Guodian Medicine Advances Multiple Exosome Drug Pipelines into Clinical Trials with Self-Sustaining Innovation Strategy

A $1.5 billion deal has ignited this sector.

On September 17, 2024, Capricor Therapeutics (“Capricor”), a biotechnology company developing cell and exosome therapies, entered into a commercialization and distribution agreement with Nippon Shinyaku Co., Ltd. Capricor will receive a $15 million equity investment (at a 20% premium) and a $20 million upfront payment, bringing the total potential value of the distribution agreement to approximately $1.5 billion, setting a new record for the largest transaction in the exosome therapy sector.

Yet less than two years ago, Codiak Biosciences (hereinafter referred to as “Codiak”), widely recognized as a pioneer in exosome therapeutics, declared bankruptcy. The stark contrast is lamentable.

“Exosomes” was formally coined in the 1980s. As a major subtype of extracellular vesicles, exosomes are membrane-bound structures with a diameter of 30–150 nm (nanometers), composed of naturally occurring human proteins and lipids. Most cells secrete exosomes; consequently, they are present in various biological fluids, where they can penetrate tissues, disseminate into the bloodstream, and even cross the blood-brain barrier. Leveraging these properties, exosomes hold therapeutic potential for disease treatment and can serve as drug carriers to optimize drug delivery systems.

In 2012, Professor Shinya Yamanaka of Kyoto University in Japan was awarded the Nobel Prize in Physiology or Medicine, jointly with British scientist Sir John Gurdon, for his development of “the technology to reprogram adult cells into induced pluripotent stem cells (iPSCs).”

Subsequently, in 2013, American scientists James E. Rothman and Randy W. Schekman, along with German scientist Thomas C. Südhof, were jointly awarded the Nobel Prize in Physiology or Medicine for their discovery and elucidation of the vesicle transport system and its regulatory mechanisms. Marking this milestone, exosomes, as a major type of extracellular vesicles, have gained prominent recognition in both the scientific and industrial communities. With increased research investment, they have carved out a clear path toward commercialization amidst initial industry chaos, leading to the emergence of numerous related companies and products.

At that time, the major milestones achieved in induced pluripotent stem cell (iPSC) and exosome research greatly inspired Professor Zhang Jianmin, who was conducting research and preparing to launch a startup across the ocean. Professor Zhang’s primary research focuses on the pathogenesis and therapeutic targets of major neurodegenerative diseases and cancers. These two innovative research achievements aligned closely with both his scientific work and his entrepreneurial vision.

He pointed out that induced pluripotent stem cells (iPSCs) can be directed to differentiate into organoids, such as brain and heart organoids, thereby addressing critical challenges in drug screening, efficacy evaluation, and safety assessment. Many drugs demonstrate efficacy in animal trials but fail in human clinical trials due to differences between animals and humans in aspects such as the amino acid sequences of drug targets or protein modifications. By leveraging human organs derived from iPSC differentiation to simulate the human physiological environment, the accuracy of drug screening can be significantly improved.

Zhang Jianmin holds a deeper understanding of exosomes. He believes that exosomes have shattered the traditional framework of cellular regulation knowledge. By packaging molecules such as proteins and small RNAs into small vesicles, exosomes can rapidly fuse with other cells, directly regulating specific intracellular targets. This novel mechanism of regulation has positioned exosomes as a new frontier in drug development.

In 2017, Guodian (Beijing) Pharmaceutical Technology Co., Ltd. (hereinafter referred to as “Guodian Pharma”) was officially established and immediately completed its angel financing round.

At the time of Guodian Medicine’s establishment, the industrialization trajectory of exosomes remained unclear, with academic research on exosomes still in a nascent, undercurrent phase. Meanwhile, translational research related to exosomes was experiencing exponential growth. However, within China’s industrial landscape, exosomes remained an untapped frontier.

Against this backdrop, Zhang Jianmin pointed out, “If a company’s operations rely entirely on investors’ capital, it may face significant risks.” Therefore, even though Guodian Pharmaceutical received capital support in its early stages, the company still adopted a diversified business strategy, which included launching CRO services and entering certain segments of the regenerative medicine raw materials market.

Guodian Medicine initially chose to enter the CRO sector, a decision driven by the broad application prospects demonstrated in drug development by the disruptive technology of directing iPSC differentiation into organoids such as brain and heart organoids. This technology not only significantly accelerates the pace of the drug development industry but also creates opportunities for the company to provide technical services and accumulate technical expertise.

In the course of conducting its CRO business, Guodian Medicine is also actively promoting the practical application and accumulation of technology. Given the high degree of professionalism and complexity in the field of drug development, the company recognizes the importance of cultivating talent with relevant skills. Therefore, CRO services not only generate cash flow for the company but, more importantly, significantly drive talent development and enhance technological capabilities.

Furthermore, leveraging its expertise in exosome-based drug development, the team has expanded into the medical aesthetics sector. By establishing a robust large-scale manufacturing and quality control system, Guodian Pharmaceuticals produces medical aesthetic raw materials according to pharmaceutical-grade standards—a strategy that can be described as “asymmetric competition.” This approach grants Guodian Pharmaceuticals a significant competitive advantage in the market for medical aesthetic ingredients.

Currently, Guodian Pharma has provided platform-based services, including CRO/CDMO, to nearly 400 domestic and international pharmaceutical R&D enterprises and scientific research institutions. The company has obtained relevant certifications for international cosmetic ingredients and attracted inquiries and collaboration from foreign cosmetic companies. Although its scale is not yet large, the company has consistently maintained over RMB 100 million in unrestricted cash reserves. By diversifying risks and ensuring healthy cash flow, the company’s new drug R&D efforts are well-supported by the continuous “self-sustaining” revenue generated from its diversified business operations.

The development of exosome-based therapeutics represents a true zero-to-one exploration.

First, traditionally, the sources of exosomes have been mainly limited to a few specific cell types, such as mesenchymal stem cells and 293 cells. Although exosomes derived from 293 cells can achieve scalable and standardized production, these exosomes serve merely as drug delivery vehicles and are difficult to develop into standalone therapeutics.

On the other hand, mesenchymal stem cell (MSC)-derived exosomes possess certain anti-inflammatory and pro-regenerative capabilities. However, from a pharmaceutical perspective, the application of these cell-derived exosomes faces two major bottlenecks. The first is the challenge of scalable production; specifically, when cells are cultured beyond the sixth passage, their characteristics change, making it impossible to consistently produce exosomes that meet quality standards. Furthermore, the heterogeneity of MSCs presents another difficulty, as cells at different developmental stages vary in growth rate and exosome production, thereby compromising the batch-to-batch consistency of exosome products.

Finally, leveraging the extensive expertise accumulated by Zhang Jianmin and his team in induced pluripotent stem cell (iPSC) research, the company remains committed to using iPSCs as the source for exosomes. A significant advantage of iPSCs is that a master cell bank can be established from a single cell through expansion, followed by the creation of a working cell bank via further cultivation. This manufacturing approach ensures that each batch of exosomes originates from a consistent cellular source, thereby enabling scalable, reproducible, and stable production.

Although Codiak, the pioneer, has lost its former luster, it continues to inspire successors in the exosome therapy industry. In Zhang Jianmin’s view, Codiak’s proprietary technology platform is remarkable, but the company encountered challenges in its clinical applications. For instance, the R&D team treated exosomes merely as a delivery system, and the design of its pipeline lacked guidance from clinicians, resulting in certain flaws in experimental design.

Therefore, Guodian Medicine has adopted distinct strategies in the exploration of indications and routes of administration. First, regarding indication selection, Guodian Medicine collaborates closely with clinicians to thoroughly identify unmet clinical needs, focusing its R&D efforts on refractory diseases that are currently “untreatable” or “incurable” in clinical practice.

Secondly, the R&D team conducted omics analyses to thoroughly investigate the specific composition of iPSC-derived exosomes, clarify their functional efficacy across various fields, and design the development pipeline based on these analytical results. iPSC-derived exosomes exhibit favorable druggability, characterized by extremely low immunogenicity, high safety, excellent stability and reproducibility, as well as scalability in production and quality control. They can be utilized for the development of Class 1 innovative drugs or for engineering modifications, offering broad application prospects. The team believes that by leveraging the inherent properties of exosomes and implementing a “1+1+n” model innovation, it is promising to successfully develop potential innovative therapeutics.

iPSC-derived exosomes contain cell source-specific bioactive molecules and exhibit potent anti-sterile inflammatory activity, attributed to the presence of anti-inflammatory cytokines such as TGF-β. Furthermore, these exosomes demonstrate robust capabilities in promoting regeneration and tissue repair, which are closely associated with their cargo of stem cell growth factors.

The team is capable of engineering natural exosomes through strategies such as cell engineering, genetic engineering, bioengineering, and materials chemistry to enhance their targeting capability, improve bioavailability and therapeutic efficacy, and facilitate translation from laboratory research to clinical applications, thereby meeting the therapeutic needs for specific diseases.

Currently, Guodian Medicine’s R&D pipeline for iPSC-derived exosome therapeutics is structured into three segments: natural exosomes, engineered exosomes, and exosome-based drug delivery systems. The company initially focuses on the natural exosome pipeline, as these products are considered to have a more favorable safety profile and are more likely to gain regulatory approval.

Several natural exosome pipelines are advancing rapidly. For instance, in the treatment of atopic dermatitis, clinical studies have demonstrated that this therapy is not only highly effective for the condition but also exhibits significant therapeutic benefits for hard-to-heal wounds. Consequently, the company plans to initially develop it as a medical dressing for the treatment of conditions such as diabetic foot ulcers and pressure ulcers in long-term bedridden patients.

Furthermore, Guodian Medicine is also developing an exosome-based therapy for the treatment of refractory epilepsy. The mechanism of action of this therapy is entirely distinct from that of all currently available antiepileptic drugs. It promotes normal neuronal development and function, improves the reuptake and recycling of neurotransmitters, thereby effectively controlling epileptic seizures, and demonstrates a significant beneficial effect on patients’ cognitive function.

In the treatment of ischemic stroke, Guodian Medicine’s exosome therapy has also made significant progress. This therapy targets cerebral edema—a critical clinical challenge following cerebral infarction—and aims to prevent sequelae by controlling brain swelling. Reportedly, the therapy has demonstrated favorable outcomes in clinical trials at Xuanwu Hospital.

It is worth mentioning that Guodian Medicine is also developing exosome-based therapies for chronic rhinitis. Through in-depth research, Professor Zhang Jianmin and the team led by Professor Lv Wei from Peking Union Medical College Hospital discovered that the root cause of recurrent chronic rhinitis lies in the loss of the nasal mucosal protective barrier. This loss compromises its protective function, leading to significant infiltration of inflammatory cells and hyperplasia of basal cells, which in turn causes persistent inflammation recurrence.

After in-depth research, Zhang Jianmin and his team identified a crucial gene named “Alox15,” which plays a pivotal role in the pathogenesis of chronic rhinitis, acting as a key regulator of inflammatory responses. These findings were published in the prestigious international journal Nature Immunology. The team further identified an inhibitor of this gene and encapsulated it within exosomes to formulate a nasal drop. This therapy not only controls inflammation but also leverages the regenerative properties of exosomes to repair the nasal mucosa, thereby fundamentally preventing inflammatory recurrence and achieving a true cure.

Furthermore, Guodian Medicine is advancing the R&D of multiple other pipeline candidates, including gene-engineered exosome therapy for systemic lupus erythematosus (SLE), exosome therapy for Alzheimer’s disease (which has not yet entered clinical trials due to funding constraints, though the company plans to collaborate with major pharmaceutical firms to advance this project in the future), and exosome therapies for burn injuries and premature ovarian insufficiency. These projects are currently in the preclinical stage but are expected to rapidly progress into clinical trials.

In China, the field of exosome therapy has seen the emergence of first-in-class technologies entering clinical trials, along with corresponding pipeline layouts. Companies such as Guodian Pharma have gradually stabilized their operations through accumulated experience, laying a foundation for connecting various segments of the exosome industry chain.

Nevertheless, exosome therapy currently continues to face challenges. In addition to technical barriers, there is a lack of universally accepted industry standards, particularly quality standards for pharmaceutical-grade exosomes. Zhang Jianmin attributes this situation to the fact that technological advancement often outpaces the development of regulatory guidelines and technical standards.

Therefore, leading companies have a responsibility to engage in efficient communication with regulatory authorities to jointly promote the establishment of industry norms. He noted that some enterprises, including Guodian Pharmaceutical, are actively drafting consensus-based technical principles and maintaining close contact with regulatory bodies such as the National Medical Products Administration (NMPA) and the National Institutes for Food and Drug Control (NIFDC) to collaboratively develop technical guidance documents and industry standards. He emphasized that leading companies should proactively establish technical standards, which may eventually evolve into industry-wide or even national standards.

Furthermore, Professor Zhang Jianmin noted that regulatory authorities also face challenges such as staffing constraints and the learning curve associated with emerging technologies like exosomes. Nevertheless, regulators are actively engaging with enterprises to discuss relevant principles and continuously refine regulatory mechanisms. He suggested that companies prioritize communication with regulatory bodies and even consider filing an Investigational New Drug (IND) application in the United States first to gain experience before submitting applications in China, thereby accelerating the approval process.

“To address the aforementioned challenges, enterprises need to maintain close collaboration with regulatory authorities, and it will take time for the entire industry to achieve breakthroughs.”