JesiGen's Zhang Jintao: Driving Original Drug Innovation through Cutting-Edge Translational Medicine Research

In May 2021, Amgen’s small-molecule KRAS G12C inhibitor AMG510 received FDA approval for marketing in the United States, becoming the world’s first targeted anticancer drug for the treatment of non-small cell lung cancer (NSCLC) with KRAS G12C mutations. This breakthrough shattered the four-decade-long “curse” of RAS being considered “undruggable,” ushering in a revolution in targeted therapy for this oncogenic driver.

RAS is a critical cancer driver gene, present in approximately 30% of tumors. RAS gene mutations ultimately lead to cellular carcinogenesis and promote cancer cell metastasis by activating downstream signaling pathways.

The MAPK (RAS-RAF-MEK-ERK) signaling pathway, initiated by RAS, is one of the classic signaling pathways in oncology. Mutations in this pathway are common in various types of solid tumors. For instance, KRAS (a member of the RAS gene family) mutations are frequently observed in pancreatic cancer (90%), colorectal cancer (30%-50%), lung cancer (25%-30%), ovarian cancer (15%-39%), and endometrial cancer (18%). In melanoma, NRAS (a member of the RAS gene family) mutations and BRAF V600 (a member of the RAF family) mutations can reach 20% and 50%, respectively.

Currently, several inhibitors targeting the MAPK signaling pathway have been approved for the treatment of melanoma, non-small cell lung cancer, thyroid cancer, and other malignancies, including the BRAF inhibitors vemurafenib and dabrafenib, as well as the MEK inhibitors trametinib and cobimetinib. However, the vast majority of patients with tumors associated with abnormalities in this signaling pathway still face very limited therapeutic options.

In the global oncology market, Jacobio focuses on precision therapies for tumors driven by the RAS/MAPK signaling pathway. By adopting a differentiated competitive strategy, the company has targeted multiple nodes both upstream and downstream of this pathway, building a comprehensive product pipeline with distinct competitive advantages. At the forefront of its pipeline is JSI-1187, an ERK kinase inhibitor targeting a high-potential downstream node of the signaling pathway. Additionally, from a complementary perspective, Jacobio is developing VIC-1911, an Aurora A kinase inhibitor that targets the cell cycle activation signaling pathway, aiming to overcome resistance to targeted therapies at various nodes within the RAS/MAPK signaling cascade.

Zhang Jintao, founder of ChemPartner, holds a Ph.D. from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and completed his postdoctoral training at the University of Chicago Pritzker School of Medicine. He was honored with China’s prestigious First Prize in Natural Science. Originally planning to return to China for further scientific research after his postdoctoral fellowship, Zhang chose to remain in the United States due to family considerations, marking a pivotal turn in his career toward the U.S. pharmaceutical industry. After seven years of experience in the U.S. biopharmaceutical outsourcing sector, he decisively returned to China and co-founded Medicilon, a well-known contract research organization (CRO).

Jiesingda’s multiple product pipelines are ranked among the top tier globally, with the potential to develop global leading First-in-class drugs. In December 2021, its Aurora A small-molecule oral inhibitor, VIC-1911 tablets, received approval from the National Medical Products Administration (NMPA) for Phase I clinical trials. The approved indication is combination therapy with paclitaxel for patients with advanced ovarian cancer, fallopian tube cancer, and primary peritoneal cancer, making it the first Aurora A selective inhibitor to enter clinical trials in China.

From CRO to Innovative Drugs

"I served as Department Director at MediChem for many years, where I managed projects and engaged in external business development with clients. Through this experience, I learned the importance of regulatory compliance and other critical considerations, all of which laid a solid foundation for establishing Medicilon."

In 2004, I returned to China to co-found Medicilon. At that time, a reporter from C&EN News interviewed me. I told him that I was starting a business in Shanghai and insisted that he include “Zhangjiang Hi-Tech Park” in the article. I explained to the reporter: “Shanghai is the Paris of the East, and Zhangjiang will become like Cambridge, Massachusetts.”

In those early years, much of the core area of Zhangjiang Hi-Tech Park was still under construction. During the initial startup phase, we had to personally oversee everything from laboratory setup to staff training. Even drivers required retraining: they were instructed not to run red lights, not to honk their horns, and not to cut into other lanes. When driving foreign guests to restaurants, we could only take the main roads through the Biyun International Community, avoiding Zhangjiang Road with its construction sites, so as to leave a favorable impression on our international visitors. To excel in the CRO (Contract Research Organization) industry, one needs strong industry connections and high-quality services, with particular attention paid to details.

In recent years, China’s innovative drug R&D has flourished, with Zhangjiang High-Tech Park and Suzhou Industrial Park having established new drug development ecosystems comparable to those in Cambridge, Massachusetts. The Chinese market is playing an increasingly important role on the international stage.

Jiuyou: Medicilon provides CRO services for new drug development, but you chose to develop innovative drugs in your second venture. What are the differences between the two? What is the entrepreneurial strategy of Jiesida?

Zhang Jintao:CRO and innovative drug R&D are two distinct business models. The CRO business follows the principle of “the more, the better”—more personnel and more clients are always preferable.Innovative drug R&D requires assembling a “special forces” team composed of elite professionals from various disciplines to complete phased tasks with high quality and speed.。

After leaving Medicilon, I founded Jaslin Pharma. Initially, we provided CRO services while exploring new drug development, essentially using the revenue generated from these services to fund our exploratory research, with the ultimate goal of developing original innovative drugs. The company established facilities including animal housing, cell culture rooms, bioanalysis laboratories, and synthesis laboratories, and assembled a mid-to-senior-level scientific research and management team with extensive practical experience.

Since 2017, Jiesi Yingda has focused on the R&D of innovative new drugs. After Dr. Li Qun joined the company, he led the team to independently develop multiple preclinical candidate drugs, including the ERK kinase inhibitor JSI-1187.

Meanwhile, we have established a U.S. clinical management team composed of industry veterans. Dr. Keizo Koya, General Manager of Jiesiyinda’s U.S. subsidiary, is a Japanese-American with extensive experience in new drug development and business development. Chief Medical Officer Tom Myers and Chief Development Officer Linda Paradiso both previously held executive positions at major U.S. pharmaceutical companies, having successfully developed and launched 6 and 11 new drugs, respectively. After two to three years of collaboration, we have achieved the integration of Chinese and foreign innovative cultures.

Jiesiyingda adopts a product development strategy of “rapid risk mitigation and progressive investment escalation.” It identifies the scientific rationale for clinical development initiatives by leveraging real-world data from clinical studies and the latest translational medicine literature, and conducts translational medicine research and proof-of-concept clinical trials (Phase II) through close collaboration with internationally renowned clinical experts.。

Achievements in the RAS/MAPK Signaling Pathway

Jiuyou: What is the product pipeline layout of Jiesingda? Which market does it primarily target?

Zhang Jintao:Jesitanda’s pipeline development Phase I focuses on precision oncology therapies targeting the RAS/MAPK signaling pathway. RAS is the most commonly mutated oncogene, with approximately 30% of cancers associated with its mutations. Other targets within the MAPK signaling pathway are also closely linked to tumorigenesis. Globally, an estimated 5.5 million new patients each year have conditions related to the RAS/MAPK pathway, and approximately 90% of these patients lack highly effective treatment options, indicating a substantial unmet clinical need.

For instance, RAS gene mutations are present in the vast majority of pancreatic cancers, as well as a significant proportion of colorectal, lung, and ovarian cancers. Currently, beyond conventional radiotherapy and chemotherapy, therapeutic options for patients are extremely limited; only Amgen’s AMG510 has been approved for marketing in the United States. This field represents a potential market worth over $10 billion.

Jiesheng Yinda’s first independently developed novel drug project is JSI-1187, an ERK kinase inhibitor. ERK kinase is a downstream target in the MAPK signaling pathway, and its efficacy and safety have been preliminarily validated in clinical settings.The targets in this signaling pathway exhibit high druggability, as evidenced by the successful treatment of BRAF-mutant melanoma with BRAF and MEK inhibitors, or KRAS G12C-mutant non-small cell lung cancer (NSCLC) with KRAS G12C inhibitors. Despite the success of combination therapy with BRAF and MEK inhibitors, clinical responses are typically short-lived, with many patients eventually developing resistance after approximately 9 to 11 months. A similar pattern has been observed in clinical studies of recently approved KRAS G12C inhibitors.

Among the several established mechanisms of acquired resistance following monotherapy or combination therapy (including BRAF amplification, NRAS or MEK mutations, receptor tyrosine kinase [RTK] activation, and upregulation of bypass or compensatory pathways), ERK reactivation is commonly observed. Therefore, in these patientsTreatment with ERK inhibitors offers the opportunity to avoid, delay, or overcome resistance to inhibition of upstream kinases in the pathway. Currently, Jisiyinda’s JSI-1187 is undergoing Phase I clinical trials in the United States and has already received clinical trial approval in China.

Jiesida has developed a pipeline of products targeting multiple nodes both upstream and downstream of the RAS/MAPK signaling pathway. For each target, multiple clinical trials are being conducted based on different mechanisms of action and for various indications, primarily including pancreatic cancer, colorectal cancer, gastric cancer, lung cancer, ovarian cancer, and melanoma.

VCBeat: Jiesiyingda’s Aurora A inhibitor is a star pipeline asset in the global first tier, but many previous Aurora products failed in clinical stages. Why introduce this product?

Zhang Jintao:VIC-1911, an Aurora A inhibitor, is a Phase I clinical product licensed by Vitrac Therapeutics LLC, the U.S. subsidiary of Jiesida.Jesse Bio typically considers the following factors when evaluating in-licensing opportunities: global rights, incorporation of the latest translational medicine research findings, and preferably products in the clinical development stage.

Kinases that regulate the cell cycle have long been a hot topic in oncology research. However, when we initially evaluated the Aurora A project, we held reservations about this target, as there were already more than 20 clinical candidates in the field, the majority of which faced development setbacks due to bone marrow suppression toxicity.

In May 2018, we observed that Eli Lilly and Company licensed a clinical Phase I Aurora A inhibitor product with an upfront payment of $110 million and a total deal value of $575 million, prompting us to begin tracking advancements in Aurora A research. In late 2018, Eli Lilly published a research paper on Aurora A, and in early 2019, a professor of clinical medicine at the University of California, San Francisco, published an article on translational medicine research related to Aurora A in Nature Medicine.With these two translational medicine studies, we rapidly initiated project acquisition and promptly established a clinical advisory team comprising the original discoverers of the translational research findings and the most authoritative clinicians in the field.Developed preclinical and clinical study protocols, and ultimately secured the project after arduous negotiations.

The most important reason for introducing Aurora is the emergence of new translational medicine research findings. Throughout this process, we have had the opportunity to learn from the world’s most authoritative clinicians, gaining insights into the latest developments and information in the forefront of clinical research—knowledge that cannot be obtained from published literature alone.

So far, weThe Aurora project has signed multiple translational medicine/preclinical research collaboration agreements with U.S. universities and research institutions, and has obtained one clinical trial approval each in the United States and China. In 2022, Jiesiyinda plans to initiate four Phase 1/2 clinical trials on Aurora A in China and the United States.。

To translateMedical Research-Driven

VCBeat: You have particularly emphasized the role of translational medicine research in innovative drug development. Why is that?

Zhang Jintao:In the process of new drug development, translational medicine is a continuous, bidirectional, and open research process that transforms basic research findings into practical therapeutic interventions for patients, embodying the concept of "from bench to bedside."In precision oncology, translational medicine enables the precise selection of patient populations, enhances the success rate of clinical development, and thereby significantly reduces healthcare insurance expenditures.

Taking KRAS G12C inhibitors as an example, in April 2019, Amgen presented the Phase I clinical data of AMG 510, the world’s first KRAS G12C inhibitor, at the AACR Annual Meeting, causing a sensation. However, by January 2020, Professor Lito from Memorial Sloan Kettering Cancer Center (MSKCC) published a translational medicine paper in Nature, pointing out that the therapeutic efficacy of KRAS G12C inhibitor monotherapy might be limited, as some cancer cells rapidly develop resistance under drug pressure. The primary approach to addressing this resistance is combination therapy with SHP2 inhibitors, EGFR inhibitors, and Aurora A inhibitors, among others.

It has also been demonstrated that AMG 510, approved for marketing in the United States in May 2021 for the treatment of non-small cell lung cancer (NSCLC), exhibited an overall response rate (ORR) of only 36% and a median duration of response (DoR) of approximately 10 months, indicating that its efficacy clearly requires improvement. It is therefore essential to conduct further translational medical research to enhance therapeutic outcomes by employing strategies such as simultaneous inhibition of multiple targets or combination therapy.

Jiuyou: What strategic initiatives has Jiesingda implemented in the field of translational medicine research?

Zhang Jintao:Under the leadership of its senior U.S.-based clinical management team, Jiesida has initially established a translational medicine research network composed of top-tier U.S. clinicians, signed more than ten collaborative agreements on translational medicine and preclinical research with leading U.S. universities and research institutions, and secured multiple opportunities for investigator-sponsored trials (ISTs).

After more than a year of dedicated efforts, the translational medical research projects at Jiesida are beginning to bear fruit. In October 2021, a research team from Yale University presented a study at the AACR Annual Meeting demonstrating that Aurora A inhibitors can overcome KRAS G12C resistance. This paper was selected as an Official News Program by AACR, garnering significant attention, and related clinical studies are scheduled to commence in the near future. The Phase 1/2 clinical trial (NCT05120570) of VIC-1911, an Aurora A inhibitor, for acute graft-versus-host disease (aGVHD) is expected to initiate in February 2022, with the University of Minnesota Cancer Center serving as the sponsor.

Jiuyou: Currently, innovative drug R&D in China is booming. Dozens of companies are working on each popular target, competing fiercely for clinical trial resources. How do you view this situation?

Zhang Jintao:China’s new drug sector has evolved from the arduous journey prior to 2016 to the U.S. listings of BeiGene and Zai Lab, as well as the Hong Kong Stock Exchange’s 2018 policy allowing pre-revenue biopharmaceutical companies to go public. A cohort of outstanding innovative drug R&D enterprises has emerged, achieving a leap from zero to one in novel drug development, while China’s pharmaceutical market is assuming an increasingly prominent role on the global stage.

A booming market and fierce competition are positive developments, as they will ultimately allow more outstanding companies to emerge. In my view, whether a new drug is Me-too, Best-in-class, or First-in-class, and regardless of whether it is independently developed or in-licensed, its origin is irrelevant. As long as it truly addresses unmet clinical needs, it is a good drug.

However, under the new landscape of global competition, it is foreseeable thatGoing forward, the first innovative drug to gain approval in China will inevitably be among the top-tier global innovative drug candidates.. Because the U.S. pharmaceutical market continues to hold a pivotal position within both national health insurance and commercial insurance systems for a considerable period, innovative drugs developed in any country are likely to incur losses if they fail to benefit from the U.S. market. ThereforeBuilding an innovative, internationally competitive R&D pipeline and developing novel drugs with superior performance compared to existing standards of care (not merely equivalent) will be the goal for most new drug development companies.