Despite First Claudin18.2 Drug Rejection by FDA, the Target Remains a Promising Frontier in GI Cancers
Astellas
Pharmaceutical R&D Manufacturer
However, so far, no Claudin18.2 product has been approved for marketing globally. The arrival of the first Claudin18.2 product has been highly anticipated. Among many candidate drugs worldwide, Zolbetuximab was the fastest in development. Unfortunately, after more than half a year of waiting, Zolbetuximab recently received disappointing news of rejection by the FDA, which raises doubts: Is Claudin18 still worth expecting?
Claudin18.2 Rejected by FDA
Zolbetuximab was originally developed by Ganymed, a subsidiary of Astellas, as a Claudin18.2 monoclonal antibody. Preclinical studies have shown that Zolbetuximab induces cancer cell death by activating two different immune system pathways (antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity).
At the 2016 ASCO, Zolbetuximab made a stunning debut and became the biggest highlight of the conference with its excellent clinical data. Soon after, Zolbetuximab, which was in Phase II clinical trials at the time, caught the attention of the keen-eyed Astellas, which spent $1.4 billion to acquire Ganymed and bring Zolbetuximab under its wing.
In the hands of Astellas, the development of Zolbetuximab has proceeded smoothly. In November and December 2022, Astellas successively announced the experimental data from two pivotal Phase III clinical trials of Zolbetuximab, SPOTLIGHT and GLOW. The results showed that its combination with standard chemotherapy could extend the survival period of patients with advanced gastric cancer or gastroesophageal junction cancer expressing CLDN18.2, offering inspiring clinical data.
Based on excellent data, the FDA granted Zolbetuximab priority review for first-line treatment of patients with unresectable, locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) cancer in July 2023, with a target action date set for January 12, 2024.
The recent FDA rejection came as a surprise to Astellas, which was quite confident, and also caught many people off guard. This is because the SPOTLIGHT and GLOW studies, on which Zolbetuximab's marketing application was based, not only successfully validated the druggability of Claudin18.2 but also showed no issues regarding safety or efficacy. According to the response letter received by Astellas, the FDA did not raise any concerns about Zolbetuximab’s clinical data, nor did it request additional clinical trials. The FDA merely pointed out unresolved deficiencies at the third-party manufacturing facility responsible for producing Zolbetuximab.
For Zolbetuximab, this is considered a significant positive development despite the rejection. Astellas stated that these manufacturing deficiencies do not pose any safety or efficacy data risks. They are currently working closely with the FDA and third-party manufacturers to resolve the issue as soon as possible.
In addition, except for the United States, Astellas has successively submitted the marketing application for Zolbetuximab in China, Japan, and Europe, and Zolbetuximab remains highly anticipated.
Potential Targets for Gastrointestinal Cancer
After the occurrence of malignant tumors, tight junction proteins are disrupted, exposing the Claudin18.2 epitope on the surface of tumor cells and making it a specific target. Meanwhile, the Claudin18.2 gene also exhibits abnormal activation, with highly selective and stable expression in specific tumor tissues.
Schematic Diagram of Claudin Protein Structure
Source: Cancer-Free Home
Claudin18.2 was initially found to be consistently and stably highly expressed in various gastric cancer tissues. Later, it was also discovered to be abnormally activated and overexpressed in multiple primary malignant tumors, such as breast cancer, colorectal cancer, liver cancer, head and neck cancer, bronchial cancer, and non-small cell lung cancer, particularly in digestive system malignancies, including gastric cancer (70%), pancreatic cancer (50%), and esophageal cancer (30%). Moreover, its expression is not limited to the primary tumor site but is also present in metastatic lesions. This high selectivity makes Claudin18.2 an ideal therapeutic target for cancers such as gastric and pancreatic cancer.
According to a Frost & Sullivan report, the global gastric cancer drug market size is expected to reach $30.3 billion by 2025 and $46 billion by 2023, indicating a huge market demand. Due to the lack of typical symptoms in the early stages of gastric cancer, it is difficult for patients to detect it on their own. Once diagnosed, more than 70% of gastric cancer patients are already in the advanced stage, losing the opportunity for surgery. Moreover, the overall prognosis for gastric cancer is poor, with a 5-year survival rate of only 10%-30%, making the treatment situation severe.
In addition, in 2022, the global number of pancreatic cancer cases reached approximately 512,000. It is projected to increase to 542,000 by 2024 and further rise to 639,000 by 2030. By 2030, the mortality rate of pancreatic cancer worldwide will rank second. Pancreatic cancer has proven difficult to treat with conventional drugs and has developed a certain resistance to early immunotherapy. This is partly due to the thick fibrous crown surrounding the tumor, which inhibits the entry of therapeutic drugs and immune cells into the tumor. More effective treatment methods are still needed in this field.
Currently, there are no biologics available globally for pancreatic cancer, and existing immunotherapies such as PD-(L)1 still lack high-quality evidence-based medical proof in treating pancreatic cancer. However, Claudin 18.2 exhibits high expression characteristics in pancreatic cancer, offering hope to potentially break the current treatment pattern for pancreatic cancer in the future.
When it comes to currently marketed tumor-targeted drugs, the HER2 target is unavoidable. To this day, because HER2 targets major cancer types and represents an ideal druggable target, it remains a core focus for pharmaceutical companies. Research has found that HER2 gene abnormalities occur in many diseases, with HER2 overexpression observed in approximately 20% of breast cancers and about 22.1% of gastric cancers. It has been proven that HER2-targeted drugs are highly favored upon market entry, especially Daiichi Sankyo's Enhertu, which has repeatedly created sales miracles since its launch.
The high expression positivity rate of Claudin18.2 in gastric cancer patients exceeds that of HER2, making it highly likely to be the second most important target in tumors, especially gastric and pancreatic cancer, after HER2.
China is a country with a high incidence of gastrointestinal cancers. The tremendous potential of Claudin18.2 in the treatment of gastrointestinal cancers has led to active investment by Chinese pharmaceutical companies in the research and development of Claudin18.2-targeted drugs. Currently, both the number of pipelines and technological approaches are at the forefront globally.
According to statistics from the PharmaCube Nextpharma database, there are nearly 50 Claudin18.2-targeted drugs in clinical development globally, with 42 of them originating from Chinese pharmaceutical companies. In China, the Claudin18.2 target has attracted numerous players, and the competing technological approaches are diverse, including monoclonal antibodies, CAR-T, ADCs, and bispecific antibodies.
Clinically Investigated CLDN18.2-Targeted Drugs Produced in China
Source: PharmaCube
In terms of clinical progress, six Claudin18.2-targeted drugs with disclosed early clinical results come from CARsgen Therapeutics, Transcenta Holding, Tian Guang Shi, and QureBio. Transcenta Holding's Osemitamab has completed a Phase I study; CARsgen Therapeutics' CT041 has completed three Phase I studies and one Phase I/II study; Tian Guang Shi's MIL93 has completed a Phase I study; QureBio's Q-1802 has completed a Phase I study.
As Claudin18.2 sees a flourishing of multiple technological approaches in China, in recent years, the international market has turned its attention to domestically developed Claudin18.2 products. Chinese companies have been actively licensing out their Claudin18.2-targeted innovations. Starting from 2022, the pace of Claudin18.2's expansion overseas has accelerated, with four deals completed in 2022 alone, amounting to a total of $3.481 billion.
Summary of Claudin18.2 Export Status in China Over the Past Two Years
Source: Public data compilation
From the perspective of the Claudin18.2 technology route going overseas, ADCs are undoubtedly more favored. After 2022, there have been five licensing deals for Claudin18.2 in China, four of which focus on Claudin18.2 ADC. It is reported that there are eight Claudin18.2 ADCs approved to enter clinical trials, and four of them have successfully gone overseas.
AstraZeneca, MSD and other multinational giants have also taken actions to introduce the potential Claudin18.2 pipeline from China. Especially AstraZeneca has shown higher activity, successively deploying the Claudin18.2 target through different technical routes such as bispecific antibodies and ADCs twice. In 2023, AstraZeneca again spent $1.188 billion to purchase CMG901 from Akeso and Lepu Biopharma, once again pushing the overseas development of Claudin18.2 to a climax.
Although Zolbetuximab has been temporarily rejected by the FDA, Claudin 18.2 remains a highly promising target with a bright future ahead!
References:
1. "Introduction to Popular Tumor Targets - Claudin18.2" Beijing Cancer Medical College
2. "Chinese-produced CLDN 18.2 New Drugs Rush to Expand Overseas" PharmaCube