A Visit to a Dalton Venture Family Company | Heyuan Bio's Lulu Lyu: China's Homegrown CAR-T Therapy Is About to Become Reality, Bringing New Hope for Relapsed or Refractory Acute Lymphoblastic Leukemia Patients

The following article is from China Times, by Sun Mengyuan

Inside the Dalton Venture Family

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Immunotech Biopharm — a Dalton Venture Family company — has treated more than 100 Chinese patients with acute lymphoblastic leukemia in clinical studies of its first core product, CNCT19 injection. This represents the largest accumulated dataset to date on the clinical safety and efficacy of CD19 CAR-T in Chinese patients, with an overall response rate of 82.1%. CNCT19 is also the first CD19 CAR-T drug with fully independent intellectual property rights to file a new drug application in China, and is expected to gain approval for market launch within the year. Recently, Dr. Lulu Lyu, CEO of Immunotech Biopharm, sat down with a China Times reporter for an in-depth conversation.

"Under the strong leadership of the Party Central Committee, China's biopharmaceutical industry is moving onto a track of innovative development, and innovation has become the conscious pursuit of the industry," said Bi Jingquan, member of the Standing Committee of the 14th CPPCC National Committee, Vice Chairman of the Economic Affairs Committee, and Executive Vice Chairman of the China Center for International Economic Exchanges, at the first International Conference on Biotech Innovation and Investment.

In recent years, cell and gene therapy has gradually become an important direction for pharmaceutical industry development, representing a new generation of precision therapies following small-molecule and large-molecule targeted treatments. As this therapeutic approach has delivered impressive results, the clinical value of cell therapy has become increasingly apparent, addressing a wide range of previously unmet clinical needs.

According to Frost & Sullivan data, the global CAR-T cell therapy market will expand to $6.6 billion in 2024 and further grow to $21.8 billion by 2030. In China, driven by increasing cancer patient numbers, favorable policies, and improved patient affordability, the CAR-T market is projected to grow to 5.3 billion yuan in 2024 and 28.9 billion yuan by 2030.

2022 was a record-breaking year for global approvals of cell and gene therapies, with over 2,000 clinical trials currently underway worldwide in this field. Domestically, China approved two CAR-T cell injections for market launch in June and September 2021 respectively, with four additional CAR-T products under regulatory review. Taking Immunotech Biopharm as an example, its CAR-T therapy CNCT19 injection had its new drug application (NDA) accepted by the National Medical Products Administration in December and granted priority review, for the treatment of adult relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) — making it the first domestic CAR-T therapy for this indication.

"After nearly five years, Immunotech Biopharm's first core product, CNCT19 injection, has treated more than 100 Chinese patients with acute lymphoblastic leukemia in clinical studies. This represents the largest accumulated dataset to date on the clinical safety and efficacy of CD19 CAR-T in Chinese patients, with an overall response rate of 82.1%. Some patients have achieved sustained remission for over 24 months to date and remain in remission. CNCT19 is also the first CD19 CAR-T drug with fully independent intellectual property rights to file a new drug application in China, and is expected to gain approval for market launch within the year. Immunotech Biopharm is also steadily advancing clinical terminal certification work at top-tier hematology treatment hospitals nationwide, expecting to cover 50 hospital clinical terminals domestically by the end of 2023, with the hope of bringing more effective treatment options and long-term survival prospects to Chinese adult r/r B-ALL patients," said Dr. Lulu Lyu, CEO of Immunotech Biopharm.

China's First Original CD19 CAR-T Product Nears Market Reality

Leukemia is one of the most common blood cancers. Acute lymphoblastic leukemia (ALL) accounts for approximately 15% of all leukemias, with B-lymphocyte ALL (B-ALL) comprising about 75% of ALL cases. Adult B-ALL patients have significantly worse overall survival compared to pediatric B-ALL patients. Adult B-ALL has a high relapse rate after initial treatment, with approximately 60% of patients eventually progressing to r/r B-ALL. Adult r/r B-ALL patients have extremely poor prognoses, posing severe life-threatening risks, and effective clinical treatment options are lacking.

CAR-T therapy works by genetically engineering T cells to express chimeric antigen receptors (CARs) that can specifically recognize tumor antigens, creating CAR-T cells. CD19 is universally expressed on B lymphocytes, so CD19 CAR-T can effectively target B-cell tumors, with high complete remission rates and durable efficacy observed clinically.

Currently, only two CAR-T products have been approved globally for acute lymphoblastic leukemia: Kymriah for children and adolescents, and Tecartus for adult ALL. CNCT19 injection is China's first and the world's second CAR-T product for treating adult acute lymphoblastic leukemia, filling a gap in the domestic cell therapy landscape for this disease.

Her background as a hematologist has always driven Dr. Lyu to bring more treatment options and hope to patients in China and globally. In 2018, Dr. Lyu left a multinational pharmaceutical company, bringing with her experience successfully introducing drugs like Gleevec to the Chinese market and a passionate commitment to delivering innovative treatments to clinicians and patients. She co-founded Immunotech Biopharm, positioned in the cell and gene therapy (CGT) direction, and serves as its CEO. After nearly five years of dedicated effort, Immunotech Biopharm's first core product, CNCT19 injection, has emerged, offering a ray of hope for adult r/r B-ALL patients.

At the 64th American Society of Hematology (ASH) Annual Meeting held in December 2022, Immunotech Biopharm disclosed pivotal clinical data for CNCT19 in treating Chinese adult r/r B-ALL patients, generating strong industry attention. The data for adult r/r B-ALL showed that CNCT19 demonstrated durable high response rates and significantly reduced severity of CAR-T treatment-related toxicity, with an overall response rate (ORR) as high as 82.1%. Among patients who remained in remission at 3 months, an estimated 80% were projected to remain in sustained remission at 1 year. The durable high response rate and safety profile significantly outperformed existing treatment options, representing a major breakthrough in treating adult r/r B-ALL. "Whether or not patients subsequently undergo hematopoietic stem cell transplantation, they can demonstrate sustained remission and long-term survival benefits," Dr. Lyu emphasized.

Supported by this compelling data, CNCT19 injection stands out among existing therapies for adult r/r B-ALL with superior efficacy and safety, giving Immunotech Biopharm competitive confidence. "We believe this is a major breakthrough in the treatment of adult r/r B-ALL," Dr. Lyu said.

Earlier, CNCT19 injection was granted Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of the National Medical Products Administration, and received Orphan Drug Designation (ODD) from the FDA.

In December 2022, the NDA for CNCT19 injection in treating adult r/r B-ALL was formally accepted by the CDE and granted priority review.

In March 2023, the clinical trial application for CNCT19 injection was approved by the FDA for the treatment of adult relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).

A Frost & Sullivan research report noted that CNCT19 injection, despite being a later entrant, has moved ahead to become the first to enter and complete pivotal registration clinical studies domestically. As the first CAR-T drug to file an NDA in China's leukemia field, it is expected to bring breakthrough treatment options to domestic leukemia patient populations and provide new, effective treatment choices for the broad r/r B-ALL patient base. Meanwhile, given that no other company's CAR-T drug for this same indication has entered pivotal clinical study stages, CNCT19 is projected to enjoy a substantial period of market exclusivity after launch.

Building on its first NDA application for adult r/r B-ALL, Immunotech Biopharm is targeting the clinically urgent pediatric patient population, with registration clinical studies for children and adolescents with r/r B-ALL approved in August 2022.

Treatment positioning is also a direction worth exploring. For greater commercial value and broader patient benefit, innovative products will inevitably move from last-line to earlier-line treatment. Immunotech Biopharm is currently conducting trial designs for front-line CAR-T treatment. "In the future, early-stage patients may even be able to receive CAR-T treatment in day wards," Dr. Lyu envisioned.

Since its founding, Immunotech Biopharm has established a strategic partnership with the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences — currently China's largest national-level research-oriented hematology specialty institution integrating medical care, scientific research, teaching, and industry. The two parties have formed complementary advantages, supporting each other in technological innovation, talent development, clinical resources, innovative drug R&D, manufacturing, and clinical application, jointly leading and accelerating the industrialization of China's independently innovated immune cell therapy and gene therapy technologies. Meanwhile, the pivotal clinical study of CNCT19 in treating adult r/r B-ALL was conducted at 10 top-tier hematology clinical centers nationwide, accumulating rich clinical practice experience and laying a solid foundation for the commercial clinical application of CNCT19. It is reported that Immunotech Biopharm began hospital certification training for CNCT19 in early 2023, and has completed certification training at multiple core tertiary hospitals including the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences; Henan Cancer Hospital (Affiliated Cancer Hospital of Zhengzhou University); Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; and Nanfang Hospital, Southern Medical University. By the end of 2023, certification is expected to be completed for 50 domestic hospital-based treatment centers, covering all of China's top hematology treatment hospitals, making thorough preparations for bringing the product to patients upon market launch.

On another front, as an autologous product, CAR-T product quality control and non-clinical research are of significant importance for ensuring patient medication safety and efficacy, while also presenting considerable challenges and difficulties. To address this, Immunotech Biopharm has gradually built a full-process medical quality control system covering both hospital and enterprise ends, establishing standardized Centers of Excellence (COE) equipped with unique traceability codes to achieve full-process traceability from drug manufacturing to application.

Immunotech Biopharm has built a GMP-compliant intelligent commercial manufacturing base in Tianjin High-Tech Zone, achieving 100% success rate in cell manufacturing during the ALL indication clinical trial phase. In June 2021, it received Tianjin's first Drug Manufacturing License for immune cell therapy drugs, with capacity to meet annual medication needs for approximately 2,000 patients upon full capacity utilization. Dr. Lyu stated that as commercialization progresses and indications expand, Immunotech Biopharm is also planning a second commercial manufacturing base to meet the medication needs of more patients.

"We hope that with the launch of CNCT19 injection, physicians and patients will have more effective treatment options. As the first fully independently developed CD19 CAR-T product in China, we will also work to drive innovation in payment systems and improve CAR-T drug accessibility, allowing this innovative therapy to benefit more patients," Dr. Lyu said.

Pipeline Expansion Hits "Acceleration Mode"

As the first product to emerge from Immunotech Biopharm, obtaining the marketing approval for CNCT19 is only the first step toward commercialization.

In Immunotech Biopharm's planning, the continued expansion of a pipeline covering more clinically urgent, independently innovated products is currently a greater focus for Dr. Lyu.

Relying on an independent innovation model, Immunotech Biopharm currently has three technology platforms based on CAR, gene editing, and iPSCs, actively building a highly expandable, internationally competitive innovative pipeline with forward-looking strategic layout covering hematological tumors, solid tumors, and non-tumor diseases such as autoimmune conditions, encompassing over 10 pipeline products including innovative single-target and multi-target products and universal cell therapy products.

On April 18, 2023, according to the CDE website, Immunotech Biopharm's dual-target CAR-T cell therapy product (HY004 cell injection) received clinical trial approval for two indications: treatment of adult relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) and treatment of relapsed or refractory B-cell non-Hodgkin lymphoma (r/r B-NHL).

HY004 cell injection is a dual-target (CD22/CD19) CAR-T with a uniquely designed LOOP CAR structure. Preclinical in vitro and in vivo studies have shown that Loop 22×19 CAR-T has stronger proliferation and tumor-killing effects compared to CAR-T with other structures. Dr. Lyu stated that HY004 cell injection is another innovative CAR-T cell therapy product entering registration clinical studies at Immunotech Biopharm, marking another important milestone in the platform-based output of the company's innovation technology-driven pipeline products.

At the 2022 ASH Annual Meeting in December, HY004 cell injection was presented as an oral report (Structural Optimization of Dual-Target CD22/CD19 CAR-T and Its Anti-Tumor Effects on B Cell Malignancies, Abstract #255), demonstrating data on the structural optimization of CD22/CD19 dual-target CAR-T, its anti-B-cell malignancy effects, and early IIT clinical study data. The data showed that HY004 cell injection demonstrated stronger proliferation and anti-leukemia effects compared to CAR-T with other structures. In early investigator-initiated clinical studies, 6 r/r B-ALL patients received CAR-T cell infusion, with an ORR of 100%. All 6 patients achieved MRD-negative remission, with no severe CRS (≥Grade 3) or ICANS of any grade observed within 3 months.

"The commercial success of core products, forward-looking layout of innovation platforms and R&D pipelines are crucial for Immunotech Biopharm's sustainable development. The imminent successful launch of our first core product demonstrates the company's core capabilities in drug development pathways and rapid commercialization. On this 'highway,' Immunotech will continue to drive expansion from autologous products to universal platforms, continue to deepen its presence in hematological tumors, while using more innovative products to break through into solid tumor and non-tumor disease treatment areas," Dr. Lyu said.

China's Original CAR-T "Dream Team"

Independent innovation has never been a smooth road, and innovative drug development faces even greater difficulties. Dr. Lyu once compared immune cell therapy drug development to venturing into "uncharted territory" — during this period, there was no experience to draw upon, and the team could only feel its way forward. Dr. Lyu and her Immunotech Biopharm team persevered.

From physician to pharmaceutical R&D professional to entrepreneur, her professional roles have undergone several transformations, but Dr. Lyu's original aspiration as a pharmaceutical professional has not changed — adhering to a "patients first" principle, firmly believing that immune cells, this "living drug," will become a primary means of treating tumors and many other diseases in the future.

Drawing on her previous work experience and following a complete drug development pathway, Dr. Lyu has built a team whose knowledge structure and experience cover the full process from early R&D, medical and clinical development, CMC process development, clinical studies, drug registration, to commercialization. It is with the support and dedication of this dream team that Immunotech Biopharm has been "in full glory from birth," consistently traveling on the fast track of development.

Along the way, Dr. Lyu has experienced role transitions from clinical physician to pharmaceutical R&D professional to entrepreneur. "As a clinical physician, every day you face life and death; innovative drug development is similarly a matter of life and death. Although each stage's position differs, the ultimate direction of the work is always the patient — all to meet patients' clinical needs and give them higher quality of life. This is my original aspiration, and also the motivation that supports me to keep going," Lyu said.

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