R&D Milestone: HebaBiz Biotech's application for phase III clinical trial in China for Clevudine (L-FMAU), an anti-hepatitis B virus drug candidate under development has been approved

BEIJING, Nov. 15, 2021 /PRNewswire/ -- HebaBiz Biotech is pleased to announce that in November 2021, the Center for Drug Evaluation (CDE) of The National Medical Products Administration (NMPA) of China has approved the application for phase III clinical study of Clevudine (L-FMAU), a drug candidate under development for chronic hepatitis B virus (HBV), the application of which was made by HebaBiz Biotech on August 18, 2021, marking another major milestone on its achievement on advancing the clinical study for liver diseases.

L-FMAU was introduced from Yale University and HebaBiz Biotech obtained its exclusive license for anti-hepatitis B virus in Greater China. With the help of Professor Yung-Chi Cheng, Chairman of HebaBiz Biotech's Biotechnology Advisory Committee (postdoctoral supervisor at Yale University of Dr. James Zhou), Dr. Zhou, HebaBiz Biotech's founder, as one of the participants in the pharmacology research program of the world's first-in-class anti-HBV drug Lamivudine, has a deep understanding of the pharmacology and limitations of current anti-hepatitis B drugs, and are committed to developing L-FMAU as a new generation best-in-class anti-HBV new drug with potential in pursuing the aim of functional cure. HebaBiz Biotech practices the research strategy of "introduction, absorption and re-innovation" and initiative. Upon obtaining the license from Yale University, one of the world's top universities, HebaBiz Biotech continued in-depth research, focusing on the drug-feasibility and practical aspects, and has achieved new breakthroughs and progress.

HBV infection is a worldwide epidemic. According to WHO, there are about 257 million chronic HBV infected patients worldwide, and about 887,000 people die of HBV-related diseases every year. In China, 77% of patients with cirrhosis and 84% of patients with HCC were caused by HBV. It is estimated that the prevalence of HBsAg in the general population in China is 5%-6%, and there are about 70 million chronic HBV infections, of which about 20-30 million are CHB patients. At present, it is difficult for drugs on the market to achieve functional cure of hepatitis B virus. Drugs of various mechanisms are still in clinical stage to develop breakthrough therapy, but most of them are in phase I or phase II clinical stage, and none has been approved for new drug application.

L-FMAU is a synthetic β-L nucleoside analogue discovered in the laboratory of Professor Yung-Chi Cheng at Yale University. Unlike most NAs, L-FMAU is phosphorylated to Clevudine-5'-triphosphate (CLV-TP) in cells and binds to reverse transcriptase to inhibit HBV replication non-competitively. It is not incorporated into the HBV DNA chain and does not participate in mitochondrial DNA and nuclear DNA chain replication. Therefore, L-FMAU is different from other NAs in its mechanism of action, inhibiting all the processes of HBV DNA replication to form viral genome, including initiation, polymerization, elongation and so on, thus inhibiting cccDNA formation.

In addition to inhibiting virus replication and reducing cccDNA copy number, HebaBiz Biotech also discovered that L-FMAU can regulate hepatocyte immune-related genes, modify cell microenvironment, reactivate autoimmunity, and induce apoptosis in cells. Given L-FMAU's dual regulatory mechanism of antiviral and immune reactivation, HebaBiz Biotech designed the pulsed administration protocol to achieve the purpose of sustained virus suppression after drug withdrawal, and can potentially achieve functional cure for some patients.

L-FMAU has two key development values as follows: 1. It can realize long-term drug withdrawal for some patients, and solve the long-term medication compliance issues of patients and the risk of renal function damage caused by long-term use of NAs; 2. Pulsed administration can give full play to its immune reactivation advantage and further clearance capacity of cccDNA/HBsAg to a certain extent while avoiding and solving the disadvantage of long-term continuous administration of L-FMAU; It is expected to realize the potential of achieving the long-term goal of functional/clinical cure for some patients and provide patients with better treatment options.

Responding to this milestone, Dr. Zhou remarked:

"While I was studying pharmacology guided by my supervisor, Professor Cheng, at Yale University, I had been determined to address the clinical needs in connection with liver diseases from the moment I participated in the study of Lamivudine, the world's first anti-hepatitis B virus drug. Approval for phase III trial application in China for L-FMAU is a great encouragement to our team. Comprehensive analysis of all aspects of research data also allows us to see the simultaneous synergistic effect of this drug on viral targets and cell targets, which is very characteristic. We hope to verify the possibility of functional/clinical cure of hepatitis B virus via both antiviral and immunomodulatory mechanisms in future clinical trials. In addition, we are also advancing the development of L-FMAU in cancer, hoping to further the characteristics of L-FMAU to better service clinical needs.

Functional/clinical cure for hepatitis B virus is the goal that many biotech companies are pursuing, albeit in the early to mid stages. There is currently no approved drug in this line. Liver diseases are a major health problem that Chinese people need to solve, and it is also one of the key areas of focus of our Company. I hope to implement the ethos of R&D serving clinical needs and putting drug-feasibility first with the aid of my experience and background, and lead our Company to accelerate and excel."

L-FMAU

Summary of previous phase II/III clinical studies

Preliminary clinical studies of L-FMAU have shown a sustained inhibitory effect after drug withdrawal:

1. L-FMAU-102

L-FMAU-102 is an open, non-randomized, multi-center, dose-increasing phase II clinical trial evaluating sustained antiviral activity of L-FMAU. Patients were followed up for 24 weeks after a 28-day treatment, and then to week 40 and 52 if the patients meet the standard at week 28. The results show all doses had a continuous inhibitory effect after the 28-day treatment. Up to 6 months (24 weeks) after treatment, at least 1.2lg of median HBV-DNA remained persistently lower in all dose groups.

2. L-FMAU-201

A total of 99 HBV patients were randomly assigned 1:1:1 to one of three groups (placebo, L-FMAU 30 mg (once daily), or L-FMAU 50 mg (once daily)). All patients were followed for 24 weeks at the end of the 12-week treatment course (total 36 weeks). 88 patients completed the 36-week study and there were 63 patients in the L-FMAU group. The L-FMAU 30 and 50 mg groups showed significant HBV-DNA inhibition during 12 weeks of treatment. The inhibition of HBV could still be maintained after treatment. HBV DNA was still below baseline at week 36 (24 weeks after treatment was stopped).

3. CLV-304

A total of 63 patients were enrolled to investigate the long-term virus inhibition effect of CLV 30 mg after treatment. Trial results showed that L-FMAU demonstrated a sustained virological response after withdrawal over a relatively short treatment period (24 weeks of administration and 72 weeks of withdrawal). After drug withdrawal, HBsAg titer of patients with persistent virus response decreased continuously (-0.5log IU/ mL), suggesting that patients with persistent virus response could achieve short-term administration and long-term drug withdrawal. At present, other nucleoside analogues for the treatment of HBV generally show rapid viral rebound after discontinuation.

About Dr. Zhou

Dr. James Zhou is the founder, Chairman and Chief Scientist of HebaBiz Biotech. His academic and research achievements include the following:

• Postdoctoral Fellow, Department of Biology / School of Medicine, Yale University
• Ph.D. in Genetics, Iowa State University
• National "Innovative Talents Promotion Plan" Scientific and Technological Innovation and Entrepreneurship Talents
• Director, National & Local Joint Engineering Research Center for Anti-tumor Drug Development
• 863 Evaluation Expert in Agricultural Biology, Ministry of Science and Technology
• 863 Expert and Host of Special Biological Resources Major Project of Ministry of Science and Technology
• Evaluation Expert in Biotechnology and Medicine Program of Evaluation Center of Ministry of Science and Technology
• Zhongguancun "High-End Leading Talent"

About HebaBiz Biotech

Founded by Yale University scholars and their team returning to China, HebaBiz Biotech is committed to creating personalized, precise and improved solutions for the treatment of cancers and liver diseases, guided by clinical value and patients' needs and systematically improving the quality of traditional Chinese medicines by the use of cutting-edge biotechnology.

HebaBiz Biotech has established a National & Local Joint Engineering Research Center for Anti-tumor Drug Development, systematic technology platforms for small-molecular drugs and innovative traditional Chinese medicines. HebaBiz Biotech has a number of international and domestic patented technologies, and seven new drug candidates in its pipeline under research and development, including China's Category 1.1 Anti-cancer Innovative Drug under the National New Drug Development Major Project. HebaBiz Biotech's pipeline is also strategically positioned to comprehensively cover liver disease indications including Liver Cancer, Chronic Hepatitis B virus, Nonalcoholic Steatohepatitis (NASH), Alcoholic Liver Disease, weight, lipid and other metabolic disorders; at the same time, HebaBiz Biotech is seeking breakthroughs in Glioblastoma (GBM), Pancreatic Cancer and Renal Cell Carcinoma etc.

In addition to small-molecular chemical drugs, HebaBiz Biotech is also committed to writing a new chapter of exploration on the track of innovative multi-molecular and multi-targets traditional Chinese medicines to solve chronic diseases, which is completely implemented in accordance with the international standard evaluation of CMC, preclinical pharmacodynamics and pharmacology, as well as clinical effectiveness, supplementing the disadvantage of easily missing the target(s) and cannot effect a radical cure of chronic diseases of many single target small-molecular drugs. In this line, HebaBiz Biotech is hopeful in telling "a new China story".

In parallel with innovative research and development, HebaBiz Biotech practices the principle of using the best from both Chinese and Western sources and implements a commercial layout of chemical medicines and natural medicines being mutually complementary. HebaBiz Biotech currently has nine types of drug production lines, 82 product approvals; it has built and put into operation a modern production base of 68,000 square meters and has a productive sales team, and is strategically positioned as an all-rounded innovative enterprise of "integration of research and development, production and sales".

Forward-looking statements

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SOURCE HebaBiz Biotech

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