On October 18, the FDA announced the approval of the Claudin18.2 monoclonal antibody Vyloy (zolbetuximab) for marketing, and will use it as the first-line treatment for adult patients with locally advanced unresectable or metastatic gastric cancer with Claudin18.2-positive tumors, and HER2-negative gastroesophageal junction adenocarcinoma. With the announcement of this good news, zolbetuximab officially became the first anti-Claudin18.2 drug approved by the United States. This means that Astellas has taken the lead in this hot target. In the past few years, Claudin18.2 has been a hot target in the field of oncology, attracting the interest of giants such as AstraZeneca, Merck, and Moderna. Of course, the entrants also include many domestic pharmaceutical companies. However, in the face of many entrants, Astellas's "defending" ability has also been extremely demanding. At present, it may not be easy for it to maintain its leading position.

Zolbetuximab has always attracted much attention, and the core reason is the particularity of the Claudin18.2 target. It seems that the Claudin18.2 target has the potential to become a blockbuster target. On the one hand, this is because the clinical needs of the cancers targeted by the Claudin18.2 target are far from being met. Studies have shown that Claudin18.2 is positive in tumor cells of 70%-80% of gastric cancer patients and 60% of pancreatic cancer patients. In other words, the presence of Claudin18.2 protein can be detected on the surface of most gastric cancer and pancreatic cancer tumor cells. Whether it is gastric cancer or pancreatic cancer, the effective demand for its treatment is very urgent. Pancreatic cancer, in particular, is called the "king of cancer" because of its high mortality rate, so the Claudin18.2 target is highly expected. On the other hand, the drug logic of the Claudin18.2 target is relatively clear. Under normal circumstances, Claudin18.2 is only expressed on the surface of differentiated epithelial cells of the gastric mucosa. However, after the occurrence of malignant tumors, tight junction proteins are destroyed, exposing the Claudin18.2 epitope on the surface of tumor cells, making it less likely to harm normal cells.

What is even more valuable is that even in the advanced metastatic stage of cancer patients expressing Claudin18.2 protein, tumor cells in other parts of the body still highly express Claudin18.2 protein. This means that Claudin18.2 protein can be targeted with precision, and potential side effects are safe and controllable. The performance of zolbetuximab is already comparable to that of Herceptin. The FDA's approval of zolbetuximab is based on the positive results of two phase 3 trials called SPOTLIGHT and GLOW. The SPOTLIGHT trial showed that the median progression-free survival (PFS) of the zolbetuximab combination treatment group was 10.6 months, and that of the control group was 8.7 months; the median overall survival (OS) was 18.2 months, and that of the control group was 15.5 months.

In the GLOW study, the median OS of the zolbetuximab treatment group was 14.4 months, and that of the control group was 12.2 months. Herceptin is the first monoclonal antibody therapy approved for HER2-positive metastatic gastric cancer or gastroesophageal junction (GEJ) cancer, with a reduced risk of death of 23%, a median overall survival of 13.5 months versus 11.0 months, and a 2.5-month extension of patient survival compared with the placebo group. At least, the current anti-tumor activity of zolbetuximab in gastric cancer is close to the HER2 target, which makes the future of Claudin18.2 look brighter. Therefore, it is not surprising that zolbetuximab has been approved by the FDA. With its official approval, expectations for the Claudin18.2 target are bound to continue to heat up.

The future of the Claudin18.2 target is not a solo for Astellas. Although it was the first to cross the finish line, zolbetuximab has certain limitations. An excellent Claudin18.2 monoclonal antibody needs to have the ability to efficiently bind to tumor cells and recruit effector cells. The limitation of Zolbetuximab is that its molecule has a weak affinity, which limits its combat effectiveness. Therefore, it can only limit its "combat" range to patients with high expression of Claudin18.2 (≥75%).

Even for patients with high expression, it does not mean that the therapeutic effect of zolbetuximab is the upper limit; and for patients with low expression, other players have a greater chance. Among all solid tumors, patients with high expression of Claudin18.2 account for only 33%-37%. In the field of gastric cancer, which has the largest patient population, the proportion of high-expression patients is only about 20%. Therefore, zolbetuximab leaves a lot of room for latecomers to break through. At present, many domestic pharmaceutical companies, including Chuangsheng Group and Innovent Biologics, are hunting for Claudin18.2 targets in a comprehensive way from monoclonal antibodies, bispecific antibodies, ADCs, and CAR-T therapies. Among them, some molecules represented by Chuangsheng Group's Osemitamab have great competitive potential. Obviously, in this field, domestic pharmaceutical companies are expected to write a new order in the future.

Of course, for some early molecules, whether they can break through may require further observation. For example, the overseas clinical data of EO-3021 of Shijiazhuang Pharmaceutical Group has declined sharply. In domestic clinical trials, the data released by Shijiazhuang Pharmaceutical Group showed that the ADC molecule EO-3021 not only has good efficacy, but also has no specific requirements for the Claudin18.2 expression level of the enrolled patients. However, according to the data released by the overseas importer Elevation, not only the clinical efficacy has dropped significantly, but the safety is also more serious, causing Elevation's stock price to suffer a heavy blow. There are great opportunities in the competition for the Claudin18.2 target, but it also requires domestic pharmaceutical companies to do better.

The breakthrough of the Claudin18.2 target is not limited to efficacy. CMC is also a topic that pharmaceutical companies need to be vigilant about. The so-called CMC, the full name is Chemical Manufacturing and Control, including production process, impurity research, quality research and stability research, that is, the pharmaceutical research part. Zolbetuximab, which did not fall in the clinical stage, encountered obstacles in the industrialization stage. On January 9 this year, Astellas announced that due to unresolved defects in third-party production plants, zolbetuximab could not be approved for marketing before the PDUFA date of January 12. Compared with the clinical stage, CMC problems are relatively easy to solve. After encountering problems, Astellas worked closely with the FDA and third-party manufacturers to develop a timetable to quickly resolve feedback issues. It is for this reason that Astellas ushered in a belated victory.

However, even so, the time for zolbetuximab to obtain FDA approval was still delayed by 9 months. For a field with many competitors, this is still not good news. At the same time, pharmaceutical companies also need to make efforts in companion diagnostic tools. Patients must confirm that their tumors are Claudin18.2 positive through testing. For this reason, the FDA also approved new companion diagnostic products from Ventana Medical Systems and Roche. For domestic companies, there is also a need for a forward-looking layout in the development of companion diagnostic antibodies. Of course, some domestic companies have not ignored the details in this regard. For example, the companion diagnostic antibody developed by Transcenta and Agilent announced the early positive research results of Claudin18.2 IHC 14G11 pharmDx reagent at this year's AACR annual meeting. At present, the development work supporting registration clinical trials has been basically completed, and the GMP companion diagnostic kit can be used for patient screening. In general, the breakthrough of the Claudin18.2 target is a problem of both need and need. We look forward to more domestic pharmaceutical companies bringing good news in the future.

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