With the same target, over ten domestic layouts of Hengrui are making the fastest progress. Who will become the leader?

The Merck M7824, which had previously developed a four-game losing streak, encountered resistance again

The PD-L1/TGF-β bifunctional fusion protein bintrafusp alfa (M7824), once known as the "second-generation PD-1", has experienced four consecutive failures in R&D in 2021.

As early as February 2019, the two parties had reached a cooperation on the research and development of M7824 in refractory cancer, and signed a global cooperation development agreement of up to 4.

Now Merck said that the cessation of cooperation with GSK is mainly based on the failure of the Phase III clinical INTR@PIDLung037 study to replicate the encouraging data observed in earlier studies

Although no TGF-β target-related drugs have been successfully marketed globally, there is no doubt that PD-L1/TGF-β is already one of the hottest targets in China, including Hengrui, Promis Biosciences, and pioneering drugs.

The world's first PD-LI/TGF-β bifunctional fusion protein M7824 has been developed one after another, making the efficacy of this therapy continue to be questioned

01 "Mercury Retrograde" in 2021

Before this year, M7824 was regarded as a rising star in the field of tumor immunity, and 2021 seemed to be the year of the Mercury retrograde for M7824, and R&D suffered a four-game losing streak

This pioneering dual-function immunotherapy can simultaneously block the two immunosuppressive pathways of TGF-β and PD-L1 in the tumor microenvironment, relieve the immune system’s suppression state, and improve the immune system’s killing effect on cancer cells.

M7824 used to have a lot of beauty

At ASCO in 2018, Merck announced the clinical research data of its new drug M7824 under development

In animal experiments, the effective rate of M7824 has reached an astonishing 100%

The excellent test data made M7824 attract attention, and it was once known as the second-generation PD-1

In January this year, M7824 R&D suffered successive setbacks

Firstly, M7824 was used in the phase II (NCT03436563) study of patients with advanced microsatellite instability (MSI-H)/mismatch repair defect (dMMR) solid tumors after receiving immune checkpoint inhibitors (ICB).

Immediately afterwards, the Independent Data Monitoring Committee (IDMC) also recommended that the INTR @PID Lung 037 clinical trial of this therapy in non-small cell lung cancer be stopped because the study is unlikely to reach the common primary endpoint of progression-free survival (PFS)

In March of this year, the phase II INTR@PID BTC 047 of M7824 used alone for the second-line treatment of locally advanced or metastatic biliary tract cancer (BTC) failed to reach the primary endpoint again, and the clinical trial was terminated again

However, the "decline" of M7824 has not passed
.

In August of this year, the independent data monitoring committee concluded that M7824 combined with gemcitabine and cisplatin, used in the first-line treatment of locally advanced or metastatic biliary tract cancer (BTC) patients, is unlikely to reach the primary endpoint of overall survival (OS).
Ke said that he will stop the Phase 2 INTR@PID BTC 055 trial of this therapy
.
This is the second failure of M7824 in the indications of biliary tract cancer, and it also announced that all the exploration of M7824 in biliary tract cancer ended in failure
.

According to Merck’s previously announced clinical plans around M7824, clinical trials will include trials for breast, urothelial cancer and cervical cancer, including M7824 combined with chemotherapy for the second-line treatment of cervical cancer and HMGA2-positive triple-negative breast cancer ( TNBC), and a phase II trial for the first-line treatment of non-small cell lung cancer.
However, as the clinical trials of this therapy have repeatedly failed, the efficacy of PD-L1/TGF-β bifunctional fusion protein therapy has also been more questioned
.

R&D has suffered four consecutive defeats, and the future of PD-LI/TGF-β is full of haze
.

02 Follower Hengrui is the fastest, who will be the leader?

After the success of M7824, who among the followers will stand out and even become the next leader in this field?

More than ten pharmaceutical companies such as Hengrui Pharmaceuticals, Pumis Biotechnology, Chuangsheng Group, and Kaixing Pharmaceutical have deployed in this field.
From the perspective of progress, Hengrui's SHR-1701 has made the fastest progress and has reached phase III clinical trials.
At this stage, similar products of other companies are also in different clinical trials at home or globally
.

Hengrui's SHR-1701 is the first product to be declared for clinical use in China, and it is also the fastest-growing product currently
.
In February 2018, SHR-1701 was applied for clinical application for the first time, even earlier than the time when Merck’s M7824 was first applied in China
.
Currently, SHR-1701 has initiated 13 related clinical studies
.
On September 6 this year, SHR-1701 has two more indications approved for clinical phase III
.

SHR-1701 is an anti-PD-L1/TGF-βRII bifunctional fusion protein, which can promote the activation of effector T cells, and at the same time can effectively improve the immune regulation in the tumor microenvironment, and ultimately effectively promote the immune system to tumor cells.
The killing
.
According to Hengrui's disclosure, SHR-1701 injection has carried out a number of solid tumor clinical trials in China and phase I clinical trials in Australia
.
In the 2021 ASCO annual meeting, Hengrui announced the Phase I clinical data of SHR-1701 for solid tumors and EGFR-mutant NSCLC.
Among them, SHR-1701 was used for solid tumors with an ORR of 17.
8% and a DCR of 40%; SHR-1701 was second-line The ORR for the treatment of EGFR-mutant NSCLC (EGFRTKI resistance) reached 16.
7%, DCR was 50%, and the TRAE rate above grade 3 was 7.
4%, including anemia, hypokalemia, etc.
, without grade 4-5 TRAE
.

As of September this year, SHR-1701 related projects have invested a total of about 222 million yuan in research and development expenses
.

Pumis Bio's PM8001 is also in a relatively leading position
.
From the structural point of view, PM8001 is similar to M7824.
The N-terminus can recognize the antibody structure that binds to PD-L1, and the C-terminus can bind to the TGF-β receptor type II fusion protein of TGF-β; it does not contain a light chain structure, and there is no light or heavy Chain mismatch problem; and the molecular weight is small, and the ability to penetrate solid tumors is strong
.

On August 14, 2020, PM8001 registered a phase I/IIa clinical trial.
The trial is a single-arm study.
The phase I part plans to enroll 37 patients with advanced solid tumors and the phase IIa plan to enroll 210 patients with advanced solid tumors
.
Part of the phase I studies tolerability, safety, and pharmacokinetic characteristics, phase IIa explores the preliminary efficacy of PM8001 in solid tumors
.

As of September this year, of the 11 PD-(L)1/TGFβ double antibodies or bifunctional fusion proteins that have entered the clinical stage in the world, with the exception of M7824, the remaining 10 products are all from China
.

Different from other companies who are gathering in PD-L1/TGF-β research and development, Junshi Bio has chosen the PD-1/TGF-β dual target to develop JS201, which is also the world's first PD-1/TGF-β dual antibody
.

Just recently, another company entered this track
.

On October 9th, the clinical trial application for TST005 injection of Mabos Biotech was accepted by the State Food and Drug Administration
.
It is understood that Chuangsheng Group announced on April 21 this year that the TST005 clinical trial application has been approved by the FDA, and on July 15 announced that the TST005 global phase I clinical study has completed the first patient administration
.
After the domestic clinical acceptance, TST005 became the second bifunctional anti-PD-L1 and TGF-β trap fusion protein to initiate global clinical research, and simultaneously targeted two pathways commonly used by cancer cells to escape immunosuppression, namely transforming growth Factor-β (TGF-β) and programmed cell death ligand-1 (PD-L1)
.

Obviously, the amazing data of M7824 not only "captured" GSK, but also made domestic pharmaceutical companies choose to follow up the research of PD-L1/TGF-β double antibody
.
Now, M7824 has frequently broken, and partners have terminated global cooperation, increasing the risk of research and development of this target
.
For domestic pharmaceutical companies with existing layouts, if M7824 eventually fails, it will cast a shadow over the future of products that follow research and development
.