On August 16, 2024, the Phase III clinical trial of NORTHLAND’s “Recombinant Human Hepatocyte Growth Factor Naked Plasmid Injection” (code-named NL003), for the treatment of rest pain in lower-limb ischemic disease, was unblinded according to the pre-established schedule. The primary endpoints met expectations. Preliminary results indicate that, in terms of the primary endpoint—the rate of complete pain disappearance at 180 days— the NL003 group significantly outperformed the placebo control group (p<0.0001). The product demonstrated a favorable safety profile, with no serious adverse reactions related to the drug identified.

Lower limb ischemic disease is a common clinical condition typically caused by conditions such as atherosclerotic occlusive disease (ASO), diabetic atherosclerotic occlusive disease (DAO), and thrombo-obliterative vasculitis (TAO), which lead to narrowing or occlusion of the lower limb arteries, resulting in insufficient blood perfusion and subsequently causing ischemic symptoms such as intermittent claudication, pain, ulcers, or gangrene in the lower limbs. Based on the degree of ischemia, clinicians use the Rutherford classification system to grade lower limb ischemic disease from mild to severe, ranging from Grade 0 to Grade 6. Grades 4 through 6 are classified as critical limb ischemia (CLI). The primary clinical symptoms of CLI include rest pain in the legs and feet, ulcers, and gangrene. As the disease progresses, infections, ulcers, and gangrene tend to worsen progressively; in severe cases, patients may face amputation or even death.

The Phase III clinical trial of NL003 is primarily focused on CLI and is being conducted separately for two indications: ulcers (Rutherford Class 5) and rest pain (Rutherford Class 4). The trial adopts a randomized, double-blind, placebo-controlled, parallel-group study design. Peking Union Medical College Hospital’s Department of Vascular Surgery serves as the leading center, and the clinical study is being carried out at a total of 24 hospitals nationwide. Specifically, 242 patients have been enrolled in the ulcer indication trial, and 302 patients have been enrolled in the rest pain trial. The ulcer indication trial was completed ahead of schedule in February 2024 and officially received acceptance of its New Drug Application (NDA) from the CDE in July. This makes NL003 the first naked plasmid-based gene therapy product in China to submit an NDA. Following the unblinding of the rest pain indication trial, comprehensive and in-depth analyses will be conducted according to the protocol and statistical analysis plan, and the clinical trial summary report will be finalized. The company is simultaneously preparing the application materials for the new drug marketing authorization for this indication and will actively communicate with regulatory authorities regarding the submission process. The company plans to submit a Biologics License Application (BLA) within this year.

Currently, there are no effective therapeutic drugs available worldwide for CLI. Clinical treatment primarily relies on surgical interventions such as percutaneous coronary intervention and vascular bypass surgery, leaving treatment options limited and outcomes less than ideal. NL003 is an innovative gene therapy drug that uses a naked plasmid as its delivery vector. By locally injecting NL003 into the ischemic tissue via intramuscular injection, the plasmid transfects striated muscle cells, enabling them to continuously express and secrete hepatocyte growth factor (HGF), a protein with angiogenic properties. This promotes the regeneration of new blood vessels, establishes collateral circulation in the ischemic area, and creates a “molecular bypass” mechanism, thereby enhancing blood flow to the ischemic site and achieving therapeutic effects. Compared with traditional vascular reconstruction procedures, NL003 offers distinct advantages in terms of invasiveness, ease of operation, patient compliance, efficacy, and durability, potentially bringing sustained clinical benefits to patients.

According to the 2022 China Cardiovascular Health and Disease Report, the prevalence of lower-limb PAD (peripheral arterial disease) among the general population aged 35 and older in China is 6.6%, corresponding to approximately 45.3 million cases. About 10% of lower-limb PAD patients will progress to CLI. CLI features a high incidence rate, a prolonged disease course, and a high disability rate; its 5-year mortality rate exceeds 50%, significantly higher than that of most serious diseases such as cancer. With the socio-economic development and improved medical conditions in China, life expectancy has increased, the elderly population continues to grow, and the aging process is accelerating. Consequently, the number of PAD patients is expected to keep rising in the future, creating substantial unmet medical needs.

The biopharmaceutical industry is one of China’s strategic pillar industries. Recently, many regions including Beijing and Shanghai have issued “Several Opinions on Supporting the Innovative Development of the Entire Biopharmaceutical Industry Chain,” stepping up support for the research and development of innovative drugs and medical devices, proactively laying out plans for cutting-edge fields such as gene and cell therapies and mRNA technologies. Gene therapy drugs have become a hot spot 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, our company’s first naked-plasmid gene therapy drug submitted for an NDA application, boasts leading R&D progress in China. To realize the company’s strategic transformation from a biotech firm to a biopharmaceutical company, we are currently constructing a bioengineering drug production base. The three main buildings—the comprehensive office building, the production workshop, and the intelligent warehouse—were topped out in 2023, and the production workshop will be ready for bulk drug substance production by the end of this year. The company is also collaborating closely with the internationally renowned pharmaceutical consulting firm IQVIA to actively advance the commercialization efforts for NL003. We look forward to NL003 receiving regulatory approval and being launched onto the market at an early date, becoming the world’s first-ever naked-plasmid gene therapy drug in the true sense, thus providing a new treatment option for patients suffering from lower-limb ischemic diseases.