Clarified Stem Cell Policies Propel iPSC Industry Toward Commercialization
In recent years, global research into stem cell applications has provided new therapeutic opportunities for addressing many refractory diseases. Clinical studies have been conducted across various indications, including tissue repair, gene therapy, autoimmune diseases, neurodegenerative disorders, and oncology. Some products have already received marketing approval, while the number of clinical trials involving domestic stem cell products in China continues to rise.
On August 17, 2021, the Center for Drug Evaluation (CDE) released the “Technical Guidelines for Pharmaceutical Research and Evaluation of Human-Derived Stem Cell Products (Draft for Comments).” Previously, on August 24, 2020, the CDE had issued the “Technical Guidelines for Clinical Trials of Human-Derived Stem Cells and Their Derived Cell Therapy Products (Draft for Comments)” (hereinafter collectively referred to as the Draft Guidelines). The gradual improvement of policies has increasingly clarified the legal and regulatory framework governing the research and clinical trials of iPSC-based drugs. Does this signal that the CDE is releasing positive indications for the iPSC field?
On August 31, VBInsight, in collaboration with Alpha Regenerative Medicine, Shize Biotechnology, Zhongsheng Suyuan, and Legend Capital, convened industry experts to discuss the technical guidelines issued by the Center for Drug Evaluation (CDE) in August. Leveraging these guidelines as a catalyst, the group explored how the iPSC sector can navigate challenges and seize emerging opportunities.
The following are excerpts:
The transition of an industry from being unregulated to regulated is undoubtedly a very positive signal.
In recent years, the continuous issuance of national policies has significantly propelled the cell therapy industry while simultaneously preventing irregular clinical translation and use within the sector. Founders of various companies have shared their perspectives on how the newly released guidelines, along with a series of previously issued policies, will impact the development of the iPSC industry.
Dr. Wang Jiaxian, Founder & CEO of Aipu Regenerative Medicine, stated“Compared with the previous guidelines related to cells, the Guidelines for Research and Evaluation of Cell Therapy released in 2017 is a principle-based document. The current guidelines have more practical guiding significance for iPSCs, and can provide more detailed opinions for enterprises to solve the pharmaceutical problems encountered in the process of application and approval of cell therapy products.”
Dr. Zhang Ying, Co-Founder of Zhongsheng Suyuan, stated: “Overall, the areas covered in the guidelines include mesenchymal stem cells (MSCs), hematopoietic stem cells (including gene-edited hematopoietic stem cells), and cell products derived from pluripotent stem cells (PSCs). However, due to the comprehensive scope, these guidelines only set forth some basic requirements for the entire industry, covering aspects such as cell banking, collection of source cells, product quality control, research, process development, and quality studies.”Moreover, the specific cellular characteristics of each company’s products vary, providing an excellent opportunity for companies to engage in detailed discussions with regulatory authorities regarding relevant regulations.
“Meanwhile, the guidelines also highlight several issues that need to be addressed in the future., including genomic stability. Currently, the evaluation methods and criteria for assessing genomic-level differences among various metabolically active cells, pluripotent stem cells, and their corresponding differentiated progeny remain undefined. Another aspect concerns the unintended differentiation of pluripotent stem cell products, encompassing both in vitro and in vivo scenarios. Furthermore, given the diversity of cell products derived from pluripotent stem cells, the corresponding methodologies are still under development worldwide. This necessitates that innovative domestic enterprises conduct more comprehensive research and publish their findings in international journals.
Dr. Pi Xi Yan, Co-Founder & CTO of Shize Biotech, stated: “With regard to its impact on the future development of induced pluripotent stem cells (iPSCs), the newly released guidelines can effectively promote the healthy development of the stem cell industry.By integrating last year’s draft guidelines for clinical trials, it is evident that a clear regulatory framework has largely been established across the entire drug development lifecycle of stem cells, from R&D and translational research to clinical application."The guidelines have also served as a catalyst for the industry, raising entry barriers and strengthening regulatory oversight to a certain extent. This has triggered a reshuffling within the sector, enabling companies with core proprietary technologies to enter a period of rapid growth, while simultaneously enhancing the overall standardization of the industry."
In the future, there may be second and third drafts, and possibly even manuscripts targeting different categories of cell types derived from iPSCs. As the industry continues to evolve, it is even possible that guidelines will be developed and issued at the level of specific indications.
While China has continuously rolled out policies in the field of cell therapy in recent years, several foreign products have already entered clinical trials. In contrast, no domestic induced pluripotent stem cell (iPSC) products have yet reached the clinical stage. Several industry experts shared insights on the current state of global development within their respective areas of focus.
Aierpu focuses on the field of cardiac cell regeneration, stated Dr. Wang Jiaxian: “Cardiac regeneration is divided into endogenous and exogenous regeneration. The Harvard Medical School cardiomyocyte stem cell incident, which occurred several years ago, helped separate fact from fiction in this field, effectively putting an end to the concept of endogenous cardiac regeneration.”
“Thus, most international R&D efforts in this field currently rely on exogenous cardiomyocytes—commonly referred to as the use of iPSC-derived regenerative cardiomyocytes for therapeutic purposes. Overall, while upstream scientific research is advancing rapidly, several challenges remain due to the unique nature of cardiac regenerative therapy:”
“First, how to regenerate a sufficient number of standard-compliant cardiomyocytes, this is the first point to focus on and overcome;Second, how to address the issue of cell delivery, whether for hematologic malignancies, the heart, or the nervous system, delivery remains a challenge;Furthermore, there is the issue of host integration of cardiac cells.；Finally, how to resolve the issue of electrophysiological coupling between cells and the host heart.
“Based on a comprehensive assessment of the above four dimensions, the cardiac regeneration industry generally presents high barriers to entry. Japan currently ranks among the leading tier. In addition, other countries such as the United States and France also conduct research in the field of cardiac regeneration, but these efforts are primarily carried out by academic and research institutions rather than through industrialization.”
Dr. Zhang Ying delivered remarks on the field of immune cells.: “NK cells and T cells derived from pluripotent stem cells (PSCs) have developed rapidly in recent years, largely because they offer an off-the-shelf product that can significantly reduce the cost of tumor immunotherapy, enabling the advance production and stockpiling of immune cell therapy products with predictable efficacy.”
“Currently, the United States, Japan, and Australia are at the forefront of development in this field. In the U.S., three major companies are leading the way: Fate Therapeutics, Shoreline Biosciences, and Century Therapeutics. Notably, Fate Therapeutics obtained Investigational New Drug (IND) clearance for its NK cell product as early as 2018. Overall, judging from the various products that have progressed into clinical trials, the technical pathway for generating NK cells through induced differentiation from pluripotent stem cells (PSCs) has been successfully established.”
“However, the process from pluripotent stem cell (PSC)-derived cells to the final cell therapy product actually involves the manufacturing of two distinct products. The first product is the PSCs themselves., PSCs can exhibit variability across different cell lines due to differences in reprogramming and culture methods, as well as donor-to-donor variation.The second product is the final cell therapy product, which involves layering a differentiated cell CMC onto the PSC CMC. The characteristics of the final cell products manufactured by different companies or institutions are likely to vary significantly.
“I believe that, in the near future, R&D efforts will likely focus on elucidating the mechanisms of action and enhancing the value potential of efficacy models for iPSC-derived cell therapies;”"and how to standardize the stability of processes for cell therapy products derived from PSCs is also an issue we should pay attention to."
Dr. Yan Pixi finally shared his views on the field of neurology“From a policy perspective, Japan, as the birthplace of iPSCs, classifies cell therapy as a regenerative medicine product and has achieved relatively advanced development based on established safety profiles. In contrast, the United States has established a comprehensive regulatory framework for cell therapy, which has accelerated the translation of its cellular drug ecosystem.”
“For Shize, neural differentiation is a key area of focus. Neural differentiation refers to the process by which iPSCs differentiate into various lineages or specific cell subpopulations. In terms of differentiation direction, neural research has a relatively long history, with substantial foundational accumulation in the early stages. Currently, representative entities in this field include BlueRock Therapeutics in the United States and Kyoto University in Japan. They generate specific neuronal cells through differentiation into particular neural cell types to treat Parkinson’s disease. However, these companies and institutions still need to publicly disclose data on safety and other aspects. At present, Shize Biologics is also gradually building its expertise in this area.”
“However, this industry faces numerous challenges amidst its rapid growth, such as downstream clinical translation and scaled-up manufacturing. The accumulation of late-stage clinical data may, to some extent, feed back into improving cell quality and optimizing cell processing technologies, thereby promoting industry development. Furthermore, addressing translational issues across the entire industry chain—including securing raw material and auxiliary supply chains and enhancing equipment automation—is essential to ensure the long-term, stable development of the stem cell therapy field.”
Although the United States and Japan are advancing more rapidly in the clinical development of induced pluripotent stem cells (iPSCs), the field globally remains in an early stage of research and development, with no clinically approved products yet on the market. Moreover, the current policy is not limited to iPSCs; it also has implications for other stem cell areas, including mesenchymal stem cells (MSCs).
In response, Dr. Wang Haotian, Vice President of Investment at Legend Capital, stated: “The MSC track is actually a sub-track within the stem cell sector. Traditionally, MSCs refer to a broad category of cells derived from mesodermal differentiation. These cells can originate not only from embryonic stem (ES) cells or induced pluripotent stem (iPSC) cells, but also from various human adult cells. The advantage of this cell type lies in its derivation from human adult cells, which makes the entire manufacturing process relatively easier.”
“In the past, we have observed promising therapeutic efficacy in MSC-based research across multiple fields, including osteoarthritis, ARDS, acute liver failure, and the mitigation of graft-versus-host disease. This has served as a positive and encouraging impetus for the current development of the iPSC field.”“In the future, we will continue to closely monitor the field of MSCs. Meanwhile, considering factors such as batch-to-batch stability, MSC products derived from iPSCs or ESCs are also a direction we view favorably.”
Although iPSCs have witnessed rapid development in recent years, with various policies being introduced and R&D initiatives launched across countries, they possess core distinctions within the broader field of cell therapy.
From the perspective of domestic development, Dr. Yan Pixi stated: “In fact, the genuine acceptance of iPSCs in China has only begun in recent years. However, given the high research threshold, complex manufacturing processes, and extended culture cycles associated with iPSCs, along with the extensive scope of work involved in the early stages of pharmaceutical development, the quality standards outlined in the currently issued guidelines represent merely baseline requirements. Further collective efforts across the industry are needed to enhance the overall pharmaceutical quality of iPSC-based products.”
Highlighting its differences from CAR-T and MSC therapies, Dr. Zhang Ying stated, “PSC involves the CMC development of two cell products, evaluation of pluripotency, development and validation of assays for residual components in the corresponding products, and assessment of genetic stability of the products.”, which differs from other cell therapies. However, the standards for microbial safety, endogenous and exogenous viral factors, and studies on cells in both drug product and bulk substance are consistent with those for other cell therapies.”
From the perspective of Fate, the current leader in iPSCs, Dr. Wang Haotian stated“Fate Therapeutics’ entry into clinical trials has, to some extent, ignited R&D enthusiasm in China’s iPSC sector. However, behind the glamour lies a long period of waiting and accumulation. Fate has been in operation for over a decade, and it was not until approximately ten years after its establishment that it obtained its first FDA approval.”Therefore, public optimism should be tempered with appropriate caution for two reasons:
“First, because all the clinical data currently presented by Fate represent the best therapeutic outcomes achieved after treatment.However, in real-world oncology patients, we need to observe whether they can maintain long-term efficacy, and we still need to wait for Fate to release more data in this regard.
“The second reason is that data from the Fate study indicate that disease progression may recur in some patients after achieving remission.This may be attributed to the short in vivo survival or activity duration of NK cells. When NK cells are derived from a single master cell line, certain immune rejection reactions may occur after infusion. Currently, relevant companies are working to address this issue, with measures including the establishment of iPSC super-donor banks or universal cell lines, aiming to reduce the immunogenicity associated with iPSCs.
Therefore, while iPSCs represent an exciting field, we should maintain a cautiously optimistic perspective and evaluate them comprehensively and rationally.
However, from the perspective of upstream consumables required for iPSC, MSC, and CAR cell therapies as well as other biopharmaceuticals (including single-use equipment, resins, bags, etc.), another wave of localization has emerged for comprehensive biopharmaceutical solutions.
“Although the stem cell industry currently appears to be developing more rapidly in Europe and the United States than in China, from a long-term perspective, the gap between China and Western countries in the entire stem cell field is not significant, especially when compared to the state of macromolecular antibody development a decade ago.“Accordingly, in terms of the localization of equipment and materials, the global upstream industry is still in its early stages, with the maturity of both equipment and materials remaining in a phase of refinement. We hope to see more efficient and mature technologies emerge in the future,” said Dr. Wang Haotian.
The entire industry is still in its early stages, and there are significant opportunities for domestically produced supplies to replace imported ones. Moreover, the development of domestic production is imperative for three reasons.
First, Dr. Zhang Ying stated: “In view of future industrial safety, regulatory audits of raw materials during the application process, and batch-to-batch consistency of products, domestically sourced materials can offer greater convenience.”
Dr. Yan Pixi added,“The newly released guidelines also impose stricter controls on raw material management, as evidenced by comprehensive evaluations covering supply chain audits, necessity of use, rationality, and safety. The tightening of upstream supply chain requirements has accelerated the high-quality development of domestically produced alternatives and enhanced the international competitiveness of China’s cell therapy sector.”
Secondly, the localization of upstream pharmaceutical supply chains can ensure that our future R&D will not face bottlenecks in raw materials.Particularly during the COVID-19 pandemic, many pharmaceutical companies faced critical bottlenecks in their upstream supply chains due to their reliance on imported equipment and consumables. This forced them to source materials from around the globe, incurring substantial labor and financial costs.
Finally, Dr. Wang Jiaxian stated, “In the early years following the market launch of cell therapy drugs, China’s cell therapy market will most likely be an out-of-pocket market.”"In the direct-to-consumer (C-end) market, patients naturally evaluate the cost-effectiveness of cell therapy. From the perspective of ultimate patient benefit, the localization of raw materials is the most effective way to reduce the cost and pricing of cell therapy, thereby benefiting more patients."
Overall, as domestic companies deepen their involvement in upstream materials and equipment, the batch production scale and capacity of China’s biopharmaceutical industry will continue to expand, thereby reducing batch-to-batch variability to some extent. The improvement in the quality of domestically produced consumables has also indirectly enhanced the international competitiveness of this sector, increasing the likelihood that China’s biopharmaceutical industry will achieve global integration from the product end.
We have gathered here in response to the guidelines recently issued by the Center for Drug Evaluation (CDE) to share insights and experiences for the development of this industry. However, these guidelines merely represent baseline requirements for the industry. Ultimately, the evaluation of iPSC products or cell therapy products as a whole hinges on their safety and efficacy, as well as the benefit-risk ratio of iPSC-based therapies built upon this foundation.
The next inflection point in China’s iPSC sector is highly likely to occur when the first domestically developed iPSC product officially receives approval for clinical trials in China. The second inflection point will likely emerge upon the release of definitive results from that product’s clinical trials.
In the future, the iPSC industry may face numerous challenges, yet these challenges also represent opportunities.