for different active molecules.

The QTsome™ technology platform is tailored for nucleic acid drugs. Whether it's oligonucleotides, mRNA, or plasmids, they all carry multiple negative charges that interact electrostatically with charged lipids. Although this phenomenon has long been observed, how to form stable electrostatic complexes and ensure that the nucleic acids within them can be effectively released is a challenging problem, which is also very important for the industrialization of nucleic acid drugs. I am very interested in this area, focusing on nucleic acid drug formulation research and successfully developing the QTsome™ technology platform. Haichang Biotechnology has invested significant resources in clinical translation of this technology and achieved industrialization.

In addition to focusing on nucleic acid drugs, Haichang Biotech has also positioned itself in the field of high-end complex injections. HC007 paclitaxel for injection (albumin-bound type) has obtained domestic drug marketing authorization, and its GMP production workshop has successfully passed pre-EU site inspection. Moreover, we are developing products such as enteric-circulating liposomes and polycystic liposomes. PEGsome refers to irinotecan liposomes, whose surface is modified with PEG so that it is not rapidly cleared by the reticuloendothelial system. Currently, clinical research is underway. Exparel, a product based on DEPOsome technology, is a bupivacaine polycystic liposome. The process development and GMP production of this product have been completed, and it will enter clinical research this year.

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The research and development of innovative drugs requires a strong team background, which is very important for new drug research and development as well as forward-looking market control.

Haichang Biotech places great emphasis on building its innovation capabilities. The founder and chairman of Haichang Biotech is Dr. Zhao Xiaobin, who has worked at institutions such as the FDA, Abbott, Shanghai Pharmaceutical Industry Research Institute, and James Cancer Hospital. He has accumulated over 20 years of scientific research experience in the fields of pharmaceutical formulation and pharmaceutical regulations. His research areas include targeted drug delivery systems, siRNA therapy, liposomes, nanopharmaceuticals, etc. In 2010, he was hired as a senior reviewer at the Center for Drug Evaluation (CDER) of the US Food and Drug Administration (FDA), responsible for complex formulation approvals, focusing on reviewing the CMC consistency evaluations and cGMP quality systems of peptides, liposomes, and other drugs. He also participated in the FDA's coordination working group for nanodrug regulatory guidelines, formulating several declaration guidelines related to liposomal drugs. Since November 2022, he has served as the leader of the ICH Q1/Q5C Expert Working Group. Dr. Zhao Xiaobin holds a qualification certificate as a Level III (highest level) drug site inspector from the FDA.

In 2021, Haichang introduced Dr. Yang Yongsheng, Senior Vice President and Dean of the Nucleic Acid Innovation Research Institute. Dr. Yang worked at the US FDA for 16 years, serving as a senior pharmacologist responsible for the research and evaluation of biopharmaceutics and drug quality for new drugs and generic drugs. He reviewed the results of bioequivalence studies for generic drugs, including complex preparations such as liposomes, microspheres, and local acting drugs, and participated in the formulation of several industry guidelines for bioequivalence studies of high-end complex preparations. Currently, the Nucleic Acid Innovation Research Institute under Dr. Yang's leadership has more than 30 R&D personnel. The institute uses the QTsome™ technology platform to encapsulate different nucleic acid molecules such as siRNA and mRNA for the development of nucleic acid innovation products.

In 2022, Professor Li Jianguang, an expert in the development of liposome/nanoparticle delivery systems and small nucleic acid delivery systems, joined Haichang Biotech as the Chief Scientist, providing a solid backing for the innovative new drug research and development at Haichang Biotech.

The clinical department I work in is divided into preclinical and clinical teams, which are further subdivided into Chinese and American teams to synchronize the progress of clinical trials in China, the United States, Hong Kong, and other regions. Our clinical team members are highly specialized and have experience in innovative drug research and development or clinical trials from pharmaceutical companies, CROs, and other institutions. After obtaining my Doctor of Biomedical Sciences degree from Virginia Tech in the United States, I joined the FDA's Clinical Pharmacology Department in 2003, working in the oncology department for nearly six years and in the neurology new drug department for twelve years. In 2021, I joined Haichang Biotech, mainly responsible for advancing the clinical research and development of our pipeline including the AKT-1 product, supporting FDA filings and Chinese CDE filings.

Our colleagues at Haichang possess a profound scientific background and rich work experience, laying a solid foundation and providing strong support for the company's drug research and development projects.

From a clinical perspective, nucleic acid drugs encapsulated in LNP are a type of heterologous protein upon entering the human body. They can trigger an immune response in the body and may mediate immune rejection or other side effects. At the same time, from the perspective of drug design philosophy, we hope that target validation is precise. However, in reality, off-target effects and side effects of nucleic acid drugs are difficult to avoid, and drug safety faces certain uncertainties.

When designing the clinical trial protocol for HC0301, Haichang placed great emphasis on drug safety and conducted a comprehensive evaluation of the drug. Although during the non-clinical research phase, animal experiments and in vitro tests of HC0301 did not show cytokine storms or other severe immunotoxic adverse reactions, we still attached importance to the management of human immune toxic side effects when formulating the clinical trial protocol. On one hand, we focused on preventive interventions by establishing pre-intervention measures to avoid the occurrence of toxic side effects; on the other hand, in response to potential adverse events, especially severe adverse reactions such as cytokine storms, we formulated corresponding graded response plans. In addition to paying attention to potential related side effects such as LNP use and drug synthesis of the drug itself, we also conducted extensive literature retrieval and analysis, and considered the possible adverse reactions of other small nucleic acid encapsulated drugs approved by the FDA and CDE.

When submitting the clinical trial application HC0301 to the FDA, our team made comprehensive and thorough preparations. The application protocol included corresponding preventive measures and treatment plans, laying a solid, scientific, and theoretically based foundation for the clinical trial of HC0301. After receiving the first human trial application for HC0301, the FDA granted a one-time approval.

When formulating the HC0301 clinical research protocol, our team conducted extensive literature searches on issues such as the efficacy of the drug and its combination with other drugs. Starting from the mechanism of action, we conducted a comprehensive analysis of different aspects such as pharmacokinetics, efficacy, and safety. Combining past research information and the needs of clinical patients, we finally determined the clinical protocol.

HC0301 is about to initiate Phase II clinical trials for liver cancer treatment. In the United States, liver cancer is a rare disease mainly induced by alcoholic liver disease. In China, liver cancer is mainly caused by hepatitis, with a large patient population. The main causes of liver cancer differ between China and the United States, as well as there are significant differences in the number of cases. HC0301 received orphan drug designation from the FDA in September 2023 in the United States and will soon start clinical trials simultaneously in China, the United States, and Hong Kong. Recruiting rare liver cancer patients in the United States faces significant challenges.

In response to the above issues, our clinical team has actively taken action. We have contacted a cooperative principal investigator (PI) and a clinical trial center in the United States, and collected relevant information on the monthly patient enrollment for recent liver cancer research projects in the US. We have made every effort to prepare comprehensively in advance so as to smoothly progress the clinical trials after their launch.