The world's first approval in China, the domestic drug "encirclement" war is about to start!

On the last day of 2024, the heavyweight drug Zutuximab under Anstai (ALPMY.US) was officially approved for listing in China. This is the world's first and currently the only approved CLDN18.2 targeted drug: in October 2024, Zutuximab was first approved by the FDA, and then successfully launched in Europe, Japan, and other major markets. As a hot target for gastric cancer drug development globally after HER2, the competition for CLDN18.2 is fierce. According to Insight database, apart from the approved Zutuximab, there are more than 70 drugs in active development globally. Among them, domestic drugs hold absolute dominance, with nearly 90% of the 70 drugs being domestically produced, and the 7 CLDN18.2 targeted drugs currently in Phase III clinical trials are all developed by domestic companies. However, with Zutuximab being the first to be approved globally, the original competitive landscape has been disrupted, and domestic drugs with "group advantages" have begun to catch up. For example, Kozi Pharmaceutical, with its independently developed targeted CLDN18.2 autologous CAR-T therapy - Shurikioransai injection, recently made a significant breakthrough in the Phase II clinical trial of gastric cancer in China, with a disease control rate (DCR) as high as 91.8%; INNOVENT BIO has also made significant progress recently, with its CLDN18.2 antibody IBI343 entering Phase III in clinical trials in Japan, potentially becoming the world's first CLDN18.2 ADC new drug. In addition, Mingji FG-M108, Beijing Aosaikang Pharmaceutical ASKB589, Hengrui SHR-A1904, Conidia CMG901, and other CLDN18.2 targeted drugs have also made significant breakthroughs recently. It can be said that domestic drugs are currently accelerating and attempting to become the first approved domestic drug on the CLDN18.2 target, in order to break the market dominance of Anstai. The "Immortal" target, with continuous high-value BD deals From the market response, CLDN-18.2 is currently the most focused target in the Claudin family, mainly because of its high expression in multiple tumors such as gastric cancer, pancreatic cancer, esophageal cancer, and lung cancer. It is reported that under normal circumstances, CLDN-18.2 is lowly expressed in the differentiated epithelial cells of the gastric mucosa, mainly serving to connect between cells. When CLDN-18.2 is activated, it can damage the cell membrane function, increase tissue permeability, and open the "convenient door" for tumor metastasis, indicating tumor proliferation, differentiation, invasion, and metastasis. According to research findings, CLDN-18.2 can be expressed in gastric cancer up to 60%-80%, making it a dark horse in the field of gastric cancer treatment. This has also been positively rewarded in terms of BD. For example, the first approved drug Zutuximab was acquired by Anstai for a whopping $1.4 billion from Ganymed Pharmaceuticals in 2016. In recent years, domestic drugs have also begun to participate frequently. In May 2022, Turning Point acquired part of the developmental and commercialization rights of LM-302 from Lixinyi Medicine for a total price exceeding $1 billion; in July 2022, Colombo signed a cooperation and exclusive licensing agreement with Merck & Co., Inc. for SKB315, with a total transaction value exceeding $900 million; in February 2023, Conidia and Leap announced a total price of over $1.1 billion for the authorization of CMG901 to Astrazeneca PLC Sponsored ADR; in October 2023, Jiangsu Hengrui Pharmaceuticals announced an exclusive licensing agreement with Merck for its independently developed SHR-A1904, with a potential transaction value of up to 1.4 billion. According to incomplete statistics from Arteries, in the past 2 years, there have been over 25 BD partnerships in the CLDN-18.2 target, involving a total amount of nearly $15 billion, and top MNCs have all increased their investments. Being able to "cash in" in such a harsh environment, there are certainly reasons for this. The first point is the market, as CLDN-18.2 mainly targets gastric cancer, which is difficult to detect in the early stages, coupled with a very low five-year survival rate, resulting in a huge demand for drugs. According to Frost & Sullivan, the global gastric cancer drug market is estimated to have grown to $22.1 billion in 2024 and is expected to reach $36.4 billion by 2030. The huge potential market undoubtedly provides more choices for pharmaceutical companies in urgent need of finding growth points. Secondly, in terms of crucial efficacy, in recent years, targets such as HER2, PD-L1, MET, and FGFR-2 have all made efforts, creating many possibilities for gastric cancer treatment. As a new target, CLDN-18.2 is also not to be underestimated, and several heavyweight drugs have shown breakthrough performance in clinical trials. Taking INNOVENT BIO's IBI343 as an example, it was officially included in the breakthrough therapy category by the CDE recently, which is a definite affirmation of its efficacy. In June 2024, Innovent orally announced clinical data for IBI343 in the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC), with an overall objective response rate of 32.3% and a disease control rate of 75.8%. Additionally, Hengrui's SHR-A1904, according to its latest data, has objective response and disease control rates of 55.6% and 88.9%, respectively, in the treatment of G/GEJ AC. The last point is market competition, as there is currently only one approved drug for the CLDN-18.2 target, making the market landscape very open, with plenty of opportunities for "latecomers". Who will secure the first approved domestic drug? In fact, as domestic drugs continue to make efforts, a question arises: who will be the first to secure the domestically approved drug?Also increasingly loud, who will be the first to cross the finish line and become the first domestically produced drug approved for the CLDN18.2 target?Figure 3. Clinical Phase III Targeted Therapies for 7 CLDN18.2 (Data Source: Public Information) As of now, the 7 targeted therapies that have progressed to Phase III clinical trials clearly have a better chance, including 3 monoclonal antibody drugs (Mingji FG-M108, Beijing Aosaikang Pharmaceutical ASKB589, Chuangsheng Osemitamab) and 4 ADC drugs (Lixin TPX-4589, Hengrui SHR-A1904, Connoa CMG901, Synda IBI343). It is reported that on the CLDN18.2 target, various forms such as monoclonal antibodies, bispecific antibodies, ADCs, and CAR-T are flourishing, but in terms of clinical performance and quantity, the status of monoclonal antibodies remains unshakeable. For example, the first monoclonal antibody drug to come out, Ontruzant, belongs to monoantibody. Similarly, domestic monoclonal antibody drugs are also progressing rapidly, with 3 monoclonal antibody drugs all starting Phase III clinical trials in September-October 2023, which is clearly earlier than the 4 ADC drugs also in Phase III. This is mainly due to their structural characteristics, as monoclonal antibodies are antibodies produced by a single B cell clone, coupled with their mature technological route and lower development costs, hence they progress faster in clinical trials. In addition, monoclonal antibodies also have a say in crucial efficacy data, with disease control rates of over 80% in the treatment of late-stage gastric or gastroesophageal junction adenocarcinoma with monoclonal antibodies targeting CLDN18.2 that have been publicly disclosed. As a result, apart from Mingji, Beijing Aosaikang Pharmaceutical, and Chuangsheng, leading pharmaceutical companies like Stone Medicine, Junshi, Qilu, and Zendong also have high hopes of obtaining the first domestic batch. Figure 4. Clinical Progress of Representative CLDN18.2 ADC Drugs (Data Source: Insight) Apart from monoclonal antibodies, ADCs are next in line. In terms of drug mechanism, ADCs can be considered as a combination of monoclonal antibodies and chemotherapy, with the only difference being the chemotherapy drugs used. However, ADC drugs may be superior in mechanism and composition compared to combinations of monoclonal antibodies with chemotherapy. For example, the CLDN18.2 ADC drug CMG901 developed jointly by Connoa and Lepu consists of CLDN18.2 monoclonal antibody, cleavable linker, and cytotoxic small molecule monomethyl auristatin E (MMAE), and based on clinical data, it has shown an objective response rate of 75% in the treatment of late-stage gastric or gastroesophageal junction adenocarcinoma, with excellent performance. Additionally, in terms of safety, because ADCs use antibodies as "navigators" to precisely deliver chemotherapy drugs to tumor cells, they can reduce the harm to normal cells and make the treatment process more gentle and effective. This has also been validated in Synda IBI343, where in a non-head-to-head comparison, the incidence of gastrointestinal adverse events, hypoalbuminemia, and discontinuation due to adverse events were all lower, making it a strong competitor as the world's first commercially launched CLDN18.2 ADC. Continuing to focus on CAR-T, this is also worth paying attention to. According to the Insight database, there are as many as 21 CLDN18.2 ADCs in development worldwide, but most are concentrated in Phase I and Phase II. Among them, the fastest progress has been made by Koji CT041, which announced preliminary clinical efficacy data as early as 2021, showing an overall response rate of 61.1% in GC/GEJ patients who have high CLDN18.2 expression, which can rival some ADC drugs. However, as research progresses, the downsides of CAR-T therapy are beginning to show gradually. On the one hand, this is reflected in a slight decrease in key clinical data; on the other hand, it relates to the cost and affordability of CAR-T therapy, where the high cost and development expenses of CAR-T therapy are in stark contrast to the current domestic payment environment and the economic capacity of patients. Finally, bispecific antibodies should be mentioned. In fact, under the market structure of monoclonal antibodies in front, ADCs following, and CAR-T beside, bispecific antibodies targeting CLDN18.2 have not received much attention. The main reason for this is that their clinical development is relatively lagging, and based on the clinical data of CLDN18.2 bispecific antibody drugs that have been publicly disclosed, there is no particularly noteworthy aspect. However, this is still an undeniable force in the future, mainly because it can exert anti-tumor effects through multiple mechanisms, and also has significant advantages in safety. It is not difficult to see that the existing CLDN18.2 targeted drugs have their pros and cons, and as to who will take the lead, there is no standard answer at present, but the key criteria are gradually becoming clear. In this regard, a senior executive told Artery Network, "An ideal CLDN18.2 targeted drug should have two key characteristics - one is high safety, which depends on the selectivity of the molecule. If the selectivity is insufficient, it is easy to mistakenly bind with CLDN18.1, affecting the therapeutic effect of the drug and causing significant side effects to the human body; the other is high affinity. In most cases, the higher the affinity, the stronger the drug's expression ability, and the corresponding anti-tumor efficacy will be more apparent". Of course, the pace of clinical progress and selection are equally important. 03 Pearls in front, Commercialization to the left or to the right? Currently, CLDN18.2 primarily targets gastric cancer, which is a huge potential market with a market size already exceeding billions of dollars and still growing rapidly. However, in this disease area, HER2 has already achieved commercialization, with representative drugs including Roche's trastuzumab, Merck & Co., Inc.'s pertuzumab, Hengrui's apatinib, and REMEGEN's vedotinib. Figure 5. Market size of CLDN18.2 Antibodies for Different Indications in China and the United States (Source: Zheshang) Among these, Roche's trastuzumab has shown the most dominant performance, with sales of 1.244 billion Swiss francs in the first three quarters of 2024, a year-on-year growth of 58%, and occupying a leading position in the global market. The standout performance domestically is the self-developed drug apatinib by Hengrui, which achieved remarkable results in 2023.The sales of the ball exceeded 10 billion, reaching 10.8 billion.Therefore, with the gems in front, CLDN18.2 wants to catch up from behind, it needs to demonstrate more solid strength while also learning to take a different path. The first point is to accelerate the approval speed and speed up the listing process to seize the market's first-mover advantage. This is particularly important, as a senior investor emphasized, "Because the disease area of CLDN18.2 is far less extensive than PD-1, latecomers will not have a diverse selection of indications, so winning in speed is important, and using it to seize the market's initiative." Secondly, it is important to expand into more indications as much as possible to break away from a single market dependency. It is reported that besides being highly expressed in gastric cancer, CLDN18.2 can also be highly expressed in various other tumors such as pancreatic cancer, esophageal cancer, and lung cancer, presenting potential opportunities for CLDN18.2-targeted drugs. Taking IBI343 as an example, in June 2024, IBI343 officially received FDA fast track designation (FTD), intended for late-stage pancreatic ductal adenocarcinoma patients who have tested positive for CLDN18.2 expression, and have already undergone at least one systemic therapy. Lastly, it is crucial to seize more opportunities for monetization, including but not limited to going overseas, business development, mergers, and acquisitions. In the current market environment, innovative drugs are also seeking more opportunities for monetization, and in the past year or two, going overseas, business development, and other methods have been highly praised, with many successful cases. CLDN18.2-targeted drugs can also follow suit, for example, in the case of going overseas, IBI343 has taken the lead, with clinical trials in Japan currently in Phase III, and nearing market approval. In terms of business development, aside from existing cases, there are many large-scale collaborations in the pipeline, mainly focusing on Phase II targeted drugs, all of which are expected to materialize in the first half of this year. In light of this, a senior professional remarked, "As the market tightens overall, the competition for innovative drugs is not only about technology and clinical performance, but the ability to monetize is equally important, especially for emerging targets like CLDN18.2, where commercialization capabilities are particularly emphasized. Therefore, seizing all means of monetization to timely obtain cash flow, and investing it into the development of more indications, is evidently the more ideal choice." In fact, with the widespread approval of pembrolizumab globally, CLDN18.2, which has been in a long competition in terms of drug modality and speed, is rapidly shifting towards the commercial competition of clinical value. In this battle that has already begun, many domestically produced innovative drugs are launching fierce attacks against pembrolizumab, inevitably challenging the current dominant position of AstraZeneca. This article is a repost from the WeChat public account "" (Artery Network), written by Mou Lei; GMTEight editor: Liu Xuan.