Frost & Sullivan releases the 'Blue Book on the Current State and Future Development of the Induced Pluripotent Stem Cell (iPSC) Industry' (with full text available for download)

Induced pluripotent stem cells (iPSC) refer to a type of multipotent stem cell that has characteristics similar to human embryonic stem cells, developed through artificial reprogramming of somatic cells and reverse differentiation culture. iPSC have the potential for multi-directional differentiation and strong self-replication, and under certain conditions, they can differentiate into various functional cells. They can also be cultured in vitro to obtain millions or even billions of clinically relevant phenotype cells such as cardiomyocytes, neurons, and pancreatic islet cells. iPSC have broad application prospects in multiple fields including clinical treatment, drug research and development, and medical aesthetics.

iPSC is similar to human embryonic stem cells, capable of infinite replication in vitro and suitable for large-scale culture; iPSC can be induced to differentiate into desired cell lines according to needs, with relatively stable characteristics between batches, avoiding inconsistencies in clinical efficacy; iPSC can originate from the patient's own body, thus reducing the issue of immune rejection; since the source of iPSC cells is adult cells, ethical issues are avoided.

As an emerging technology, iPSC's industrial application is still in its early stages. However, iPSC has been used clinically for various applications, mainly involving disease research, drug screening, and cell therapy.

Source: Public information, analysis by Frost & Sullivan

The 'Blue Book' details the definition, technical advantages, development history, and application fields of iPSCs. For more detailed content, please refer to the full report.

The preparation of iPSC mainly involves four main steps: somatic cell isolation and culture, mediated vector construction, induction factor introduction and cell culture, and iPSC screening and identification. The preparation of iPSC is affected by various factors, among which the selection of somatic cells, the choice and optimization of mediators and vectors, iPSC cell culture, iPSC screening and identification, and reprogramming efficiency are all key factors for successful preparation.

The Blue Book details the key factors for iPSC preparation. For more detailed content, please refer to the full report.

In OSKM, Oct3/4, Sox2, and Klf4 are positive regulators of stem cell pluripotency genes, while they also inhibit the expression of genes that promote differentiation. The fourth factor, c-Myc, has been shown to be unnecessary for reprogramming, but its addition can significantly improve reprogramming efficiency. During reprogramming, the c-Myc transcription factor affects cell proliferation but does not affect pluripotency. The c-Myc transcription factor acts before activating pluripotency regulators, by downregulating cell recognition genes and promoting cellular metabolism into a pluripotent state.

The combination of NANOG and LIN28 can also co-ordinate with Oct3/4 and Sox2 to complete the induction process. Oct4, Sox2, and NANOG are located at the central nodes of the regulatory network that maintains stem cell self-renewal and pluripotency. They form a transcriptional regulatory complex that achieves transcriptional regulation of a large number of target genes and their own coding genes through feedforward and autoregulatory networks.

With the in-depth study of iPSC reprogramming, more transcription factors have been discovered, and the reprogramming process has been continuously optimized. GLIS1, cyclin D1, and TP53 can replace c-Myc in function, solving the potential tumorigenic issues associated with c-Myc; NR5A2 can replace Oct3/4 in function, improving reprogramming efficiency; SALL4 and Sox2 work together to regulate Oct3/4 transcriptional activity, thereby significantly enhancing reprogramming efficiency. In addition, miRNAs or genes that control miRNA synthesis [miR-302, miR-372, and Lin28] and epigenetic modifiers [Suv39h, Wrd5, and Jhdm1a] can also effectively reprogram cells.

Currently, iPSC reprogramming methods can be divided into integrated reprogramming techniques (such as lentiviruses and retroviruses) and non-integrated reprogramming techniques (free vectors, Sendai virus, mRNA, miRNA, proteins, other small molecules, etc.) based on whether transcription factors are integrated into the cell genome. Different reprogramming techniques have their own characteristics in terms of reprogramming efficiency, material preparation, delivery process, and safety due to the different technical routes used.

Source: Public information, analysis by Frost & Sullivan

There are numerous iPSC reprogramming methods, each with differences in reprogramming efficiency, technical difficulty, and genomic integration. In clinical applications, the appropriate reprogramming method should be selected based on the purpose of iPSC research, the efficiency and safety of different technologies.

Source: Literature review and analysis by Frost & Sullivan

IPSC still faces technical bottlenecks in terms of differentiation efficiency, tumorigenicity, immunogenicity, and heterogeneity, which urgently need to be overcome.

New technologies such as gene editing and machine learning are being rapidly applied in the field of iPSC.

The 'Blue Book' details the preparation process and key factors of iPSC, transcription factor screening and analysis, reprogramming methods and comparisons, analysis of technical bottlenecks in iPSC, and the application of new technologies in iPSC. For more detailed content, please refer to the full report.

The Center for Biologics Evaluation and Research (CBER), a division of the US FDA, has newly established an Office of Therapeutic Products (OTP) to optimize the review and approval process for stem cell therapy products, forming a relatively complete regulatory system consisting of laws, regulations, management systems, and guidelines.

The Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) is responsible for the approval of clinical trials, marketing applications, classification and certification of therapeutic products for stem cell products. Its main legal basis is the Medicinal Products Directive (2001/83/EC) and ATMP Medical Products Regulation (Regulation(EC) No 1394/2007), which are approved according to a centralized review procedure.

From 2013 to 2014, Japan successively introduced the 'Regenerative Medicine Promotion Law' and the 'Regenerative Medicine Safety Law', serving as the legal basis for the development of stem cell products. It also revised the 'Drug, Medical Device and Other Products Law', classifying and registering new drugs and medical technologies related to stem cell products for supervision by the Drug Administration (Comprehensive Agency for Pharmaceuticals, Medical Devices and Other Products) and the Health and Welfare Administration (Ministry of Health, Labour and Welfare), respectively, accelerating the clinical research and market approval speed of regenerative medicine products in the country.

China started basic research and clinical trials in cell therapy relatively early, with clinical studies dating back to the 1990s. However, at that time, regulatory policies and laws related to cell therapy were relatively lagging behind. There were no detailed requirements or regulations for the specific content of multiple aspects of research and development, resulting in weak constraints.

In 2015, the state began to strengthen safety research and clinical standard management of cell therapy, introducing a series of regulatory policies from drug research and development to clinical application, including the 'Administrative Measures for Stem Cell Clinical Trial Research Bases (Trial)', 'Administrative Measures for Stem Cell Clinical Research (Trial)', 'Technical Guidelines for Clinical Trials of Human-derived Stem Cells and Their Derived Cell Therapeutic Products (Draft for Soliciting Opinions)', etc. These reflect the state's emphasis on the development of stem cell therapy technology, aiming to promote the healthy development of the industry by enhancing the supervision of stem cell products.

Source: National Health Commission, NMPA, CDE, Frost & Sullivan analysis

The 'Blue Book' details the regulatory situation and related policies of the United States, the European Union, Japan, and China regarding iPSC. For more detailed content, please refer to the full report.

Several companies around the world already have iPSC product pipelines, but most of their products are in preclinical research stages. Among them, Cynata Therapeutics' CYP-004 is the first iPSC-derived product globally to enter phase III clinical trials, and another product, CYP-001, has entered phase II clinical trials. Chinese company Aier Pharma's product has entered phase I/II clinical trials, Heartseed's product has entered phase I/II clinical trials, and both Fate Therapeutics and BlueRock Therapeutics have products entering phase I clinical trials.

According to the search results of the ClinicalTrials database, as of the end of March 2023, there were 137 clinical trials related to iPSC (by registration number). Since 2015, the number of clinical trials related to iPSC has significantly increased, reaching a peak in 2018 and then declining. By 2022, the number of clinical trials increased again to 15. Since 2023, 6 clinical trials related to iPSC have been registered.

Source: Clinical Trials, Frost & Sullivan analysis

According to incomplete statistics, as of the end of March 2023, there were 11 ongoing clinical trials or implied clinical trial approvals for iPSC pipelines globally. Among them, there was 1 phase III clinical trial, 1 phase II clinical trial, 3 phase I/II clinical trials, 4 phase I clinical trials, and 2 implied clinical trial approvals. The indications involve diseases such as arthritis, graft-versus-host disease, heart failure, multiple myeloma, lymphoma, respiratory failure, Parkinson's disease, etc.

According to public data, globally and in China, iPSC treatment products under development mainly focus on tumors, Parkinson's disease, ophthalmic diseases, heart failure, type 1 diabetes, bone/joint diseases, etc. Among them, bone/joint diseases, heart failure, graft-versus-host disease, hemangioma, and Parkinson's disease have entered the clinical trial phase. In the future, as research continues to deepen, the coverage of indications will continue to expand.

According to public data, the main types of iPSC treatment products under research globally and in China include CAR-iNK, dopamine-responsive neurons, CAR-iMac, i-MSC, cardiomyocytes, other neurons, CAR-iT, pancreatic islet cells, etc. Among them, CAR-iNK-derived cells are the most numerous, accounting for 27%. The types of iPSC-derived cells that have entered clinical trials include i-MSC, cardiomyocytes, CAR-iNK, CAR-iT, and dopamine-responsive neurons.

The 'Blue Book' details the global layout of companies in the iPSC field, clinical research progress, indications for ongoing pipelines, and technical routes. For more detailed content, please refer to the full report.

Hematological malignancies mainly include non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). IARC data shows that in 2021, there were approximately 556,000 new cases and 181,000 deaths globally, respectively.

Non-Hodgkin lymphoma includes a variety of lymphomas, among which diffuse large B-cell lymphoma and follicular lymphoma are the most common. NCCR data shows that in China, the number of new patients with non-Hodgkin lymphoma and multiple myeloma in 2021 was about 95,000 and 22,000 respectively, showing a rapidly growing trend. Age, immunodeficiency, and viral infections are the main risk factors.

Source: IARC, NCCR, Frost & Sullivan analysis

Currently, the main iPSC hematological malignancy treatment products entering clinical research are Fate Therapeutics' FT-576 and FT-819.

The 'Blue Book' sorts out the current diagnosis and treatment status of hematological malignancies, as well as unmet clinical needs. It also provides information on ongoing products for iPSC-based treatment of hematological malignancies. For more detailed content, please refer to the full report.

Age-related macular degeneration (AMD) is a structural aging disease of the retina's macular area, which damages the central part responsible for specific vision. It can lead to the appearance of dark spots, shadows, or distorted central vision. As the disease progresses, central vision gradually declines, eventually leading to blindness. AMD is divided into wet and dry types, with risk factors including age, family history, smoking, cardiovascular disease, Omega-3 fatty acid deficiency, etc.

According to the 'World report on vision' released by the WHO in 2019, the global number of AMD patients is 196 million, among which 5.3% are suffering from moderate or severe hyperopia or blindness. The analysis results from 'The current status and thirty-year change trend of eye disease burden in China' published in the Journal of Zhejiang University (Medical Sciences) show that in 2019, the DALY caused by AMD in China was approximately 100,000.

Source: Literature search, Frost & Sullivan analysis

In 2014, a team led by Professor Masayo Takahashi from the RIKEN Center for Developmental Biology in Japan successfully implanted retinal pigment epithelial cells derived from patient autologous iPSCs into the right eye of a 77-year-old female patient, completing the first clinical trial of iPSCs.

The 'Blue Book' sorts out the current diagnosis and treatment status of age-related macular degeneration (AMD) and unmet clinical needs, as well as the research products for iPSC treatment of AMD. For more detailed content, please refer to the full report.

Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder characterized mainly by the loss of dopaminergic neurons in the substantia nigra and the deposition of synaptic nuclear proteins. It predominantly affects the elderly population and tends to worsen with age, severely impacting the quality of life of patients. GBD data shows that in 2019, there were 8.51 million people worldwide suffering from Parkinson's disease, including 2.85 million in China. The global number of new cases was 1.08 million, with 300,000 in China.

Parkinson's disease has an insidious onset, with resting tremors as the initial symptom. Symptoms such as muscle rigidity and bradykinesia may occur. As the disease progresses, symptoms like unsteady gait, postural instability, and sleep disorders may appear. In the late stages, patients may develop dementia symptoms. Autosomal mutations are a major cause of Parkinson's disease, and 10% of patients have a family history of the disease.

Source: GBD, analysis by Frost & Sullivan

BlueRock Therapeutics' investigational iPSC product BRT-DA01 for the treatment of Parkinson's disease has entered Phase I clinical trials.

The 'Blue Book' sorts out the current diagnosis and treatment status of Parkinson's disease, as well as unmet clinical needs. It also provides information on ongoing research products for iPSC treatment of Parkinson's disease. For more detailed content, please refer to the full report.

Heart failure (HF), commonly referred to as heart disease, is a syndrome caused by various reasons leading to abnormal cardiac structure and/or function, which impairs the systolic and/or diastolic functions of the ventricles. Heart failure is divided into left ventricular failure and right ventricular failure. Left ventricular failure can cause shortness of breath and fatigue, while right ventricular failure leads to peripheral tissue and abdominal edema. Both the left and right ventricles can be affected alone or simultaneously, mainly manifested as dyspnea, fatigue, and fluid retention. Cardiac and systemic causes can lead to heart failure, such as coronary heart disease, hypertension, abnormal cardiac structure, arrhythmia, high metabolic demands, etc. Primary myocardial damage and abnormalities are the main causes of heart failure. At the same time, infection, myocardial ischemia, and exertion are the three major triggers of heart failure attacks.

A study published in the journal 'European Journal of Preventive Cardiology' shows that the number of heart failure patients globally has risen rapidly from 33.5 million in 1990 to 64.3 million in 2017. A study published in the journal 'Eur J Heart Fail' estimates that the number of heart failure patients aged 35 and above in China has reached 13.7 million. In the future, with the deepening aging of China's population, the number of heart failure patients will continue to increase.

HiCM-188 is an 'off-the-shelf' cell therapy product developed by Elp Regenerative Medicine, indicated for the treatment of severe chronic ischemic heart failure.

The 'Blue Book' sorts out the current diagnosis and treatment status of heart failure, unmet clinical needs, and the research products for iPSC therapy in treating heart failure. For more detailed content, please refer to the full report.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is a clinical syndrome in which donor lymphocytes attack the recipient's organs during the process of immune reconstruction. It is one of the main complications after transplantation, with an incidence rate of 30% to 70%.

Acute GVHD, chronic GVHD, and overlapping syndromes with both acute and chronic GVHD characteristics are distinguished. Acute GVHD usually occurs within 100 days after transplantation or presents as persistent, recurrent, or delayed symptoms after 100 days post-transplantation. Target organs affected include the skin, liver, and digestive tract. Chronic GVHD is similar to autoimmune diseases and may appear (progressively) after an acute episode, or start after a period of remission (asymptomatic or intermittent) of the acute disease, or recur. Clinical manifestations are variable and can involve any one or more organs throughout the body, with the longest-affected organs being the skin, hair, nails, oral cavity, liver, eyes, gastrointestinal tract, genitals, joint fascia, or bone joints.

In 2016, Cynata Therapeutics initiated the world's first clinical trial of a allogeneic gene iPSC product, CYP-001, for the treatment of graft-versus-host disease (aGVHD), which was completed in 2018.

The 'Blue Book' sorts out the current diagnosis and treatment status of graft-versus-host disease, as well as unmet clinical needs. It also provides information on ongoing research products for iPSC treatment of graft-versus-host disease. For more detailed content, please refer to the full report.

The driving forces of the iPSC market include unmet clinical needs, development of emerging technologies, policy encouragement and promotion, and favor from capital markets.

The future development trends of iPSC include continuous expansion of application areas, the possibility of 'universal' cell therapies, improvement in iPSC safety and persistence, and accelerated industrialization of iPSC.

The 'Blue Book' summarizes and presents the market drivers and future development trends of iPSCs. For more detailed content, please refer to the full report.

The Blue Book details financing events of global iPSC-related companies, as well as global industry collaborations for joint development, acquisitions, and mergers. For more detailed content, please refer to the full report.

• Alpro Regenerative Medicine

Elp Regenerative Medicine was founded in 2016 and is a global leader in the development of innovative regenerative therapies for aging-related refractory diseases. As a builder of an iPS cell model library for refractory diseases in China, the company has developed a multi-system intelligent platform called Help Cell-foundry. To enable humans to live healthily to 120 years old, the company is continuously developing safe, effective, quality-controlled, and affordable innovative treatment products for aging-related refractory diseases such as cardiovascular systems.

• Aike Biotechnology

Aikai Biotechnology was established in 2021 and is a leading biotech company. Starting from induced pluripotent stem cells (iPSC), it is committed to empowering cell therapy with cutting-edge technologies such as iPSC, gene editing, and stem cell differentiation. The company adheres to the development philosophy of 'patient-centered, clinically driven', and is dedicated to innovating in tumor immunotherapy and regenerative medicine, providing patients with universal, effective, and affordable cell therapy drugs.

• Shize Biology

Shizex Bio was founded full-time by Dr. Li Xiang after his return from abroad. The company is dedicated to providing large-scale, low-cost stem cell treatment options for major diseases such as Parkinson's disease, which currently lack substantial clinical solutions. "To provide the world with unparalleled stem cell innovation drugs and bring relief to thousands of suffering families" is Dr. Li Xiang's long-term vision for founding Shizex Bio.

• Xingyinang Biology

Xingyinang (Shanghai) Biotechnology Co., Ltd. was established in June 2021 at the Shanghai Free Trade Zone Life Science Industrial Park. Led by a management team with rich industrialization experience in the cell therapy industry, it focuses on the research, development, and industrialization of iPSC-CAR-NK immune cell drugs. By combining independent innovation with the introduction of advanced technologies and products from globally leading companies and institutions, its goal is to develop and industrialize innovative immune cell drugs for general use, ready for mass production, and capable of treating solid tumors.

• Xueji Biology

Xueji Biotechnology is a stem cell biotechnology company founded by returnees from overseas, dedicated to the directed regeneration of hematopoietic lineage cells through stem cells for cellular therapy of various diseases and the development of related drugs. Based on a globally leading stem cell directed induction differentiation system, Xueji Biotechnology uses ex vivo produced platelets as its leading product to address the urgent need for platelets in cancer, liver disease, critical illnesses, blood disorders, and other diseases, as well as to develop innovative drugs for various platelet abnormalities, cancer, and related diseases.

• Zehui Biology

Beijing Zephyrm Biotechnology Co., Ltd. was established in 2018 and is a leading biopharmaceutical company in China focusing on the research, development, and production of multi-energy stem cell (ESC and iPSC) drugs. Zephyrm Biotechnology has a complete R&D experience and technical team for innovative drugs, has obtained multiple clinical approval documents for indications, and has won several corporate honors and qualification certifications. Adhering to the belief of "Promise for the Future, Trust in Life, Lead the Industry, Contribute to Society," it focuses on clinical value and is committed to solving clinical needs that traditional biopharmaceuticals and chemical drugs cannot address.

• Zhongyuan Union Medical College

Zhongyuan UnionTech Cell Gene Engineering Co., Ltd. takes 'Precision Medicine' as its core vision, focusing on three major sub-sectors: 'Precision Prevention', 'Precision Diagnosis', and 'Precision Treatment'. Its main business covers cell detection preparation and storage, research, production, and sales of in vitro diagnostic raw materials, reagents, and instruments, scientific research reagent products such as biological genes, proteins, and antibodies, gene detection services, and the R&D of clinical applications for stem cells and immune cells, etc., constituting the 'Precision Medicine' industrial chain. The company possesses advanced cell technology and a national cell resource storage network, and is one of the important bases in China for the research, development, and transformation of cell technology products.

• Angpu Biology

Angpu Biotech is a high-tech enterprise with gene detection technology and iPSC technology as its core capabilities. The company focuses on the genetic diagnosis, clinical research, and transformation of genetic diseases. It owns a third-party medical laboratory (CNAS/CAP quality system) and provides iPSC establishment and differentiation services. Based on the gene detection platform, it can provide clinical diagnostic services for more than 2,500 subtypes of genetic diseases, including neurological genetic diseases, hereditary eye diseases, endocrine and metabolic genetic diseases, cardiovascular genetic diseases, etc., accumulating extensive experience in the field of genetic disease gene detection and transformation research. At the same time, it can provide services for gene detection and efficacy evaluation for enterprises, including editing efficiency, off-target efficiency detection services, delivery vector quality control detection, genomic stability detection, cell quality inspection, and other related services. In terms of iPSC, it can provide iPS cell establishment services, differentiation services of iPSC cells from different cell types, disease modeling, mechanism research, and drug screening services.

• Hode Biology

Zhejiang Huode Biotechnology Co., Ltd. was established in January 2017 and is a global biotechnology company that innovates and focuses on developing iPSC-derived universal cell therapy products. Huode Biotech has leading global patents and innovative technologies in iPSC reprogramming, pluripotent stem cell neural differentiation, and various cell engineering applications. It has established a CMC platform for iPSC cell products, an all-suspension automated production process, and multiple innovative analysis methods. Huode Biotech has established GMP iPSC cell lines suitable for domestic and international authorization and production, and owns several ongoing research projects (including neural cells, ophthalmic cells, pancreatic islet cells, etc.). Among them, the first human prefrontal neural precursor cell hNPC01 is currently the fastest-developing similar iPSC cell product internationally, addressing unmet clinical needs such as stroke and sequelae of craniocerebral injury.

• Qifang Biology

Qihang Biotech was established in Hangzhou, China in 2017. It is a biotechnology company that applies high-throughput gene editing technology to the fields of cell therapy and organ transplantation. Qihang Biotech hopes to develop immune-compatible allogeneic cells and xenograft therapies using its high-throughput gene editing technology and profound understanding of immunological transplantation knowledge, bringing hope to millions of patients and their families around the world.

• Ruijian Medicine

Ruijian Medicine, as an innovative platform Biotech focusing on the new generation of chemical-induced cell therapies, applies 'AI + chemistry induction' to the precise modification of cellular functions. A combination of a few types of small chemical molecules can achieve efficient transformation of cells on an industrial scale. Through a modular and flexible integration across multiple platforms, Ruijian Medicine has created an innovative R&D model centered around a core data platform, featuring multi-drug forms, multiple pipelines, and multiple drivers. The most core aspect is the multi-dimensional integrated database of 'compound-protein targets-tissue development-disease treatment,' which is significant for revealing key molecules and targets in human developmental maps and clarifying disease treatment mechanisms.

• Ruizhen Regenerative Medicine

Guangzhou Ruizhen Regenerative Medicine Technology Co., Ltd. is committed to developing general-purpose ready-to-use cell therapy products derived from induced pluripotent stem cells (iPSCs) for the treatment of tumors and neurological diseases. The company has established a technology portfolio that includes iPSC reprogramming and library construction, differentiation and preparation of immune and neural cells, as well as gene modification to construct engineered iPS cell lines, covering the entire process of iPSC cell therapy.

• Saiyuan Biology

Saiyuan Biotechnology (Hangzhou) Co., Ltd. was established in 2018, dedicated to the engineering modification of iPSCs into CARs and their differentiation into natural immune cells such as CAR-iMac for research and clinical translation. The company combines single-cell sequencing, gene regulatory networks, and other tools to alter the iPSC differentiation process from a developmental biology perspective, improving differentiation efficiency. It also uses CRISPR gene editing and synthetic biology techniques to obtain engineered modified immune cells derived from iPSCs, with several core patents having been authorized internationally and domestically.

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