On November 24, 2023, our company “ The Phase III clinical trial of the “Recombinant Human Hepatocyte Growth Factor Naked Plasmid Injection” (code-named NL003), intended for the treatment of severe lower-limb ischemic disease (CLI), has successfully completed enrollment of the 300 subjects as per the pre-specified protocol for the resting pain indication. The ulcer indication trial had already completed subject enrollment on June 7, 2023. With the completion of enrollment for the resting pain indication—reaching the target of 300 subjects—the Phase III clinical trial of NL003 has now fully achieved its planned enrollment target, marking significant progress in the development program and representing a critical step toward product registration.

         NL003 is a Class 1 gene therapy drug—a therapeutic biological product independently developed by our company. It is supported under the national “Major New Drug Development” initiative and is indicated for the treatment of severe lower-limb ischemic disease. Lower-limb ischemic disease is the most commonly encountered clinical manifestation of peripheral arterial disease (PAD). It results from narrowing or occlusion of the arteries in the lower limbs due to various causes, leading to 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 severe lower-limb ischemic disease (CLI). The Phase III clinical trial of NL003 focuses specifically on rest pain associated with lower-limb arterial ischemia (Rutherford). The study will be conducted for two indications: critical limb ischemia (Rutherford Class 4) and ulcers (Rutherford Class 5). This clinical trial adopts a nationwide, multicenter, randomized, double-blind, placebo-controlled design. Specifically, the resting pain trial is planned to enroll 300 patients, while the ulcer trial is planned to enroll 240 patients, for a total of 540 participants. The trial is led by Peking Union Medical College Hospital, with the participation of 24 research centers across China. The primary objective of the study is to evaluate the efficacy and safety of NL003 in treating patients with severe lower-limb ischemic disease.

         CLI This represents the most severe stage of lower-limb PAD progression, clinically characterized primarily by rest pain in the legs and feet, as well as ulcers and gangrene. As the disease advances, infections, ulcers, and gangrene progressively worsen; in severe cases, amputation becomes necessary, placing a tremendous burden on both patients and society. According to data from Frost & Sullivan, China had 51.872 million PAD patients in 2021. The risk of developing peripheral arterial disease increases gradually with age. Influenced by factors such as China’s aging population, the number of people affected by peripheral arterial disease is expected to continue rising in the future. By 2025, the number of patients is projected to reach 56.5626 million, among whom over 5 million are expected to have critical limb ischemia (CLI).

At this stage, China does not yet have an effective curative treatment for CLI; the drugs currently used in clinical practice are mainly aimed at controlling disease risk factors and alleviating disease symptoms. At present, the primary treatment approach for CLI patients remains surgical or device-based interventions. However, since no other effective treatments are available, patients who opt for conservative management, those ineligible for surgery, or those whose surgeries have failed all face a high risk of amputation. According to published literature, the amputation rate among CLI patients ranges from 10% to 40%, and even five years after amputation, the mortality rate remains as high as 70%, placing a heavy burden on the nation, society, and families. Compared with traditional treatment methods, the NL003 project represents a non-invasive therapeutic approach for lower-limb ischemic diseases based on a novel gene therapy strategy. By locally injecting NL003 into the ischemic area, the plasmid is taken up by striated muscle cells, which then continuously express and secrete hepatocyte growth factor (HGF), a protein that promotes angiogenesis. This process stimulates the regeneration of new blood vessels, establishes collateral circulation in the ischemic region, and creates a “molecular bypass” mechanism, thereby increasing blood flow to the ischemic site and achieving the goal of treating ischemic diseases. This project fills a domestic gap in gene therapy for such conditions. In previously completed preliminary clinical trials, NL003 has demonstrated promising clinical efficacy.

Mr. Xu Songshan, Chairman of the company, stated that the Phase III clinical trial for the NL003 project took four years from initiation to completion of patient enrollment, during which the COVID-19 pandemic lasted for three years. Today, we are thrilled to finally receive the good news that all enrolled subjects have been successfully recruited—a truly uplifting milestone. Over the past four years, all employees of the company and the research team have worked tirelessly together, overcoming the severe and complex impact of the pandemic on patient recruitment. They have demonstrated courage in pioneering new approaches, faced challenges head-on, and maintained rigorous scientific standards throughout the trial, ensuring the highest quality of clinical research. We extend our heartfelt gratitude to every member of the research team for their unwavering dedication and hard work. The company will strictly adhere to GCP guidelines and carry out subsequent follow-up visits, data cleaning, statistical analysis, and final summarization with the utmost quality. We look forward to NL003 achieving its anticipated outcomes. Meanwhile, the company is actively preparing for the commercialization of NL003, accelerating its path to market and providing patients suffering from lower limb arterial ischemic disease with a brand-new, safe, and effective treatment option. In doing so, we aim to contribute our technological expertise to the development and advancement of China’s pharmaceutical and healthcare industry.