World's First Naked Plasmid Gene Therapy Nears Market Launch, Revolutionizing Treatment for Critical Limb Ischemia: An Interview with Mr. Xu Songshan, Chairman of Nuosiland

Critical Limb Ischemia（CLI）It is a progressive peripheral arterial disease that may cause ulcers and wounds in the legs and feet, with a high risk of amputation. According to public data, the amputation rate reaches 22% without treatment, and the 5-year mortality rate exceeds 50%. Currently, there are no drugs clinically available for treating ischemic diseases, and the most commonly used surgical and interventional treatments have certain limitations, with a high recurrence probability, making it urgent to develop more effective treatment methods.

Northland Develops an Innovative Gene Therapy Drug Based on HGF Gene + Naked Plasmid for Critical Limb Ischemia（NL003）, which can promote angiogenesis to achieve the goal of effectively treating diseases. This candidate pipeline has entered the critical NDA stage and shows significant market potential. The "Fengke Interview" column under Yima News had the privilege of interviewingXu Songshan, Chairman of Northland, he provided us with a detailed introduction to the mechanism of action of this innovative therapy, and shared its R&D process and commercialization plans, etc.

Xu Songshan NorthlandChairman and President

Graduated from Yanbian University Medical College, Master of Toxicology, Senior Engineer, Licensed Pharmacist;

Formerly served as a lecturer at the Yanbian University Medical College, director of the Jilin Chemical Occupational Disease Research Institute, and vice president of Jilin Yatai (Group) Company;

Founded Beijing Northland Biotechnology Co., Ltd. in 2004, serving as Chairman and President, leading the team in the research, production, and sales of gene therapy drugs, recombinant protein drugs, and ophthalmic drugs; the company was among the first batch to be listed on the Beijing Stock Exchange in 2021.

Former member of the Beijing Overseas Chinese Federation Committee, member of the Haidian District Political Consultative Conference, expert of the Expert Advisory Committee of the National Science and Technology Innovation Center, and evaluator of science and technology projects for the Beijing Municipal Science and Technology Commission; awarded by the China Overseas Chinese Federation and the State Council Overseas Chinese Affairs Office.「Advanced Individual of Returned Overseas Chinese and Their Relatives in China」, issued by the Beijing Municipal People's Government「The 7th Advanced Individual of Ethnic Unity and Progress in the Capital」And the "Two New Organizations" award issued by the Haidian District Committee「Party Building Buddy」And many other honorary titles.

China did not start late in this field, with the earliest approved recombinant humanp53 adenovirus, as the first gene therapy drug produced in China, has had a significant impact. In addition, the Academy of Military Medical Sciences has also conducted research on some gene therapy drugs related to adenovirus and naked plasmids. At that time, there were many similar drugs abroad that had entered clinical trials; it was just that many companies in China did not pay enough attention.

We chose the naked plasmid technology path because of its better safety.. Despite its many shortcomings, we believe that as long as we accurately target the disease, naked plasmid drugs can avoid the long-term safety issues that were of greatest concern at the time, which is undoubtedly an important direction for development. With this in mind, we initiated an internal project and have been continuously advancing it.Development of DNA Naked Plasmid Drugs. Currently, the drug has completed phase III clinical trials, and we submitted the NDA application last year.Currently in the stage of replying to supplementary inquiries,ThisMonthly submission of response materials, awaiting drug approval for market launch。

In this process, we have built a corresponding technical platform and accumulated a number of technologies centered around...Drug pipelines using DNA naked plasmids as vectors are currently in the preclinical stage. In the future, the company will focus on developing gene therapy drugs.

After years of development,The CGT field has received widespread attention, with governments and multinational companies around the world investing heavily in R&D within this area. For us, although the initial stage of new drug development does come with certain risks and challenges, we firmly believe that this represents the future direction, and thus have remained committed to the research and development of gene therapy drugs.Among them, the naked plasmid drug is the first key development target.。

Chairman Xu Songshan：I am a doctor by training, having studied clinical medicine in university. I have worked in hospitals and research institutes, and before starting my own business, I was employed by a company. Therefore, in the process of drug development,We must be guided by clinical needs.. My background as a doctor also gives me an advantage in understanding clinical needs and new drug demands more deeply, and it is easier for me to make judgments. My master's degree was in toxicology, a discipline that involves a lot of content related to drug safety evaluation. Additionally, during my work period, I participated in pharmaceutical factory construction and new drug registration, making me quite familiar with the entire process of new drug development.

Moreover, the historical context has also changed. In the past, the vast majority of drugs in China were generic drugs, but during the process of enterprise operation and management,I realize that the demand for innovative drugs in China is huge.At that time, we judged that domestic enterprises had no strong advantages in small molecule drug research and development because foreign large enterprises had already made extensive arrangements in related fields, making it difficult to discover new chemical drugs. However, in the field of biotech pharmaceuticals, the gap between China and foreign countries is not as wide as that in small molecule drugs. As long as the right projects are selected, there will be greater opportunities to achieve results in new drug research and development.

Chairman Xu Songshan：We chose gene therapy drugs based on naked plasmids mainly due to safety considerations.The probability of gene integration with naked plasmids is extremely low. If human-derived gene fragments are not used in the construction of naked plasmids, the risk of gene integration is almost non-existent.。People have been concerned about the safety of gene therapy drugs, particularly whether they might cause cancer, deformities, and potential adverse reactions that could emerge decades later. However, compared to viral vectors, naked plasmids are considered more reliable in terms of safety.

Despite the low transfection efficiency and relatively short expression duration of naked plasmids, their expression time in vivo is approximately2-4 weeks, but compared with traditional drugs, after one course of treatment with gene therapy drugs, patients can benefit in the long term without frequent repeated dosing.

At the same time, the shortcomings of naked plasmids become advantages in the treatment of certain diseases. For example, they are less likely to function in non-injected parts of the body, reducing the occurrence of adverse reactions. Naked plasmids are unstable in the body and will rapidly degrade under the action of nucleases after entering the bloodstream, without affecting distant tissues or organs.

In the process of drug development, we have established three principles:Local administration, local expression, local effectivenessThese three principles can minimize the potential risk of harm and are well-suited for the treatment of lower limb ischemic diseases, which are our primary focus. By promoting local angiogenesis through localized action, it effectively treats peripheral arterial ischemic diseases. This approach fully utilizes the characteristics of naked plasmids, transforming their shortcomings into advantages to meet the needs of disease treatment.

Director XU SongshanLong：Naked plasmid, as a vector carrying the target gene, is injected into the muscle and transfects skeletal muscle cells. It utilizes the intracellular protein synthesis system to...Objective Gene Converts into Biologically Active Hepatocyte Growth Factor（HGF）, to locally promote blood vessel growth.

Currently, a large number of scholars have confirmedHGF can promote the formation of capillaries and some small collateral arteries, but there are certain limitations in how HGF is expressed. Although we can produce large amounts of HGF protein in vitro through recombinant gene engineering technology, its half-life in vivo is extremely short, generally considered to be only 2-4 minutes. If a large amount of recombinant protein prepared in vitro is injected into patients, due toToo short half-life, which may require multiple injections per day to take effect.

In earlier animal experiments, it has been confirmed that the expression time of this gene therapy drug in the body is about one month, with the peak expression level occurring at seven days, followed by a gradual decline; its biological activity can be sustained.5-14 days. According to the dynamic expression curve over four weeksCurrently, we set a course of treatment with three doses, injecting once every two weeks.Through intramuscular injection in the leg, the effect of promoting angiogenesis can be achieved.

Chairman Xu Songshan:At that time, domestic approval authorities had relatively little experience in approving gene therapy drugs. Relevant regulatory regulations and technical guidelines were not yet well-established, and there were also few related examples abroad, making the approval process more challenging. However, during the review process,They are particularly concerned about whether the drug will cause potential or long-term adverse reactions.. We use naked plasmid vectors and adoptUse「Three Local Areas」TheStrategy, increased product safety, and ensured product quality. Thus, it successfully passed the reviews at various stages.

At present, thousands of gene therapy drugs with viral vectors or non-viral vectors have entered the clinical stage both in China and internationally, andMore than 30 varieties have been approved for marketing, and there is a new understanding of the safety of gene therapy drugs.

Chairman Xu Songshan:Compared with virus-based gene therapy, plasmid DNA-based gene therapy is less expensive and has a shorter production cycle. In terms of scaled production, we have currently achieved...500 liters fermentation scale, the scale of this NDA application is 500 liters.Our self-built factory will reachScale up to 2,000 liters from the base scale of 500 liters., technically feasible. Currently, weA production scale of 500 liters is globally leading, and if scaled up to 2000 liters, which will become one of the largest production lines in the global field of human-use plasmid DNA.。

However, there is a unique issue in the production of naked plasmids. We use E. coli for replication and then break the cells to extract the naked plasmids. But the naked plasmids must be in a supercoiled structure to enter the cells and function. Therefore, during the production process,How to maximize the percentage of supercoiled structures is critical.We can currently control this proportion to95%, and the requirement in the United States is also approximately 95%.，The measurement methods are slightly different, so the proportional values will vary a little.。

To ensure the content of supercoiled structures in naked plasmids, special techniques must be employed for control throughout the entire process from the start of production to purification and formulation. This is the most challenging aspect of naked plasmid production.

Chairman Xu Songshan:Compared with JapanFor AnGes' Collategene, we have innovated in the plasmid structure and the target gene.Can express two isomers, namelyHGF723 and HGF728These two isomers naturally exist in the body.

Academic research shows that the body'sThere are approximately 3-5 HGF isoforms, among which HGF728 and HGF723 are the most well-characterized. Since these two isoforms naturally exist in the body, they must have some synergistic effect. Therefore, we believe our product is more effective because the two isoforms can work synergistically to promote angiogenesis.

In terms of pricing, we will consider various factors comprehensively. Gene therapy drugs fall under the category of regenerative medicine, and usually, a single administration or a course of treatment can bring long-term benefits.From the perspective of the unit price of a single course of treatment, it may be relatively high, but when calculated over a year, the cost is relatively low.Moreover, we will subsequently conduct a pharmacoeconomic evaluation to determine the pricing by comprehensively considering factors such as patient efficacy, family, society, and especially the consumption of medical insurance.

Currently, our products are about to enter the stage of industrial production and commercial sales.Commercialization is the entire process."The last kilometer" must be successfully completed to form a closed loop of investment and benefit returns.Given that different provinces have different support policies, for example, in Beijing, the threshold for innovative drugs to enter hospitals is relatively low, but in other provinces, the ways for innovative drugs to enter hospitals are diverse and more difficult, which is the biggest challenge faced in the commercialization process.

This year, the National Healthcare Security Administration, the National Health Commission, and other departments have introduced several encouraging policies, such as establishing a commercial insurance innovative drug list, which is undoubtedly a positive development. However, the method for determining the commercial insurance list and the cooperation model between insurance companies and enterprises remain unclear. I hope that commercial insurance will actively participate in the commercialization process of innovative drugs, and that relevant specific policy regulations can be improved as soon as possible. This would be the greatest support for the commercialization of domestically produced innovative drugs in China.

Gene therapy drugs are usually expensive, and patient accessibility is limited.Hope Innovation BranchPayment, especially commercial insuranceCan be implemented as soon as possible to promote the full-chain development of innovative drugs in China.The support provided by the state in the early stages of innovative drug industrialization has become relatively mature, and various regions have also offered numerous incentives. There is now an urgent need to improve the innovative payment system during the commercialization phase.

Chairman Xu Songshan:The target of this innovative drug was independently discovered by us. During the research process, including preclinical and clinical studies, due to the lack of established reference protocols, every stage has been challenging."Crossing the river by feeling the stones," experiencing a lot of trial and error, usedIt has taken 20 years to reach the present.

For innovative drugs to enter overseas markets, we will inevitably consider it. However, entering foreign markets requires conducting clinical trials in the respective countries, which demands substantial investment—about ten times the cost of conducting clinical trials in China compared to the U.S. Currently, without formal approval in China, simultaneously conducting clinical trials abroad poses significant risks.

In addition,Funding is also an important constraining factor.At present, our focus is on meeting the R&D investment in China. We plan to consider overseas markets after obtaining approval in China, while also reaching out to interested companies in Europe, Russia, Southeast Asia, and other regions.