"KOT" dominates the $36 billion global PD-(L)1 market, accounting for more than 90%. Hengrui Xinda Baekje Junshi, rely on what competition?

"The PD-(L)1 inhibitor market is facing strong headwinds

Recently, IQVIA released the report "In the Eye of the Storm: PD-(L)1 Inhibitors Weathering Turbulence", which analyzes

According to IQVIA statistics, the global PD-(L)1 inhibitor market size in 2021 is 36 billion US dollars, K drug (Keytruda), O drug (Opdivo) and T drug (Tecentriq) three PD-(L) 1 accounted for 91% of the global market, of which K drug accounted for 54%, O drug accounted for 26%, Tecentriq accounted for 11%, other PD-(L)1 inhibitors accounted for only 9%.

With more than 5,600 clinical trials worldwide investigating PD-(L)1 inhibitors, regulators are alarmed

But as the PD-(L)1 market matures, the compound growth rate is expected to slow to 15% over the next 5 years, with IQVIA predicting global sales to reach $

Source: IQVIA Report

This also poses a challenge to the growth of other PD-(L)1s, with K-, O and T-becoming standard therapies for indications, and approval of new indications will have to be head-to-head with standard therapies, which means that breakthroughs

Source: IQVIA Report

Looking back at China, including the PD-1 Four Dragons Xinda, Junshi, Hengrui and Baekje, a total of 9 domestic PD-(L)1 have been approved for listing, but so far there has not been 1 domestic PD-(L)1 to enter the US market

01 How big is the gap?

How big is the gap? The size of the market is the most intuitive evidence

As mentioned above, the global market size of PD-(L)1 inhibitors will be $36 billion in 2021, and the three PD-(L)1 models of K drug, O drug and Tecentriq occupy 91% of the global market, of which K medicine accounts for 54%, O drug accounts for 26%, and Tecentriq accounts for 11%.

Iqvia counts three domestic PD-1s - Innovent Sindilliumab, BeiGene's Tirelizumab and Hengrui's Carellizumab, which occupy 0.

Then the follow-up PD-(L)1 will not have a chance at all?

Not really

Local pharmaceutical companies have made a variety of attempts at combination therapies, and even some pharmaceutical companies have developed

According to the information disclosed in the 2022 semi-annual report of Hengrui Pharmaceutical, at present, carellizumab has been approved for 8 indications in China, and the treatment areas involve lymphoma, hepatocellular carcinoma, esophageal squamous cell carcinoma, nasopharyngeal cancer and non-small cell lung cancer

It is worth noting that in addition to carellizumab, Hengrui also has a PD-L1 Adebellumab and a PD-L1/TGF-β dual antibody SHR-1701 in the pipeline

PD-L1/TGF-β dual anti-SHR-1701 has 12 indications under study, of which advanced colorectal cancer, advanced or metastatic gastric cancer or gastroesophageal junction cancer, resectable gastric cancer or gastroesophageal junction cancer perioperative treatment, and EGFR mutation advanced or metastatic non-scaly non-small cell lung cancer and other 4 indications have been carried out to clinical phase

Source: Hengrui 2022 semi-annual report

According to the official website of Xinda Biologics, Xindili monoclonal antibody has been approved in China for 6 indications and four have been successfully included in the national medical insurance directory

In addition, the listing application of sindilimab combined with bevacizumab and chemotherapy for epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment failure of EGFR mutant non-squamous non-small cell lung cancer has been accepted by NMPA for review and is expected to receive a regulatory decision
by the end of 2022.

Up to now, Innovent has more than 20 clinical studies (more than 10 of which are registered clinical trials) underway, of which 6 indications, including second-line squamous non-small cell lung cancer, first-line gastric cancer combined with ramosumab, and second-line classical Hodgkin lymphoma combined with ICE, are undergoing clinical phase
III.

It is worth noting that according to the semi-annual report, Innovent Bio also has 3 dual antibodies involving PD-(L)1 targets under study, namely CD47/PD-L1 dual antibody IBI-322, LAG-3/PD-L1 double antibody IBI-323 and PD1/IL2 double antibody IBI-363, all three dual antibodies are used to treat malignant tumors, and Innovent expects to carry out clinical 1B research on IBI-322 and IBI-323 in the second half of 2022.
and advance IBI-363 into clinical research
.

Source: Cinda Biotech 2022 Semi-annual Report

BeiGene's 2022 semi-annual report disclosed that sales of terelizumab in the first half of the year were 193 million US dollars (about 1.
326 billion yuan), an increase of 54.
8%
year-on-year.

According to the BeiGene announcement, as of August 23, a total of 9 indications of terelizumab have been approved in China, including non-small cell lung cancer, lymphoma, urinary celiac carcinoma, hepatocellular carcinoma, nasopharyngeal carcinoma
and other cancers.
In addition, the application for the first-line treatment of non-resectable locally advanced, recurrent or metastatic squamous cell carcinoma (ESCC) and combination chemotherapy for the first-line treatment of patients with advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinomas with tumor expression has been accepted
by the NmPA.

BeiGene did not disclose the specific research and development progress of tirelizumab in its semi-annual report, but according to the previous statistics of the E drug manager, CLINICALTRIALS.
GOV data showed that there were 76 clinical trials
of tirelizumab (BGB-A317).
The most notable thing about BeiGene's PD-1 is the number of multi-center clinics worldwide, with almost every clinical pipeline being globally multicentre
.

In addition, in the 2021 annual report disclosed by BeiGene, it also has a PD-L1 monoclonal antibody BGB-A333 and a PD-1+IL21 dual anti-AMG-256 in research
.
BeiGene has disclosed preliminary safety and efficacy data on BGB-A333 as a single drug and in combination with terelizumab in the treatment of patients with advanced solid tumors at the 2020 American Association for Cancer Research (AACR) Online Annual Meeting, and has now progressed to clinical phase II research
.
The latter AMG-256, one of the projects introduced by BeiGene from Amgen, is still under clinical IB study, and BeiGene has not disclosed any further relevant progress
.

Junshi Bio's treprliplimab is the first domestic PD-1 approved for listing, but unlike several other domestic PD-1 that entered the medical insurance almost at the same time, Junshi adopted the method of expanding the scope of small indications, and the first one approved was melanoma, which also led to the fact that in 2021, when only small indications were included in the national medical insurance directory, and the adaptable certificates for a larger number of people had not yet been approved for listing, although the sales volume in 2021 increased, it failed to achieve "price for volume".
This led to a negative increase
in sales revenue.

According to the latest announcement of Junshi Bio on July 7, there are 5 indications of triprimumab that have been approved in China, including melanoma, nasopharyngeal carcinoma, urinary intestinal carcinoma, esophageal squamous cell carcinoma, non-small cell lung cancer, etc
.
More than 30 clinical studies
covering more than 15 indications have been conducted in China, the United States, Southeast Asia and Europe.

Source: Junshi Bio 2021 Annual Report

Similarly, according to the 2021 annual report of Junshi Bio, PD-L1 and PD-(L)1 related dual antibodies are also laid out in the pipeline of Junshi Bio, which are PD-1/TGF-β dual antibody JS201, PD-1 monoclonal antibody JS001sc, PD-L1 monoclonal antibody JS003, PD-L1/undisclosed double antibody JS211 and IL-2/PD-1 double antibody JS206, respectively, JS201 has progressed rapidly and has completed the first clinical patient administration.
JS001sc was also approved for clinical trials
.

Source: Junshi Bio 2021 Annual Report

For the above four PD-1 companies that have entered the medical insurance, the future competition is the expansion of the indications and going to sea, and for the latecomers such as Kangfang, Yuheng, Cornerstone, and Fuhong Henlius, it may be necessary to face the test
of the 2022 medical insurance negotiations first.

Kangfang Bio's piambrolizumab has been commercialized in August 2021, with sales of 279 million yuan in the first half of 2022, and the indications for nasopharyngeal carcinoma, non-small cell lung cancer and hepatocellular carcinoma of paamprizumab have also entered the clinical stage III or NDA stage
.
In the first half of the year, CSTONE Was approved for marketing of Suglizumab, becoming the only anti-PD-1/PD-L1 monoclonal antibody
approved for phase III and PHASE IV NSCLC in China.

Slulizumab was approved for marketing in China in March 2022 for use in microsatellite instability-high (MSI-H) solid tumors
that have failed standard treatment and are not resectable or metastatic.

However, several latecomers are also developing PD-(L)1-related dual antibodies, such as Kangfang's PD-1/VEGF dual antibody AK112 and PD-1/CTLA-4 dual antibody AK104, both of which have entered the development
of clinical phase III.

02 Who will achieve the first trip to sea?

With the domestic PD-(L)1 breaking the pattern of the original 4 competition, PD-(L)1 in the domestic competition is becoming more and more fierce, going to the sea has become a necessary strategy for each enterprise, and each company also has different strategic choices
.

The first is that the four PD-1s that have already entered medicament have already entered the critical review and approval stage
.

In March 2022, Innovent Biotech's PD-1 was "rejected" by the FDA
.
In its reply letter, the FDA said that additional clinical trials need to be supplemented before approval to demonstrate the applicability of sindilizumab in the U.
S.
population and in U.
S.
medical practice, and recommend that sindilimab be combined with chemotherapy and standard therapy with first-line metastatic NSCLC for multi-regional non-inferior efficacy clinical trials
with overall survival as an endpoint.

But this is not a sign that Cinda is folding in the field of PD-1, in addition to continuing to cooperate with Eli Lilly to introduce Sindili monoclonal antibody to the U.
S.
market, according to Cinda's semi-annual report, the above-mentioned PD-L1/CD47 dual antibody IBI-322 is also advancing clinical practice
in the United States.

Unlike the way Cinda and Eli Lilly have partnered, Hengrui seems to have chosen the company's approach to bring the PD-1 to the United States
.

On May 18, EST, a new wholly-owned subsidiary of Hengrui, Luzsana BiotechnologyTM (hereinafter referred to as Luzsana), officially unveiled
in Princeton, New Jersey, USA.
Among the 11 high-potential projects that Luzsana initially selected, Carellizulizumab was among them
.
According to reports at the time, Luzsana planned to discuss with the FDA a potential application for
the combination of PD-1 monoclonal carreli beads with the VEGFR-2 inhibitor apatinib.
Once approved, Carelli beads could become the second PD-1
to enter the first-line treatment for liver cancer.

In Hengrui's semi-annual report, it was also disclosed that the international multicenter III study of carrelizumab combined with apatinib for the treatment of advanced liver cancer has submitted a listing application in China, and the project team has started the preparatory work
before the submission of the US FDA BLA/NDA.

In terms of progress, the four companies seem to be vying for PD-1 to be no.
1, but all seem to have encountered regulatory obstacles
.

According to the BeiGene Semi-Annual Report, due to travel-related restrictions that could not complete the on-site verification work, the FDA extended the approval time for the approval of
new drug marketing authorization (BLA) for second-line (2L) treatment of patients with unresectable or metastatic ESCC.
The BLA is still under approval and has not yet provided an expected approval date
for the update.

Also in July, Junshi Bio also issued an announcement that the FDA accepted Junshi Bio's resubmitted application for the first-line treatment of triprilizumab combined with gemcitabine/cisplatin as a first-line treatment for patients with advanced recurrent or metastatic nasopharyngeal cancer and a single drug for second-line and above treatment after platinum-containing treatment for relapsed or metastatic NASOPharyngeal carcinoma (BLA).

The FDA has set a target review date for the Prescription Drug User Payment Act (PDUFA) as December 23, 2022
.
The FDA earlier said that due to its need for on-site verification in China, the time limit for resubmitting the BLA for review will be six months
.
If approved, the Company's partner, Coherus, plans to launch tereplimonab in the U.
S.
in the first quarter of 2023, and it will become the first and only tumor immune drug
for nasopharyngeal cancer treatment in the United States.

CStone, on the other hand, chose to give Schuglizumab overseas commercialization rights to EQRx
.
However, it has to be mentioned that EQRx is a company dedicated to the development of low-cost homogeneous drugs, and suglizumab is used as a core product
when valuation.

It is reported that the treatment of recurrent or refractory natural killer cell/T cell lymphoma (R/RENKTL) in adults with sugliform monoclonal antibody has been recognized by the FDA as a breakthrough therapy, and suglizumab for the treatment of T-cell lymphoma has also obtained orphan drug qualification
.

References for this article:

IQVIA Report "In the Eye of the Storm: PD-(L)1 Inhibitors Weathering Turbulence"

2.
Annual reports and semi-annual reports of each enterprise