China's First Naked Plasmid Gene Therapy for Critical Limb Ischemia Meets Primary Endpoint in Phase III Trial for Rest Pain Indication
Northland
Innovative Biopharmaceutical Manufacturer
On August 16, 2024, Beijing Northland Biotechnology Co., Ltd. (Stock Code: 430047), a listed company on the Beijing Stock Exchange, announced that the phase III clinical trial for the treatment of critical limb ischemia with resting pain using its developed "Recombinant Human Hepatocyte Growth Factor Naked Plasmid Injection" (code name NL003) had been unblinded according to the established plan, with primary endpoints meeting expectations. Preliminary results indicate: In terms of the primary endpoint, the complete disappearance rate of pain at 180 days, the NL003 group significantly outperformed the placebo control group (p<0.0001); safety was good, with no significant differences between the two groups and no serious adverse reactions related to the drug found. This is the preliminary result of the second protocol of the phase III clinical trial of the NL003 project released by the company. The first key trial, the ulcer protocol, was unblinded in February this year, showing that the NL003 group significantly outperformed the placebo control group in the complete ulcer healing rate (p<0.0001). In July, it officially received NDA acceptance, entering the new drug review process.
Significant Unmet Medical Needs in Lower Limb Ischemic Diseases
Lower Extremity Ischemic Disease is a common clinical condition, usually caused by arteriosclerosis obliterans (ASO), diabetic arteriosclerosis obliterans (DAO), and thromboangiitis obliterans (TAO), which lead to lower extremity arterial stenosis or occlusion and insufficient blood perfusion. This results in ischemic manifestations such as intermittent claudication, pain, ulcers, or gangrene in the lower limbs. Based on the degree of ischemia, the Rutherford classification is clinically used to categorize lower extremity ischemic diseases from mild to severe into grades 0-6. Grades 4-6 are classified as critical limb ischemia (CLI), with primary clinical symptoms including rest pain in the legs and feet, ulcers, and gangrene. As the disease progresses, infections, ulcers, and gangrene gradually worsen, and severe cases may face amputation or even death.
According to the 2022 Report on Cardiovascular Health and Diseases in China, the prevalence of lower extremity PAD (peripheral artery disease) in the general population aged 35 and above in China is 6.6%, with approximately 45.3 million cases. About 10% of patients with lower extremity PAD will progress to CLI (critical limb ischemia), which is characterized by a high incidence, long disease course, and high disability rate. The 5-year mortality rate exceeds 50%, significantly higher than most severe diseases, including many cancers. With the development of China's socio-economy and improvements in medical conditions, life expectancy has increased, the elderly population continues to grow, and the aging process is accelerating. As a result, the number of PAD patients is expected to continue rising, reflecting a significant unmet medical need.
NL003 Phase III Clinical Trial Mainly Targets Critical Limb Ischemia (CLI), Divided into Two Indications: Ulcer (Rutherford Grade 5) and Rest Pain (Rutherford Grade 4). The trial adopts a randomized, double-blind, placebo-controlled, parallel-group study design, led by the Vascular Surgery Department of Peking Union Medical College Hospital, with clinical research conducted across 24 hospitals in China. Among them, 242 cases were enrolled for the ulcer indication and 302 cases for the rest pain trial. The ulcer indication completed the trial first in February 2024 and officially received acceptance for a New Drug Application (NDA) from the CDE in July. This marks the first plasmid-based gene therapy drug in China to apply for NDA.
NL003 is the first domestically produced plasmid gene therapy innovative drug to be registered and submitted for approval in China.
Currently, there are no effective therapeutic drugs for CLI worldwide. Clinical treatments mainly rely on surgical methods such as interventional procedures and vascular bypass grafting, which have limited treatment options and unsatisfactory outcomes. NL003 is an innovative gene therapy drug that uses a naked plasmid as a vector. By locally injecting NL003 into the ischemic muscle area, the plasmid transfects striated muscle cells and continuously expresses and secretes the hepatocyte growth factor (HGF) protein, which promotes blood vessel growth. This stimulates the regeneration of new blood vessels, forming collateral circulation in the ischemic area and establishing a "molecular bypass" mechanism to increase blood flow supply to the ischemic region, thereby achieving therapeutic effects. Compared with traditional vascular reconstruction surgeries, NL003 has significant advantages in terms of invasiveness, operational convenience, patient compliance, efficacy, and durability, offering sustained clinical benefits to patients.
The biopharmaceutical industry is one of China's strategic pillar industries. Recently, Beijing, Shanghai, and other regions have issued the "Several Opinions on Supporting the Full-chain Innovative Development of the Biomedical Industry," increasing support for the research and development of innovative drugs and medical devices, and making forward-looking arrangements in cutting-edge fields such as gene and cell therapy and mRNA. Gene therapy drugs are one of the hotspots that major pharmaceutical companies are racing to develop. Northland has been dedicated to the development of gene therapy drugs for 20 years and has established a mature technology platform. NL003, as the first gene therapy drug in China to submit an NDA application, has a leading R&D progress in China.
Beijing Northland Biotechnology Co., Ltd. was established in June 2004 and is a listed company on the Beijing Stock Exchange (stock code: 430047). It is an innovative biopharmaceutical enterprise specializing in the research, production, and sales of gene therapy drugs, recombinant protein drugs, and ophthalmic drugs. The company is primarily committed to the research and industrialization of biopharmaceuticals for cardiovascular diseases, metabolic diseases, rare diseases, and ophthalmic conditions. Northland is recognized as a key high-tech enterprise under China’s National Torch Program, a Beijing-based research and development institution, the Beijing Engineering Technology Research Center for Plasmid Gene Therapy Drugs, a Beijing International Science and Technology Cooperation Base, a G20 Innovation Leading Enterprise in China's biopharmaceutical industry, and a "Specialized, Refined, Unique, and Innovative" SME in Beijing. The company holds 22 authorized patents and has undertaken eight national projects under the "Major New Drug Development" initiative.
The company adheres to the clinical needs as the guidance, establishing core technology platforms such as gene vector construction, engineering bacteria construction, microbial expression, mammalian cell expression, biopharmaceutical production processes and their scale-up production technologies, and eye drop drug development. It has accumulated rich experience in preclinical research, clinical research, production and quality management, pharmaceutical factory construction, and pharmaceutical operations.
Beijing Northland Biotechnology Co., Ltd. has a rich and highly mature pipeline of drug research and development, currently working on 11 new bioengineering drugs corresponding to 13 indications. Among them, the recombinant human hepatocyte growth factor naked plasmid injection (code NL003) has completed Phase III clinical research, and the ulcer treatment plan has been submitted for NDA; the recombinant human interleukin-11 for injection (code NL002) is in Phase III clinical stage; the recombinant human thymosin β4 for injection (code NL005) is conducting Phase II clinical research. The ophthalmic drugs developed by the company are being successively launched, with two of them included in the national centralized procurement. The company is steadily developing and is currently constructing a bioengineering drug production base, which will have bulk drug substance production capabilities by the end of this year, achieving a strategic transformation from Biotech to Biopharm.