Focus on drug targets: PD-1 / PD-L1, when will the internal volume be closed?

In 2013, "Science" magazine listed tumor immunotherapy as the top ten scientific breakthroughs.

Programmed death receptor 1 (programmed death 1, PD-1) and programmed death-ligand 1 (programmed death-ligand 1, PD-L1) inhibitor PD-1 has two known ligands , PD-L1 Both PD-L2 and PD-L2 are highly expressed in placental tissues, and low in spleen, lymph nodes, and thymus.

Image source: ScienceDirect

When PD-1 binds to PD-L1, it causes phosphorylation of phosphatidylinositol-3-kinase, further activation of protein kinase B, activation of stimulatory T cell signaling pathways, glucose metabolism, and secretion of interferon, etc.

Blocking the PD-1/PD-L1 signaling pathway can upregulate T cell activation and activate endogenous anti-tumor immune responses, thereby exerting a therapeutic effect on tumors

Image source: Nature

1.

Global R&D landscape

At present, 15 PD-1/PD-L1 related drugs

A total of 15 PD-1/PD-L1 related drugs were approved, of which 6 were developed by domestic companies

2.

2.

It is predicted that the sales of PD-1/PD-L1 will continue to increase in the next five years.

Three, the domestic PD-1/PD-L1 research situation combing

Three, the domestic PD-1/PD-L1 research situation combing

Among the PD-1 monoclonal antibodies, 6 domestically produced PD-1 monoclonal antibodies have been approved for marketing, and 3 domestically-produced PD-1 monoclonal antibodies are in the production stage, namely Fuhong Henlius's slulimumab, Jiahe Biologics' Genozumab, Lepu Bio's Pratrizumab

6 domestically produced monoclonal antibodies have been approved for listing, and 3 domestically produced PD-1 monoclonal antibodies are in production

As a broad-spectrum immunosuppressant, PD-1/PD-L1 monoclonal antibody has achieved good clinical results in many tumors, but its overall response rate is relatively low at about 20%, which can benefit from PD-1 monoclonal antibody Of patients are always a minority

Immunobiological antibodies are expected to be differentiated from PD-1/PD-L1 monoclonal antibodies in some indications, and even have superior results.

Sorting out the PD-1/PD-L1 bispecific antibodies in the clinical stage in China

Fourth, the situation of key drugs

Fourth, the situation of key drugs

Foreign "O, K" drugs lead the PD-1/PD-L1 market, and the outcome of the two has been divided

O drug nivolumab is the world's first PD-1 inhibitor approved for marketing and the first in China

It may mean that K drug is also more effective than O drug in other cancers.

K drug pembrolizumab approved for indications

In August 2021, Odivo approved a combination of fluorouracil and platinum-based chemotherapy for the first-line treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma in China .

This is China's first immuno-oncology drug approved for the first-line treatment of advanced gastric cancer.

China is a big country with gastric cancer, and most patients are diagnosed with advanced gastric cancer
.
For the treatment of advanced gastric cancer, chemotherapy is basically the main treatment.
However, the therapeutic effect of chemotherapy is limited, and the 5-year survival rate of patients with advanced or metastatic gastric cancer is not ideal
.
Therefore, finding a better treatment plan has become an urgent need for the treatment of advanced gastric cancer
.
Previously, the phase III ORIENT-16 trial of domestic Sintilimab combined with chemotherapy showed that it can significantly improve the survival of patients with advanced/metastatic gastric cancer or gastroesophageal junction (GEJ) cancer
.
But comparing the number of participants, PFS and OS, O drug seems to be better
.

Domestic Sintilimab O drug seems to be better

Hundreds of domestic flowers bloom in full bloom, and the intensity is not inferior to that of foreign countries

The fierce domestic competition of PD-1/PD-L1 is well known
.
The first tier are the first four drugs that have been listed and have entered medical insurance, from Junshi Bio, Innovent, Hengrui Pharmaceuticals and BeiGene ; the second tier is the latest two drugs approved for marketing in August 2021 , Respectively , Pianprizumab and Sepalizumab
.
The third tier is a number of drugs in the clinical research and clinical application stage , including Genozumab (Jiahe Biotechnology), Slulimab (Fuhong Henlius), and Putlimumab (Lepu Bio)
.

Junshi Biologics, Innovent Biologics, Hengrui Pharmaceuticals , BeiGene Piplimumab and Sepalimumab Numerous clinical studies and clinical application stages

In the face of increasingly fierce competition, PD-1/PD-L1, in addition to expanding its indications and accelerating commercialization, is the key to achieving a large share of its market expansion
.
Esophageal cancer is one of the most common malignant tumors in China.
In 2020, China's new cases and deaths will account for more than half of the world
.
The five-year survival rate of esophageal cancer in China is only 15%-20%
.
Cinda's Sintilimab is expected to become the first domestically produced PD-1 drug for the first-line treatment of esophageal squamous cell carcinoma (ESCC), competing with K drug
.
In September 2021, the Phase III interim data for recurrent or metastatic ESCC was released at the ESMO conference, with a median OS of 16.
7 months (>12.
5 months in the placebo + chemotherapy control group), of which PD-L1 was positive (ESCC The positive expression rate of PD-L1 was 45.
5%) in patients with OS up to 17.
2 months (13.
6 months in the control group); the median PFS was extended to 7.
2 months compared with 5.
7 months in the control group.
Among them, patients with positive PD-L1 expression were increased by From 6.
4 months to 8.
3 months, there are no new safety signals
.

Esophageal cancer is one of the most common malignant tumors in China.
In 2020, China's new cases and deaths will account for more than half of the world
.
Sintilimab

Junshi’s teriprizumab also prioritizes the development of indications for esophageal cancer .
Its phase III clinical trial (JUPITER-06) of combined chemotherapy for the first-line treatment of advanced or metastatic ESCC is currently the best known overall survival time.
Long first-line treatment of advanced or metastatic esophageal cancer phase III clinical study
.
As of March 22, 2021, as assessed by the BICR, the median PFS of the teriprolizumab group and the placebo group were 5.
7 months and 5.
5 months, respectively, and the risk of disease progression or death was reduced by 42% (HR=0.
58) [95% CI: 0.
461-0.
738], P<0.
00001), 27.
8% of patients had no disease progression within 1 year, and the benefit ratio was more than 4 times that of the placebo group; at the same time, compared with chemotherapy alone, it prolonged patients In the survival period, the median OS was extended by 6 months, and the risk of death was reduced by 42% (HR=0.
58 [95% CI: 0.
425-0.
783], P=0.
00036)
.

Teriplizumab also prioritizes the development of indications for esophageal cancer

In August 2021, Paimprizumab (AK105) developed by Kangfang Biotechnology was approved for the third-line treatment of classic Hodgkin’s lymphoma , becoming the fifth domestically produced PD-1 monoclonal antibody product on the Chinese market, and another 2 The listing application for a new indication has been accepted by NMPA
.
At the same time, the core dual antibody products have made substantial progress : The clinical research and development of AK104 (PD-1/CTLA-4 dual antibodies) has made a number of substantive progress, with amazing clinical data; currently, registration for 2L/3L cervical cancer Phase II clinical trials have reached the main research endpoint, have obtained CDE's approval to submit NDA, and have shown excellent therapeutic potential in a number of major indications, including gastric cancer/gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, non-small cell lung cancer, etc.

.
In addition, AK112 (PD-1/VEGF dual antibody) has built a clinical development strategy with lung cancer as the core, and early research data is eye-catching [4]
.

Pianprizumab (AK105) developed by Kangfang Biotechnology is approved for the third-line treatment of classic Hodgkin's lymphoma.
Substantial progress has been made in the core dual antibody product AK104

Outlook

It has been less than 3 years since the first domestic PD-1 inhibitor teriprilimab was launched at the end of 2018.
However, the domestic PD-1/PD-L1 team on the market has grown to an amazing level.
Degree
.
How can PD-1/PD-L1 products occupy a place under the intensified internal volume and severe homogeneity of the competition? In addition to reducing production costs, expanding the layout of indications to accelerate commercialization to achieve the transformation of results, and the inclusion of medical insurance to compete for the terminal hospital market is also the key to its expansion of market share
.
In order to balance the international price stability of its PD-1/PD-L1 products, foreign-funded companies did not easily cut prices during the first two rounds of medical insurance negotiations, and they were not included in the medical insurance.
This has once again boosted prices for this year’s PD-1/PD-L1 medical insurance national talks Zhan left enough to watch and focus
.