CLAUDIN 18.2 fierce battle, who will be the first to break through the domestic pharmaceutical company?

Innovative drug research and development has always been a lifetime of death, especially the Claudin 18.
2 target
.
However, not long ago, the Japanese pharmaceutical company Astellas brought good news
.
The phase III clinical trial of the Claudin18.
2 antibody - IMAB362 was successful, breaking the previous record
of zero clinical success rate of Claudin18.
2 drug phase III.

At present, Claudin18.
2 has become another involution target after PD-1/L1
.
According to incomplete statistics, there are currently more than 50 Claudin18.
2 targeted drugs in China in the research and development stage
.
So why is Claudin18.
2 favored by domestic pharmaceutical companies? For IMAB362, which is very promising to win the "FIC crown", what are the crises it faces? Who will be the first to break through among domestic players?

Popular target – Claudin 18.
2

Claudins are a class of tight junction proteins that are primarily involved in maintaining intercellular adhesion and junctions
.
Claudin 18 is a member of the Claudins protein family with two subtypes: Claudin 18.
1 and Claudin 18.
2
.
Among them, Claudin 18.
1 is mainly expressed in normal lung cells, while Claudin 18.
2 (CLDN 18.
2) is expressed
only in differentiated epithelial cells of the gastric mucosa.

Under normal physiological conditions, the expression of CLDN 18.
2 is very limited, but it is expressed high and ectopic activation
in gastric cancer, pancreatic cancer, esophageal cancer and other tumors.
In the gastric cancer population, about 16% to 73%
of patients with positive expression of CLDN 18.
2 are present.
Therefore, CLDN 18.
2 has also become a target for the development of
new drugs for gastric cancer.

China is a big country
with gastric cancer.
According to statistics released by the National Cancer Center in 2022, there were nearly 400,000 newly diagnosed gastric cancer patients in China in 2016, and the incidence rate ranked among the top 3
tumors in China.
According to the statistics of the chemical terminal monitoring and analysis system (HDM) of China's national public hospitals, in 2016, gastric cancer treatment drugs in public hospitals in key cities in China were still mainly chemotherapy drugs, and its total market was 945 million US dollars, an increase of 12.
24%
over the previous year.
The total size is expected to reach $4 billion
by 2030.
In the face of a huge market, there are only a handful
of therapeutic drugs that have been approved for marketing.
At present, the only biological drugs on the market are anti-HER-2, anti-PD-(L)1, and anti-VEGFR targeted drugs
.
However, only 7.
3-20.
2% of patients with HER2-positive gastric cancer, PD-L1 positivity rate is 12-50%, VEGF positivity rate is 72%, and CLDN18.
2 positivity rate is 60-80%.

Therefore, the drug market targeting CLDN18.
2 can be expected, and CLDN18.
2 has also become a hot target for domestic pharmaceutical companies
.

IMAB362 is expected to take the "FIC crown", but there are still flaws

Originally developed by Ganymed, IMAB362 is a monoclonal antibody that targets CLDN18.
2
.
Its mechanism of action is: after specific binding to the antigenic determinants on the surface of tumor cells through the Fab segment of the antibody, and then binding to effector cells such as NK cells through the Fc segment of the antibody, triggering its killing activity and directly killing tumor cells
.

At the 2016 ASCO conference, Ganymed reported the results of IMAB362 research
.
IMAB362 in combination with standard chemotherapy regimen EOX (epirubicin, oxaliplatin, capecitabine) has been reported to significantly prolong median overall survival (8.
4 months to 13.
2 months) when used as a first-line agent for CLDN18.
2-positive gastric cancer and gastroesophageal junction adenocarcinoma, and chemotherapy+ in patients with the highest CLDN18.
2 expression levels The median overall survival in the IMAB362 group was 16.
7 months, compared with 9 months with chemotherapy alone, and was safe and tolerable
with treatment.

Given the excellent clinical data of IMAB362, Astellas smelled a business opportunity
.
It soon acquired Ganymed for $1.
4 billion, acquiring IMAB362
.

In a phase III clinical trial published in mid-November, results showed that the study met the primary endpoint
of PFS (progression-free survival) in 566 patients with CLDN18.
2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinoma.
In addition, the study also met the key secondary endpoint
of OS (overall survival).

The success of the phase III clinical trial of IMAB362 has injected a shot in the arm for pharmaceutical companies that deploy CLDN18.
2, and IMAB362 is also the fastest progressing monoclonal antibody drug targeting CLDN18.
2, but it is not perfect
.
The biggest drawback of IMAB362 is its weak affinity for CLDN18.
2, resulting in limited
combat effectiveness.
From the previous phase II clinical data, its efficacy is affected by the proportion of CLDN18.
2 expression in patients
' tumor cells.

In 70% of patients with CLDN18.
2 expression ratio≥ the median PFS and median OS of IMAB362+ chemotherapy regimen were 9 months and median OS was 16.
5 months, which was statistically significant
compared with the control group (PFS = 5.
7 months, OS = 8.
9 months).

In 40% ≤CLDN 18.
2≤69% of patients, the median PFS of 4.
3 months and median OS of 8.
3 months in the IMAB362+ chemotherapy regimen group were not significantly effective compared with the control group (median PFS = 4.
1 months, median OS = 7.
4 months
).

In the phase III clinical trial mentioned above, it only targeted patients with CLDN18.
2 expression ratio ≥ 75
%.
Therefore, IMAB362 may face the problem
of limited coverage.
After all, only about 20% of patients with high expression of CLDN 18.
2 are in the gastric cancer patient population
.
This flaw in IMAB362 also gives later players the opportunity to
become me-better.

Who will be the first to break through among domestic players?

As a promising tumor targeted therapy target, CLDN18.
2 has been deployed by many innovative pharmaceutical companies in China and has become a target highland
.

Domestic rapid progress includes Transcenta Group, Keji Pharmaceutical, Innovent Biologics, etc
.
Among them, Transcenta's progress on the CLDN 18.
2 track is second only to Astellas
.
The TST001 developed by it is also the only CLDN18.
2 monoclonal antibody
in the world other than IMAB362 to enter the post-Phase II stage.
So who is likely to be better than IMAB362?

From the perspective of mechanism of action, the biggest obstacle to the development of drugs targeting CLDN18.
2 is the problem
of selection specificity.
As we mentioned earlier, Claudin 18 has two subtypes
: Claudin 18.
1 and CLDN18.
2.
Among them, Claudin18.
1 is expressed in normal cells in human body in addition to tumor cells, and compared with CLDN18.
2, there is only 8 amino acid differences
.
Therefore, if the drug is not highly selective, it is easy to bind to Claudin18.
1, which not only affects the efficacy of the drug, but also brings serious side effects
.

Transcenta's TST001 achieves only the effect of binding to CLDN 18.
2 through its unique epitope design
.
In addition, Transcenta Group reduced the fucose content in the Fc region of TST001, further enhancing the binding ability
of TST001 to Fc receptors on NK cells.

In patients with advanced/metastatic gastric or gastroesophageal junction adenocarcinoma treated with TST001 combined chemotherapy, phase I interim data showed good efficacy in patients with moderate and high expression of CLDN 18.
2, with disease control rates (DCR) as high as 100% in 15 patients with evaluable efficacy, and 73.
3% of patients achieved partial response (PR).

Moreover, in one patient with low expression of CLDN 18.
2 (10% ≤ expression level <40%), the tumor shrank by 24.
3% after treatment, which is equivalent to disease stabilization (SD).

In addition, of the 11 patients who achieved PR, 5 had unknown CLDN 18.
2 expression
.
Although the Phase I study included fewer patients with low CLDN 18.
2 expression that could be evaluated for efficacy, it also showed the therapeutic potential
of TST001 in people with low expression of CLDN 18.
2.

While achieving high efficacy, TST001 has excellent safety: the adverse events in the treatment are mainly nausea, vomiting, anemia, etc.
, more than 80% are mild grade 1-2, and no discontinuation events occur
.
In the future, Transeng Group will also carry out clinical research
in patients with low expression.

There is no doubt that TST001 is likely to cover a larger patient group than IMAB362 in the future, and the market share may surpass IMAB362, and it is also expected to become the first track for CLDN 18.
2 in China
.

In addition to TST001, the study of CT-041 of Keji Pharmaceutical for advanced gastric cancer/esophageal-gastric junction adenocarcinoma has been in the confirmatory phase II clinical trial stage
.
CT-041 is an autologous CAR-T product
targeting CLDN18.
2 developed by CARsgen Pharmaceutical.
In the Phase I clinical trial, 30 of the 37 patients with evaluable efficacy (83.
3%) achieved PR with an objective response rate (ORR) of 48.
6%, a DCR of 73.
0%, and an mPFS of 3.
7 months
.
CT041 is well tolerated
in the treatment of patients with CLDN18.
2-positive digestive tumors.
On the CLDN 18.
2 track, the CT-041 also has the potential
to be seeded.

In addition, Innovent Biologics' CLDN18.
2/CD3 dual antibody IBI389 is also a player
that cannot be ignored.
IBI389 is an anti-CLDN18.
2 T cell linkage bispecific antibody independently developed by Innovent Biologics, which induces immune synapse formation, stimulates T cell activation, promotes the production of cytolytic proteins, the release of inflammatory cytokines and the further proliferation of T cells by connecting CD3 in the T cell receptor complex with CLDN18.
2 antigen on the surface of tumor cells
.

The preclinical results showed that IBI389 could still bind to tumor cells even in cell lines with low expression of CLDN18.
2, showing obvious anti-tumor effects, and was expected to cover people with low and medium expression who did not respond to conventional CLDN18.
2 antibody therapy
.

Drugs targeting CLDN18.
2 that have entered the clinical stage in China (compiled according to public information)

At present, in the fierce battle against CLDN18.
2, domestic pharmaceutical companies have made many attempts, and many technical routes
such as monoclonal antibody, bispecific antibody, ADC and CAR-T have entered.
Although no CLDN18.
2-targeted drug has been approved for marketing in the world at this stage, the success of Astellas Phase III study has sounded the clarion call for the fierce competition of CLDN18.
2 track
.
In the future, the competition on the track will definitely become more and more hot
.

Reference:

1.
"Good news: Astellas Claudin 18.
2 monoclonal antibody phase III clinical success!" Astellas China, 2022-11-24;

       2.
Claudin18.
2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results.
Nat Med.
2022 May 9；

3.
Evaluation and reflection on claudin 18.
2 targeting therapy in advanced gastric cancer.
Chin J Cancer Res.
2020 Apr; 32(2):263-270；

4.
Innovent announces the completion of the first clinical patient dosing of Claudin18.
2/CD3 bispecific antibody drug IBI389, Innovent Biologics, 2022-03-29
.