100 billion innovative drug market! TIGIT, ADC, double antibody and other potential tracks have intensified, can "going to sea and hugging" reverse the situation?

With the introduction of a series of policies to encourage the development of innovative drugs, such as accelerating drug review and approval, strengthening medical insurance control fees and increasing intellectual property protection, as well as the gradual increase in market demand for innovative drugs, domestic innovation has gradually become the main theme

Battle for the sea, combination therapy.

Intranet data show that at present, a total of 19 PD-(L)1 (including monoclonal antibody, double antibody) in the world have been approved for listing, and the market size of PD-(L)1 in 2021 will exceed 30 billion US dollars, and the three PD-(L)1 of K drug (Pabolizumab), O drug (navurizumab), T drug (altilizumab) occupy 91% of the global market, while Cinda's Xindilizumab, BeiGene's tirellizumab and Hengrui's carilizumab 3 domestic PD-(L)1 total account for less than 1%.

The three major PD-(L)1 global sales of "KOT" in 2021

Source: Intranet sales library of multinational listed companies

Monotherapy is clearly not the full potential of PD-(L)1 commercialization, and combination therapies are the real value of its clinical application, and some pharmaceutical companies have developed it as part of the dual antibody to reshape the new landscape

Hengrui Pharmaceutical's 2022 semi-annual report disclosed that at present, Carellizumab has 16 new indications in the domestic research and development process, of which only 1 relapsed refractory classic Hodgkin lymphoma indication is in development as a single drug, and the remaining 15 new indications are all developed as combination therapies, including chemotherapy, apatinib, famitinib, etc

Innovent Bio has 6 double antibodies involving PD-(L)1 targets that have entered the clinic, namely IBI-318 (IgG1/PD-(L)1 double antibody), IBI-322 (CD47/PD-L1 double antibody), IBI-323 (LAG-3/PD-L1 double antibody), IBI-321 (PD-1/TIGIT double antibody), IBI-319 (TNFRSF9/PD-1 double antibody) and IBI-315 (HER2/PD-1 double antibody) , both are intended for the treatment of malignancy

BeiGene's tirelizumab combined chemotherapy for first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) and 2 new indication applications for combined chemotherapy for the first-line treatment of advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma expressing PD-L1 have been accepted by

Partial research progress in PD-(L)1 combination therapy

Source: Excerpted from the annual reports of various enterprises, compiled by Intranet

Since the beginning of this year, a number of domestic PD-(L)1 road to the sea has been blocked, the overseas audit mechanism has become stricter, in the case of product clinical progress and indication development are not dominant, can the dream of domestic PD-(L)1 cross the ocean and find a second growth curve still be realized? The answer is: there is a

The frustration of a number of domestic PD-(L)1 seas has brought some new enlightenment to the latecomers:

1.

The success of PD-(L)1 has made many domestic enterprises "red-eyed", helpless research and development track is too crowded, the road to the sea is frequently frustrated, and another anti-tumor blockbuster target - TIGIT is gradually hot

Why is TIGIT so popular? This is because TIGIT and PD-(L)1 do have similarities in the mechanism of action

According to the data of Intranet, there are currently 13 TIGIT inhibitors in the world that have entered the phase II/III.

Some of the TIGIT inhibitors in the global pipeline

Source: New version of the database of Intranet

The fastest progress in the development of TIGIT in China is BeiGene's ociperlimab, which is intended for metastatic non-small cell lung cancer indications and has entered phase III clinical trial
。 According to the first report at the 2021 ASCO conference, the results of the phase I clinical trial of ociperlimab (BGB-A1217) combined with tirelizumab in humans confirmed that ociperlimab combined with tirelizumab had good tolerance in patients with advanced solid tumors, and the adverse events of the combination of the two drugs were similar to the use of tirelizumab monotherapy, and no dose-limiting toxicity (DLT) was observed, and the initial antitumor efficacy was observed with the combination of drugs
。

In addition, domestic TIGIT inhibitors such as Henlius Fuhong HLX-301, Junshi Biologics' JS-006, and Donghua Pharmaceutical's DW-2008S are undergoing Phase II clinical trials
.

From the perspective of comprehensive mechanism of action and market layout, TIGIT inhibitors are indeed expected to become the best "relay" of PD-(L)1, but according to the existing drug trial data, there is still a long way to go
from the drug listing, commercialization and market release stage.

Cooperative grouping, differentiated play breaks the ADC track under the innings

ADC (antibody conjugated) drugs are the most technologically mature drugs after the first wave of innovative drugs represented by PD-(L)1 monoclonal antibody, and major pharmaceutical companies are racing to develop them
.

Intranet data shows that there are currently more than 170 ADC drugs under research in China, of which 49 have entered clinical trials, most of which are Class 1 new drugs, a total of 30; There are 5 ADC drugs that have been approved for marketing, and popular targets include CD30, HER2, CD22, Trop-2, etc
.

Some of the ADC drugs in research in China

Source: New version of the database of Intranet

Judging from the current situation, some insiders believe that ADC drugs may "roll" into the next PD-(L)1, how should pharmaceutical companies further enhance their competitiveness in the fierce competition?

In this regard, the industry proposed that pharmaceutical companies can accelerate product development and commercialization
through cooperation.
It is reported that this year, a large number of pharmaceutical companies have announced that they have joined hands to develop, produce and promote the commercialization of
listed products.

On July 28, CSPC announced that it has entered into an exclusive licensing agreement
with Elevation Oncology, Inc.
for the development and commercialization of SYSA1801, the first anti-CLDN18.
2 antibody-conjugated drug of its kind outside of Greater China 。 Under the terms of the agreement, CSPC received a down payment of $27 million and was entitled to a potential development and regulatory milestone of up to $148 million, as well as a potential sales milestone payment of up to $1.
02 billion, and the right to receive a sales commission
of up to double-digit percentages based on annual net sales in authorized territories.

On July 26, Kelun Pharmaceutical announced a partnership and exclusive license agreement with Merck to develop an ADC drug
for the treatment of solid tumors.
Under the terms of the agreement, Cologne will exclusively license Merck for a fee to develop, manufacture and commercialize the ADC drug
worldwide.
The two companies will also collaborate
on the early clinical development of the ADC drug.
Merck will pay a down payment of $35 million, various milestone payments not to exceed $901 million, and a corresponding commission on net sales to Cologne in accordance with the terms of the agreement and the commercialization development phase
.

In addition, the industry believes that it can also break the game through differentiated play and consolidate its own advantages
.
For example, combined drugs provide a new solution for pharmaceutical companies
.
In theory, ADC drugs can be combined with immune checkpoint inhibitors, chemotherapy, anti-angiogenic agents and other therapies, and there is a possibility
of 1+1>2.
Therefore, compared with the "sea of people" of single drugs, ADC combined drugs also have great room for
development.