Copy PD-1?

The TIGIT target is becoming the next "sweet pastry" to go overseas
.

On the evening of January 10, 2022, Junshi Bio announced that it has expanded the scope of cooperation with Coherus, and Coherus has launched the licensing option of JS006 (TIGIT monoclonal antibody) in the United States and Canada
.
To this end, Junshi Bio will receive an upfront payment of $35 million, development, filing and sales milestone payments of up to $255 million, as well as an 18% sales share of net product sales

This is the second TIGIT monoclonal antibody in China
.

Three weeks ago, BeiGene just announced a cooperation agreement with Novartis to license the TIGIT antibody to the latter for $2.
9 billion.
This transaction also set a new domestic license out transaction record at the end of the year
.

If we go back, as early as when Innovent and Eli Lilly expanded their strategic cooperation, the PD-1/TIGIT double antibody jointly developed by them is another sense of "going overseas"
.

A similar situation occurred in early 2021.
At that time, the protagonist in the spotlight was PD-1.
The four major domestic PD-1s of Hengrui, Xinda, Baekje, and Junshi have completed their overseas trips, stirring the nerves of the entire industry
.

From the transaction point of view, TIGIT seems to be a follow-up to PD-1
.
The Junshi TIGIT transaction originated from the authorization of PD-1 in February last year.

PD-(L)1+TIGIT is becoming a power engine in the post-PD-1 era, and some people even think it is the "standard" of PD-(L)1 enterprises
.
From a global perspective, overseas multinational pharmaceutical companies have completed in-depth bundling with TIGIT biological upstarts earlier, and the first and second echelon camps have been formed; however, there are still some companies that have not yet achieved cooperation and bundling due to their late deployment

01

TIGIT magic

When PD-1 became a red sea, participants began to look for new growth points.

TIGIT is one of the hottest ones
.
In the past two years, Wang Laihui, head of BeiGene’s R&D, has often mentioned to the media that it may be outdated not to know PD-1 in the past, and everyone must remember the TIGIT target in the future

TIGIT is an inhibitory receptor shared by T cells and natural killer cells (NK cells), which can inhibit the killing effect of NK cells and T cells on tumor cells
.
The most important thing is to block the dual pathways of TIGIT and PD-1/PD-L1, which can relieve the inhibitory state of immune cells to a greater extent and allow the immune system to play a stronger killing effect

In 2009, the Genentech team published an article revealing TIGIT for the first time, initially confirming that TIGIT is an important immunosuppressive ligand
.
Combined with a paper in October of the same year, the mechanism of action was basically revealed

The earliest TIGIT project approval in China started in 2015.
During this period, when PD-1 projects got together, there were very few domestic TIGIT projects
.
The Yaodu database shows that since 2015, there have been patent applications for TIGIT antibodies in China, and all Chinese patent applicants related to the target are foreign companies except China Pharmaceutical University

In May 2016, Roche's TIGIT drug Tiragolumab began to enter Phase I clinical trials, and the TIGIT target entered the brand-name stage.
After that, some domestic companies chose fast follow-up
.

So far, only four companies worldwide have entered the Phase III trial of TIGIT antibody drugs
.
Among them, the fastest progress is Roche, whose Tiragolumab has recently been granted breakthrough drug designation by the FDA
.
Last year, Roche announced the data of the combination with PD-L1 at ASCO.
The data was amazing, and it also proved the potential of TIGIT and PD-L1 in combination
.

The potential of combination with PD-1 has always been the focus of the industry
.

02

Self-contained first camp

Roche and Merck are the top players in the combination of PD-(L)1+TIGIT
.

As the discoverer of TIGIT targets, Roche has the most extensive layout and the most advanced progress
.
According to Frost & Sullivan data, Roche entered Phase 3 clinical phase one year earlier than its fastest competitors (Merck & Co.
, Arcus).
The current layout covers small cell lung cancer, non-small cell lung cancer, esophageal squamous cell 11 indications including non-Hodgkin's lymphoma, multiple myeloma, liver cancer and cervical cancer
.
In China, Roche also covers the first-line treatment of small cell lung cancer, non-small cell lung cancer, esophageal squamous cell carcinoma and other indications
.

Its atezolizumab is the world's first PD-L1 monoclonal antibody.
The financial report shows that Roche's atezolizumab sold US$2.
7 billion in the first three quarters of 2021.
After the combination is approved in the future, it may bring considerable benefits.
growth
.

Merck's PD-1 + TIGIT combination is K drug + vibostolimab (MK-7694), vibostolimab is one of the few TIGIT drugs that have entered clinical phase 3 in the world, and the progress is the top three
.
In the PD-1 market, Merck's K drug has long been a leader.
The financial report shows that the sales of K drug in the first three quarters of 2021 reached 12.
578 billion US dollars, ranking among the top three best-selling drugs in the world
.
In February 2021, Merck's combination was approved to enter clinical phase 3.
As of June 30, 2021, its combination of PD-1 + TIGIT has covered small cell lung cancer, non-small cell lung cancer, glioblastoma, etc.
item indications
.
In China, Merck's first-line treatment of non-small cell lung cancer is in progress
.

03

The second camp

It is said that the domestic PD-1 fight has become a red sea.
In fact, the top ten global multinational pharmaceutical companies basically have PD-1 deployment
.
Even if they did not participate in research and development, they chose to introduce them in order to gain a share of the market in the later stage
.

Novartis and Eli Lilly are two such "losers", PD-1 and TIGIT are both from the outside or jointly developed
.

Lilly's "awakening" seems to be earlier.
In August 2020, Lilly and Cinda expanded their strategic cooperation and obtained the exclusive license of Cinda's PD-1 sintilimab outside of China
.
Innovent Bio received an upfront payment of $200 million and development and sales milestone payments of up to $825 million, as well as sales royalties
.
The PD-1/TIGIT double antibody jointly developed by Eli Lilly and Innovent is also based on the past cooperation.
Innovent is responsible for the research and development in China.
The double antibody completed the first patient dosing in the Phase 1 clinical trial in July last year
.

In addition, as the licensor, Innovent also has another TIGIT monoclonal antibody currently in Phase 1 clinical trials
.
In the domestic PD-1+TIGIT combination, Cinda belongs to the first camp in terms of research and development progress
.
It’s just that in the entire global market, Chinese companies are weak, and can only achieve current benefits by cooperating with large multinational companies, especially in a competitive track like PD-1
.

Novartis soaked in small-molecule warm water is also a "misser" at the macromolecular level
.
At the beginning of 2021, Novartis used a deal of up to 22 US dollars to obtain the rights of BeiGene’s PD-1 tislelizumab in some major regions except China.
At the end of 2021, Novartis used 2.
9 billion US dollars to obtain BeiGene’s TIGIT.
Project interests in some major regions other than China
.

Since BeiGene's Ociperlimab is the third TIGIT monoclonal antibody in the world to enter the Phase III clinical trial, the "PD-1 + TIGIT combination therapy" is also in the first international echelon, and three international multi-center Phase III clinical trials are being carried out and a number of Phase II clinical trials
.
From Novartis' point of view, although it spent 5.
1 billion US dollars, it obtained PD-1 and TIGIT within a year, and got a front-row ticket
.

From Baekje's point of view, this decision cannot be described as "not far-reaching"
.

For BeiGene, TIGIT is its second batch of potential products with high hopes, and its status is comparable to that of zanubrutinib
.
In its prospectus, the first project that Baiji raised funds to invest in is TIGIT products, with an investment of 1.
74 billion yuan, accounting for more than 22%
.
BeiGene has deployed 9 clinical trials with different indications including first-line non-small cell lung cancer and cervical cancer on TIGIT, and has recruited more than 2,000 people worldwide
.
The large investment made some voices in the industry feel that the authorization is a bit "pity"
.
But from a rational point of view, the commercialization of Baekje China has just begun, and the fierce international PD-1+TIGIT competition is not something that Baekje can cover at this stage
.

It is worth noting that the far-reaching consideration lies in BeiGene's determination of the potential of the company's self-developed TIGIT.
BeiGene previously introduced that the company's TIGIT monoclonal antibody is about 4 times more active than Roche's Tiragolumab in preclinical studies
.
This kind of certainty led Baiji to negotiate with Novartis to set a higher sales sharing fee in the transaction terms, with a ratio of 20-25%, generally no more than 20%
.
BeiGene would rather bear more clinical costs, perhaps because its R&D capabilities are much more mature than its commercialization capabilities
.

Perhaps due to the "weakness" of O drug sales growth, BMS always wants to pull back a round, whether it is the first to deploy LAG-3, or the crazy blessing on the TIGIT track
.
On the one hand, the self-developed TIGIT monoclonal antibody BMS-986207 owned by BMS has entered clinical phase I/II.
On the other hand, BMS is still actively looking for potential TIGIT products.
In May last year, BMS first obtained the latter's proprietary product from Agenus.
Exclusive worldwide license to the bispecific antibody program AGEN1777 (TIGIT), which targets TIGIT and another undisclosed target
.
Half a year later, COM701 from Compugen (CGEN) was shared by investment.
COM701 is a fully human monoclonal antibody against a new immune checkpoint PVRIG (the ligand is PVRL2).
It can be used in combination with O drug, or combined with BMS.
Anti-TIGIT mAb BMS-986207 constitutes a triple combination
.

Gilead is in a similar situation to Novartis and Eli Lilly
.
In May 2020, Gilead and Arcus Biosciences jointly announced a 10-year partnership to co-develop and commercialize drug candidates from Arcus' pipeline, including innovative PD-1 inhibitors and immunoassays Inhibitors of the dot protein TIGIT
.
Arcus Biosciences' AB154 is one of four TIGITs in the world that have entered clinical phase 3, but PD-1 has not been approved
.

GSK's PD-1 and TIGIT are obtained from different companies
.
Its PD-1 was acquired from Tesaro, which is the seventh listed PD-1 in the world, while TIGIT monoclonal antibody was acquired from iTeos Therapeutics for $1.
56 billion in June last year for co-development and commercialization rights, but the product was still in clinical trials at the time.
Phase I research and development stage
.

04

one worse camp

In China, there are many companies that only have PD-1 or only TIGIT
.

Their next choice is to "buy", which is the answer that the E-pharmaceutical manager got from several companies that have TIGIT in research but no PD-1 research
.
They are optimistic about the combination potential of TIGIT, and PD-1 is now readily available
.

In terms of research and development progress, Baekje, Cinda and Junshi, the top three in terms of progress, have all completed the "PD-1+TIGIT" combination
.
At present, TIGIT has entered the clinic and there are two BAT6021 and BAT6005 from Bio-Tech, and HB0030 from Hua-Aotai
.
These three TIGITs are also likely to be licensed out in the next two years
.

In the preclinical stage, there are also Hengrui, Zejing/Qilu, Kangfang Bio, Fuhong Henlius, Shenghe Pharmaceutical and other companies.
Among them, Hengrui, Kangfang, and Fuhong Henlius each hold a PD- 1.
Qilu has already started the development of O-drug biosimilars.
What choices will these companies make on TIGIT in the future? Will TIGIT become the second PD-1 to detonate the industry? E-pharmaceutical managers will continue to pay attention
.