Although the current PD-1 monoclonal antibodies are deeply involved, the global sales of O drugs and K drugs have fully proved the value of immune checkpoints in tumor treatment.
However, due to the problems of low response rate and high incidence of adverse reactions of PD-1, new immune checkpoints such as TIGIT, LAG-3, TIM-3, and B7-H3 have started a new research and development boom. Among them, is the most famous as the TIGIT target that is highly expected to be the “next PD-1”.
Even when Roche’s TIGIT monoclonal antibody suffered setbacks one after another, the popularity of the track has not diminished. According to the Insight database, judging from the global R&D situation, as of today, among the major immune checkpoints after PD-(L)1, the TIGIT target is still the number one R&D hot spot.
From: Insight database (http://db.dxy.cn/v5/home/)
1. Why has the TIGIT antibody drug track become a hot spot for research and development?
TIGIT The research and development of antibody drugs is booming, which is inseparable from its unique mechanism of action, especially the combined effect with PD-1.
TIGIT is an inhibitory receptor shared by natural killer cells (NK cells) and T cells. It can bind to the highly expressed PVR receptor on tumor cells and mediate the inhibitory signal of the immune response, thus directly inhibiting the interaction between NK cells and T cells. The killing effect of tumor cells, the effect of is similar to the inhibitory effect of PD-1 on T cells.
More importantly, TIGIT can inhibit innate and adaptive immunity through multiple mechanisms of action, and is highly expressed in tumor-infiltrating T cells of various cancer types. It is a highly potential target in the field of tumor immunotherapy . Moreover, at the molecular mechanism level, it has been verified that the combination of TIGIT monoclonal antibody and PD-(L)1 monoclonal antibody can achieve better clinical treatment effects on tumors.
From the perspective of the mechanism of action, the theoretical basis for the combination of TIGIT and PD-1 is that effector T cells are the main force in killing tumors and are mainly generated by stem cell-like memory T cells, while stem cell-like memory T cells express PD-1 and TIGIT. does not express other negative regulators (such as Tim-3), allows the combination of TIGIT and PD-1 to activate stem cells and -like memory T cells, producing a continuous stream of effector T cells.
Source of information on the mechanism of the combination of TIGIT and PD-1: Roche Investor Meeting in May 2020
To summarize, there are several major reasons why the TIGIT antibody drug track has become a hot topic in research and development:
First of all, PD-(L) 1 The monoclonal antibody track is crowded and the market competition is fierce. According to the insight database, 14 PD-(L)1 monoclonal antibodies and 1 PD-1×CTLA-4 dual antibody have been approved for marketing in China, including 10 PD-1 monoclonal antibodies (8 domestically produced, 2 imported), 4 PD-L1 monoclonal antibodies (2 domestically produced, 2 imported), and countless pipelines under development.
Secondly, PD-1 monoclonal antibodies have the problem of low response rate. In clinical practice, the response rate of PD-1 antibody monotherapy for tumor treatment is still relatively low (20%-30%), and there are clinical limitations. Therefore, the market urgently needs to find new immune checkpoint targets and drugs.
Furthermore, compared with monotherapy, the combination treatment of PD-1 monoclonal antibodies and other cancer therapies (such as other immune checkpoint inhibitors, targeted drugs, chemotherapy and radiotherapy , etc.) has greatly broadened the scope of PD- 1. The coverage of the product in the field of tumor is , and the clinical treatment effect is more significant.
Based on this, global pharmaceutical companies have entered the TIGIT antibody drug track, causing the number of pipelines to increase. According to the research report of Changjiang Securities, PD-(L)1 combination therapy in 2020 involves a total of 253 targets (except PD-1 and PD-L1), which is significantly higher than in 2017 (an increase of 129).
Types of therapies and targets used in combination with anti-PD-(L)1 monoclonal antibodies Source: Nat.Rev.Drug.Discov., Changjiang Securities Research Institute
The reason why TIGIT antibody drugs are the most famous is due to Roche’s previous A number of blockbuster clinical results of PD-L1+TIGIT monoclonal antibody combination therapy have been released.
In 2020, Roche released the TIGIT monoclonal antibody tiragolumab combined with PD-L1 atezolizumab at the ASCO conference for the first-line treatment of patients with PD-L1-positive metastatic or locally advanced unresectable non-small cell lung cancer (NSCLC) The phase II clinical trial CITYSCAPE study data, the results are very impressive.
In this global multi-center, randomized, double-blind phase II clinical trial, compared with the patient group treated with Tecentriq alone, the ORR (objective response rate) of the TIGIT + PD-L1 group reached 31.3%, while Tecentriq alone The patient group was only 16.2%; PFS was 5.4 months vs. 3.6 months, reducing the patient's risk of disease progression or death by 43%. In patients with high PD-L1 expression, had an ORR of 55.2% compared with Tecentriq alone, which was 17.2%, and the combination therapy reduced the patient's risk of disease progression or death by 67%.
In December 2021, Roche orally reported the latest data of the CITYSCAPE phase II clinical trial of PD-L1+TIGIT combined with first-line treatment of NSCLC at the ESMO-IO conference: after a median of 2.5 years After the follow-up period, for patients with high PD-L1 expression (TPS ≥ 50%), the ORR of PD-L1 combined with TIGIT monoclonal antibody was 69%, which was higher than 24.1% of PD-L1 alone; and mPFS (median no Progression survival) were 4.1 months vs. 16.6 months; DOR (median duration of response) was 8.2 months VS 15.7 months.
CITYSCAPE clinical trial results come from: Insight database web version (http://db.dxy.cn/v5/home/)
2. On the TIGIT antibody drug track, the pioneer Roche "failed twice"
In the field of new drug research and development, it has never been There is no shortage of exploration and adventure, and there is no shortage of cases of failed clinical trials.
As a pioneer, Roche helped its peers open the "door" to the research and development of TIGIT antibody drugs, but it itself "fumbled twice", and it was on the same target drug.
Roche’s “first fall” came on March 29, 2022. The TIGIT monoclonal antibody Tiragolumab developed by it was combined with the PD-L1 monoclonal antibody Tecentriq and chemotherapy for the first-line treatment of extensive stage small cell lung cancer (ES-SCLC) The Phase III clinical SKYSCRAPER-02 study failed to meet the co-primary endpoints of progression-free survival (PFS) and overall survival (OS). This is also the world's first TIGIT phase III clinical failure.
In fact, the treatment of small cell lung cancer has always been difficult to develop. Before Roche’s PD-L1+TIGIT combination therapy, many studies on the treatment of small cell lung cancer failed to achieve the expected results.
Even the world's best-selling Opdivo and Keytruda announced the withdrawal of SCLC indications approved in the United States at the end of 2020 and March 2021 respectively, and the PD-L1 products Tecentriq and Imfinzi combined with chemotherapy have clinical success in the first-line treatment of SCLC. The benefits are also limited.
This is mainly due to the fact that small cell lung cancer is the most aggressive subtype of lung cancer and has significant characteristics such as low degree of differentiation, high degree of malignancy, strong invasiveness, and easy formation of distant metastasis. This leads to rapid progression of the disease and poor survival rate. Low. Patients with 2/3 have tumors that have spread when they are diagnosed with extensive-stage small cell lung cancer (ES-SCLC). The prognosis of is poor, with a 2-year survival rate of less than 5%.
Roche’s “second fall” came from May 11, 2022, when TIGIT monoclonal antibody Tiragolumab combined with PD-L1 monoclonal antibody Tecentriq was used to treat PD-L1 high expressionhtm The Phase III clinical trial of l2 locally advanced or metastatic non-small cell lung cancer (NSCLC) failed to reach the primary endpoint of progression-free survival (PFS), and the other primary endpoint of overall survival (OS) has not yet matured. But Roche has not given up and will continue to conduct this clinical study until the next planned data analysis.
SKYSCRAPER-01 trial results from: Insight database web version
This is the blockbuster preliminary clinical data released by Roche at the ESMO-IO conference in November last year. But it is a pity that the outstanding clinical data in the early stage have not been continued .
However, in addition to these two indications, Roche has also conducted clinical studies on TIGIT+PD-L1 combination therapy for a number of other indications, covering a variety of solid tumors such as esophageal squamous cell carcinoma, cervical cancer, and head and neck cancer. . Among the phase III clinical trials, there is still one result for esophageal squamous cell carcinoma that has not yet been read out, and the results are expected to be determined this year. According to the recent semi-annual report released by Roche, the company is looking forward to submitting tiragolumab for esophageal squamous cell carcinoma in China first. listing application.
From: Roche official website
In fact, in addition to PD-L1+TIGIT combination therapy, other PD-1 monoclonal antibody combination therapies have also failed in clinical trials, mainly due to obvious immune side effects and high incidence of adverse reactions. It can be seen that improving product safety has become the focus of combination therapy research and development.
3. The enthusiasm for research and development of TIGIT antibody drugs has not diminished, BeiGene is leading
However, Roche’s TIGIT monoclonal antibody combination therapy has suffered successive setbacks, which has not affected the research and development boom on the TIGIT track.
According to the global new drug module of the Insight database, there are currently 53 TIGIT antibody drug projects under development around the world, 37 of which are monoclonal antibody projects; and the four TIGIT monoclonal antibodies with the fastest progress are already in Phase III clinical trials , and the corresponding drugs Enterprises have invested huge resources in promoting it.
Currently, the TIGIT antibody drugs in phase III development around the world are Roche's Tiragolumab, BeiGene's Ociperlimab, Merck's 's Vibostolimab, and Gilead's /Arcus' Domvanalimab.
The global TIGIT antibody drug in phase III research and development
comes from: Insight database (http://db.dxy.cn/v5/home/)
Among them, Merck is developing TIGIT monoclonal antibody Vibostolimab (MK-7684) combined with PD -1 Phase III clinical study of the monoclonal antibody Keytruda for non-small cell lung cancer (NSCLC).
Previously, Merck announced early clinical trial data of the drug, with positive results: For patients who had not received PD-1/PD-L1 therapy before, but had received at least one other therapy (73%, n=30/41) in patients with metastatic NSCLC, the ORR of Vibostolimab combined with Keytruda was 29%, mPFS was 5.4 months, and mDOR was not reached; the ORR of 13 patients who expressed PD-L1 and TPS≥1% was 46% , mPFS was 8.4 months; the ORR of 12 patients with PD-L1 expression and TPS1% was 25%, and mPFS was 4.1 months.
But whether the "good luck" in conquering non-small cell lung cancer will come to Merck this time and become a "dark horse" remains to be seen.
Vibostolimab combined with Keytruda in the treatment of NSCLC has positive clinical trial results Source: Merck official website, Guosheng Securities Research Institute
Domestic aspects. The company with the fastest progress in clinical research and development of TIGIT antibody drugs is BeiGene.
BeiGene’s Ociperlimab (BGB-A1217, ospirimab) has entered the clinical phase III stage as early as October 28, 2020. It is the world’s second TIGIT antibody drug after Roche , is currently conducting Phase III clinical trials of the combination of Ociperlimab and Tislelizumab for the treatment of non-small cell lung cancer (NSCLC). is also in the process of research and development for multiple indications such as small cell lung cancer, cervical cancer, and esophageal squamous cell carcinoma. Clinical phase II. As of 2021, the company has invested 400 million yuan in research and development funds for this drug.
In December 2021, BeiGene once again reached a strategic cooperation with "good partner" Novartis . licensed the main overseas rights and interests of Ociperlimab in the United States, EU and Japan to Novartis. received a down payment of US$300 million. In addition, according to the agreement, if Novartis subsequently exercises its option within a limited period, and after achieving regulatory approval milestones and achieving sales milestones, BeiGene will be eligible to receive a maximum total payment of approximately US$2.495 billion, and 20%-25% of sales share.
Data source of TIGIT targeted drugs entering the clinical stage in China: Insight database
In addition to BeiGene, is also being developed by domestic pharmaceutical companies including Innovent Bio, Zejing Pharmaceuticals, Kangfang Biologics, Henlius and other domestic pharmaceutical companies. TIGIT antibody drug.
Among them, Innovent Biologics has 2 TIGIT antibody drugs under development. Among them, the TIGIT monoclonal antibody IBI939 is in the clinical phase I stage. It is currently continuing to promote the combination of IBI939 and sintilimab in the treatment of advanced lung cancer. Phase b clinical trial, and it is expected to receive preliminary data from the trial in 2022; the PD-1/TIGIT dual antibody IBI321 will start clinical trials in May 2021, and plans to complete patient recruitment for the Phase I clinical trial in 2022, and based on the Phase I clinical trial As a result, a possible Phase Ib study was launched.
ZG005 powder injection developed by Zejing Pharmaceutical. is a recombinant humanized anti-PD-1/TIGIT bispecific antibody drug. It is a Class 1 innovative biological product. is also the third anti-PD-1 drug in the world to enter clinical trials. 1/TIGIT bispecific antibody drug, is conducting phase I/II clinical trials for the treatment of patients with advanced solid tumors.
In addition, Biotech’s BAT6005 and BAT6021, Kangfang Biologics’ AK104 (PD-1/CTLA-4 dual antibody) + AK127 (TIGIT), and Henlius’s dual antibody HLX301 (PD-L1/TIGIT) are all in the Clinical Phase I stage.
4. Conclusion
In summary, against the background of serious involution of PD-1 monoclonal antibodies, global pharmaceutical companies are stepping up the research and development of "next generation PD-1".
Although there have been many cases of failed clinical trials of emerging targets before, and the development of TIGIT antibody drugs is still being explored, the field of new drug research and development never lacks the spirit of exploration and adventure.
It depends on whether the "pioneers" such as Roche, Merck, Gilead, and BeiGene, as well as the "latecomers" such as Innovent, Zejing, and Kangfang in the pre-clinical stage, can break the current dilemma and "cultivation" in the future. True result."
Reference:
1. "Junshi Bio-688180-Biotech with long-standing accumulation, the construction of platform-based innovative pharmaceutical companies has begun to build", Changjiang Securities
2. "Pharmaceutical and biological industry: new crown, traditional Chinese medicine themes lead the market market, pay attention to segmented high-prosperity tracks", Guolian Securities
3. "Weekly Report on Innovative Drugs in the Pharmaceutical and Biological Industry: Seven Questions and Seven Answers, Look at Innovent Biologics Again", Guosheng Securities
4. Financial reports and announcements of various companies
5. Insight database
