Competing for the dual anti-race track, Kang Fang took the lead in starting the race. There are 67 domestic projects. Who is the hottest partner of PD-1?

Author: plus one

On August 23, Kangfang Biological announced that it had obtained CDE's approval to submit its PD-1/CTLA-4 dual-antibody AK104 new drug listing application and obtained priority review qualification
.

Bispecific antibodies (BsAb, Bispecific Antibodies) recognize and bind two different antigens at the same time, in order to achieve 1+1>2 curative effect and better safety
.

As for domestic projects, a total of 67 double antibodies have entered the clinical stage
.

Jihuo PD-1/PD-L1, companies are competing to develop "second-generation PD-1"?

The PD-1 monoclonal antibody racetrack is serious.
Whether it is to chase the glory of the PD-1 pioneers in the past, or to try to avoid the overheated monoclonal antibody track, companies have turned their attention to other biological drugs, and double antibodies are among them.
A hot spot
.

According to the Insight database, among the 67 domestic dual-antibody projects in clinical phases, one of 35 products targets PD-1/L1, followed by the classic dual-antibody target CD3.
There are 15 projects in total
.

According to the Insight database, in addition to Kangfang Bio, which has submitted a new drug marketing application, there are two other domestic dual antibodies that are closely following them.
As early as 2020, they have entered phase III clinical trials, namely Innovent Bio's PD-1 /PD-L1 double anti-IBI318 and Corning Jerry’s PD-L1/CTLA-4 double anti-KN046
.

Started clinical domestic double antibody

(As of 2021.
8.
24, fusion protein is not included)

Cinda’s IBI318 is a recombinant fully human IgG1 bispecific antibody that targets PD-1/L1, designed to block PD-1 and PD-L1/PD-L2 signaling pathways, and block PD-L1 Combined with CD80 signaling pathway, restore T cell activation and anti-tumor function
.

Corning Jereh’s KN046 is composed of a fusion of CTLA-4 and PD-L1 single domain antibodies with different mechanisms, which can target the tumor microenvironment enriched in the high expression of PD-L1 and eliminate Tregs that inhibit tumor immunity
.

According to the Insight database, currently KN046 has launched 12 clinical trials in China, including one Phase 2/3 clinical trial and one Phase 3 clinical trial, all for NSCLC
.

KN046 project details

From Insight database (http://db.
dxy.
cn/v5/home/)

PD-1/L1 partners: Who is the hottest?

According to Insight statistics, the partner target of the domestic PD-(L)1 double antibody is neither the classic combination target CTLA-4, nor the recently popular CD47, but TGFβ
.

Including dual target fusion proteins, there are currently 8 PD-(L)1/TGFβ double antibodies or dual target fusion proteins under research in China
.

Pumis Biologics PM8001 is second only to Hengrui, and has initiated phase I/IIa clinical trials for advanced solid tumors
.
Junshi’s JS201, Youzhiyou’s Y101D, and Qilu’s QLS31901 have also entered phase I clinical trials
.

The enthusiasm for PD-(L)1/TGFβ development is largely derived from Merck's M7824
.
On ASCO 2018, the clinical trial data of M7824 for NSCLC (NCT02517398) was unveiled
.
The study enrolled 80 patients with advanced NSCLC who had never used PD-1 inhibitors
.

The results showed that among the 40 patients in the 1200 mg dose group, M7824 was the second-line treatment of advanced NSCLC, the total population ORR was 27.
5%, the ORR of PD-L1 positive (≥1%) patients reached 40.
7% (11/27), PD- The ORR of patients with high L1 expression (≥80%) is as high as 71.
4% (5/7), which is double the general PD-1 efficacy data
.
In February 2019, GlaxoSmithKline signed a cooperation agreement with Merck Group for a total of 3.
7 billion pounds, authorizing the introduction of M7824 bifunctional fusion protein immunotherapy
.

The three-year follow-up results of the study were announced at the ESMO conference in 2020.
The data is still excellent.
The OS rates of the 1200 mg dose group at 12, 24 and 36 months were 66.
2%, 39.
7% and 23.
2%, respectively
.
The median OS of PD-L1 positive (≥1%) patients is 21.
7 months, and the PD-L1 high expression patients (≥80%) have not yet reached the median OS
.
The 36-month OS rate of PD-L1 positive patients was 33.
6%, and that of PD-L1 high expression patients was 66.
7%
.
Compared with the current 3-year OS rate of PD-1 monoclonal antibody, especially in the population with high expression of PDL1, there is a significant increase
.

However, the current situation of this star drug does not seem to be very positive
.
Today, Merck announced the failure of M7824 in the first-line treatment of cholangiocarcinoma in phase II clinical trials and terminated the exploration
.
This is the third clinical failure of M7824
.

The first clinical failure of M7824 came from the Phase 3 clinical trial of head-to-head PK with K drug
.
Based on the data of M7824 in second-line lung cancer superiority, M7824 continued to explore the Phase III clinical (NCT03631706) data of people with high PD-L1 expression (TPS≥50%) in the first-line treatment compared with K drug head-to-head
.
However, in the January 20, 2021, Merck announced INTR @ PIDLung037 efficacy studies below expectations, with the head to head K drug overturned
.

On March 16, German Merck announced another clinical failure of M7824, failing to reach the preset primary endpoint
.
This is a phase II clinical trial for the second-line treatment of cholangiocarcinoma (BTC)
.

On August 24th, Merck announced the failure of the first-line treatment of cholangiocarcinoma phase II
.
A number of consecutive clinical failures have cast a shadow over this blockbuster drug that was once considered to be infinitely promising
.

At present, M7824 is still exploring indications for first-line and second-line cervical cancer, advanced NSCLC, and triple-negative breast cancer
.
I hope the follow-up of this blockbuster drug will progress smoothly, and the future data of similar domestic products will bring new dawn to this field
.