Claudin 18.2 Target High Point Battle, a contest of strength and strategy

According to incomplete statistics, there are currently more than 50 Claudin18.2 targeted drugs in China in the research and development stage; the target is not only a large number of entrants, but also a variety of technical routes participating in the competition, including monoclonal antibody, dual antibody, ADC and CAR-T.

Quietly, domestic pharmaceutical companies have dominated the research and development field of Claudin 18.2 targeted drugs. While reflecting the improvement of innovation strength, the Claudin 18.2 target also reflects the responsibility of domestic pharmaceutical companies.

Innovative drug research and development has always been a lifetime of death, especially the Claudin 18.2 target. Before November this year, no Claudin18.2 targeted drug in the world had gone through phase 3 clinical trials.

In other words, the druggability of the target has not been confirmed. Many domestic pharmaceutical companies entering the market may face a situation of no return.

Fortunately, the question of whether the Claudin 18.2 target "can be a drug" has finally been answered.

On November 17, the Japanese pharmaceutical company Astellas announced the success of the first phase III clinical trial of its Claudin18.2 antibody IMAB362:

For patients with Claudin18.2-positive/HER2-negative recurrent metastatic gastric cancer, the IMAB362 chemotherapy combination not only achieved the primary endpoint of progression-free survival, but also the secondary endpoint of overall survival.

Astellas, which took the lead in breaking out of the encirclement, completely dispelled the market's doubts about whether the Claudin 18.2 target can be drugged, and also announced that the efforts of domestic pharmaceutical companies will not be in vain.

It is worth noting that the future of Claudin18.2 targets is likely to belong to domestic pharmaceutical companies. Because the IMAB362 molecule is defective, although it won the FIC crown, it is difficult to resist the impact of latecomers.

So, which domestic pharmaceutical company can win in the future?

 01 

Seeded players

Although Claudin 18.2 targets are designed for targeted drug development, it is not easy to develop a successful Claudin 18.2 targeted drug. A major obstacle facing pharmaceutical companies is the selectivity of targeted drugs.

Because Claudin 18.2's "sibling" Claudin 18.1 is abundantly expressed in the extracellular domain, and it is only 8 amino acids different from Claudin 18.2.

This leads to the fact that once the selective nature of targeted drugs for Claudin18.2 is not enough, it is easy to mistakenly combine with Claudin18.1, which affects the effect of drug treatment and brings a strong risk of side effects to the human body.

After all, Claudin18.1, unlike Claudin18.2, is widely distributed in normal cells of the human body, in addition to being expressed on tumor cells.

From this point of view, among the many pharmaceutical companies that have entered the research and development of Claudin 18.2 targeted drugs in China, the seed players who are expected to stand out roughly need to meet two conditions:

First, it has highly selective molecular research and development capabilities, proving that its future is possible; The second is to have at least convincing clinical data verification, without enough data, the problem will not be exposed.

At present, the only seeded players who meet the two benchmarks are Transcenta Group and Keji Pharmaceutical.

Transcenta's TST001 is a monoclonal antibody that, through a unique epitope design, binds only to Claudin18.2 and not to Claudin18.1.

Since TST001 is the second most advanced Claudin18.2 targeted drug in the world, the safety and efficacy data have been fully verified.

At the 2022 ESMO Conference, Transcenta announced the interim data of TST001 combined with CAPOX as a first-line treatment for advanced or metastatic gastric cancer and gastroesophageal junction cancer:

According to the RECIST1.1 standard, the disease control rate of 15 patients with measurable lesions was as high as 100%, and 73.3% of patients showed partial tumor remission.

According to the RECIST1.1 criterion, a partial response is defined as "the sum of tumor lesion diameters that are at least 30% less than baseline." This is a key indicator in the efficacy evaluation criteria for solid tumors, indicating that patients have a positive response to treatment. Therefore, the 73.3% response rate in the interim data represents a larger number of patients who are likely to achieve survival benefits from treatment.

While achieving higher response rates, the TST001 is also extremely secure:

More than 80% of the adverse events (whether causal or not) in the treatment were mild grade 1-2, and mainly controllable reactions such as nausea, vomiting, and anemia, and did not lead to discontinuation of the drug.

These data undoubtedly show that TST001 has the ability to become a seeded player.

CARsgen Pharmaceutical's CT-041 is a CAR-T therapy. CT-041 is composed of CAR genetically modified T cells fused with humanized anti-Claudin 18.2 single-stranded fragment variants, which has the potential to effectively target and eliminate tumor cells expressing Claudin 18.2 on the cell surface.

At present, CT-041 has been studied in confirmatory phase II. clinical trials for advanced gastric cancer/esophageal-gastric junction adenocarcinoma. If the follow-up clinical data is excellent, CT-041 will also become a potential dark horse.

In addition, a number of players, including Innovent Biologics, are also moving forward. Many domestic seeded players are full of ambition to attack the highest point of Claudin 18.2 target.

 02 

Grab the food

In the face of IMAB362, a temporary leader, domestic enterprises have their own competitive strategies. Different choices, rooted in the past experience of these companies, can mobilize resources and confidence in their own products.

Most companies choose to start with end-line treatment, such as CT-041 of CogenPharmaceuticals or Conoya's Claudin 18.2 ADC drug CMG901.

It is also understandable that last-line treatment is the most appropriate entry point for new therapies, which is both ethical and safest.

However, for oncology drugs, only by becoming a first-line therapy for more patients can its value be proven to the greatest extent. Therefore, the development path of the global blockbuster drug is relatively consistent, and after years of clinical trials, it has achieved expansion from the last line to the first line.

First-line therapy must also be the highest point of Claudin18.2 targeted drugs. It is precisely for this reason that Astellas' monoclonal antibody drug IMAB362 chose to combine chemotherapy to shock gastric cancer first-line therapy from the beginning.

Some domestic pharmaceutical companies did not avoid it, but chose to seize the food, such as Transcenta's TST001.

As mentioned above, TST001 is carrying out clinical research in combination with CAPOX as a first-line treatment for advanced or metastatic gastric cancer and gastroesophageal junction cancer, and the progress is the second in the world. At present, the phase III clinical trial of TST001 in China and the United States is in the planning stage.

At the same time, TST001 has launched a joint attack with the new first-line therapy O drug for gastric cancer, forming a differentiated layout.

It is worth noting that Transcenta Group is the first company in the world to carry out Claudin18.2/PD-1/chemotherapy combination therapy, which is expected to lead the next round of first-line gastric cancer treatment programs and open the gap with other players.

As far as the current situation is concerned, Astellas' IMAB362/chemotherapy combination can challenge the O drug/chemotherapy combination needs further clinical data disclosure. According to Astellas disclosed Phase 2 clinical data:

For people with high expression of Claudin 18.2, the IMAB362/chemotherapy combination has certain advantages (not head-to-head), but in view of the protein sequence overlap of Claudin 18.1 and Claudin 18.2 is as high as 92%, it is still a major challenge to screen out patients with real high expression of Claudin 18.2, which is a variable affecting the "performance" of the therapy.

Relatively speaking, the same challenge O drug/chemotherapy combination, Transcenta's TST001/O drug/chemotherapy combination has a better chance of winning.

For a long time, the efficacy of PD-1 inhibitors has been limited by the expression of PD-L1 in patients. The higher the PD-L1 expression of patients, the more obvious the clinical benefit. Conversely, the worse the benefit.

This is also the BUG in the first line treatment of gastric cancer in the combination of O drug/chemotherapy.

Although the O-agent/chemotherapy combination is effective in all patients in this group, the benefit-risk ratio is controversial in the patient population with low PD-L1 expression (CPS<5).

For patients with low expression, the survival benefit of O-drug/chemotherapy combination therapy decreased, while the risk (side effects) increased accordingly (about 10%).

Therefore, although the EU has approved the first-line treatment of gastric cancer with O drug/chemotherapy, it is limited to patients with PD-L1 CPS ≥5; There is no limit to the first-line treatment of gastric cancer approved by O drug/chemotherapy in Japan, but it is stipulated that PD-L1 in the case of CPS <5 or unknown, should consider the patient's overall health status and the opportunity to obtain subsequent treatment, and then decide to use O drug/chemotherapy or chemotherapy alone.

Most patients with Claudin18.2-positive gastric/gastroesophageal adenocarcinoma are patients with low PD-L1 expression. A study conducted in China showed that about 80% of patients with Claudin18.2-positive gastric/gastroesophageal adenocarcinoma had PD-L1 CPS<5.

This means that the powerful O-drug/chemotherapy combination is full of variables in the first-line treatment of patients with Claudin18.2-positive gastric/gastroesophageal adenocarcinoma.

Based on this, Transcenta Group has carried out first-line clinical research on the first-line treatment of gastric cancer with TST001 combined with O drugs.

Theoretically, Claudin18.2-targeted agents can promote T cell infiltration and antigen presentation, thereby improving the efficacy of immune checkpoint inhibitors.

Indeed, in preclinical models, Transcenta's TST001 produced a synergistic effect with the addition of PD-1 inhibitors and chemotherapy.

This result undoubtedly shows that the TST001/O drug combination is expected to solve the limitations of the first-line treatment of gastric cancer with O drug/chemotherapy, and provide new treatment options for patients who may not benefit from anti-PD-(L)1 therapy.

On the whole, Transcenta Group, which is chasing and blocking in the field of first-line gastric cancer and opening up a new way, may face fewer variables.

03 

Decisive limits

For an innovative drug, whether it can bring treatment options to more patients is the only factor to measure its value.

As far as Claudin18.2 targeted drugs are concerned, to judge who can go to the next level, we must first look at whether we can sit firmly on the first-line therapy, which is the most basic competitiveness; secondly, we must look at whether we can cover patients with medium expression or even low expression, which is the most core factor in determining the ceiling level.

The defect of IMAB362 is that its molecular affinity is weak, resulting in the efficacy being limited by the expression ratio of Claudin18.2 in patients' tumor cells, which is only effective for patients with high expression.

According to ClinicalTrials.gov, IMAB362 combined with CAPOX as a first-line treatment for advanced or metastatic gastric cancer and gastroesophageal junction cancer targeted only patients with high expression of Claudin 18.2 (≥ 75%).

Among all solid tumors, only 33%-37% of patients with high expression of Claudin 18.2 were patients. In the field of gastric cancer, which has the largest patient population, the proportion of patients with high expression is only about 20%.

Obviously, in the battle for Claudin18.2 targets, only to meet the clinical needs of low-expression patients is it more clinically valuable.

At present, the key to domestic pharmaceutical companies standing out is the technical strength of "optimization" molecules.

For example, Transcenta's TST001, through different epitope designs and two major measures to reduce the fucose content in the antibody Fc region, makes its antibody have two potential advantages of higher affinity with tumor cells and better binding efficiency of NK cells, and finally has the potential to meet the needs of low-expression patients and surpass IMAB362.

As shown in the figure below, according to Transcenta's research, the ADCC activity of TST001 is significantly better than that of IMAB362.

This advantage makes it possible for TST001 to cover patients with expression in Claudin18.2. As shown in the figure below, according to the clinical data released by Transcenta Group in ESMO in September this year, TST001 is also outstanding for patients with medium expression.

At the same time, Transcenta Group said that it will carry out clinical studies in patients with low expression in the future. If TST001 can eventually cover patients with medium and low expression, it will undoubtedly be able to surpass IMAB362 and lead the way.

Of course, not only Transcenta Group, but also other domestic pharmaceutical companies have the opportunity to design molecules with stronger combat effectiveness through their own capabilities, and stage a good show that comes out on top.

Innovent Biologics has laid out multiple technical routes for this purpose. At present, its Claudin18.2/CD3 dual antibody IBI389 may have some potential.

IBI389 binds Claudin18.2 expressed on tumor cells "in one arm" and CD3 on T cells "in the other arm", or has the ability to efficiently and selectively kill Claudin18.2 tumor cells.

The preclinical results showed that IBI389 could still bind to tumor cells in cell lines with low expression of Claudin18.2, showing significant anti-tumor effects.

This means that IBI389 is expected to cover people with low and medium expression of Claudin 18.2 and expand the range of potential beneficiaries. Of course, whether IBI389 can achieve its purpose needs to be reviewed by human clinical studies.

Referring to the R&D history of overseas pharmaceutical companies, there are variables in any "technology". For example, after completing the phase 1 clinical trial this year, Amgen's Claudin 18.2/CD3 dual antibody AMG 910 has quietly "disappeared" from the company's pipeline. The market speculates that Amgen's AMG 910 may have encountered security problems.

In general, how to transform more effective molecules based on their own technical strength to reach a wider range of patients is also a challenge for all domestic pharmaceutical companies whose pipelines are still in the early stages.

Of course, in any case, as Astellas proves the druggability of Claudin18.2 targets, the Claudin 18.2 targeted drug market is developing beyond expectations, and companies with competitive advantages will eventually run faster and faster.