Merck's Investigational Bifunctional Fusion Protein M7824 Receives CDE Acceptance for New Clinical Trial Application in China

Original: Little Pill

Recently, Merck KGaA has once again submitted a clinical trial application in China for its key investigational new drug M7824, which has been accepted by the Center for Drug Evaluation (CDE).

Source: CDE

Bifunctional Protein: Upgraded PD-1 Antibody

Since 2018, Opdivo and Keytruda have been successively launched in China, filling the gap in the domestic field of tumor immunotherapy. Subsequently, multiple domestically produced PD-1 monoclonal antibodies have been approved for marketing, providing more treatment options for patients in China.

From the perspective of their mechanism of action, these PD-1 immune checkpoint inhibitors primarily work by binding to immunosuppressive molecules via antibodies, thereby reactivating the body’s immune cells to attack cancer cells. Clinical practice has confirmed that patients who respond successfully to PD-1 monoclonal antibody therapy can achieve long-term survival. However, the inherent limitations of existing PD-1 immune checkpoint inhibitors cannot be ignored: the failure rate is too high, with an efficacy rate of only around 20% for most tumors.

Research has found that a key reason for the failure of PD-1 immune checkpoint inhibitors, such as Opdivo and Keytruda, lies in the transforming growth factor-beta (TGF-β) produced by tumor cells. Based on this finding, Merck is currently developing M7804, a next-generation PD-1 antibody drug.

As a novel bifunctional fusion protein, M7824 is composed of an IgG1 monoclonal antibody targeting the PD-L1 protein fused to the human transforming growth factor-beta (TGF-β) receptor type II. In terms of drug design, M7824 not only inhibits the PD-L1 ligand, thereby exerting the function of conventional PD-1 antibodies, but also suppresses the TGF-β pathway, alleviating immunosuppression of immune cells and reducing the likelihood of cancer metastasis. This dual-target synergy enhances the cytotoxic effect of immune cells against tumor cells. Compared with PD-1 monoclonal antibody drugs, this bifunctional protein can significantly improve therapeutic efficacy and reduce adverse reactions associated with combination therapy involving PD-1 monoclonal antibodies and other agents.

Given its various advantages, M7824 is referred to as an upgraded PD-1 antibody and is expected to surpass drugs O and K in the future.

Stunning Clinical Data

Early studies in multiple murine tumor models have confirmed that M7824 can specifically bind to PD-L1 and all three isoforms of TGF-β (TGF-β1, 2, and 3). Treatment with M7824 resulted in a substantial reduction in tumor volume in mice, demonstrating superior efficacy compared to the use of either anti-PD-L1 or anti-TGF-β antibodies alone.

In early June 2018, Merck KGaA presented clinical trial data for M7824 in non-small cell lung cancer (NSCLC) and HPV-positive tumors at the American Society of Clinical Oncology (ASCO) Annual Meeting, with encouraging results.

In the Phase I clinical trial for patients with non-small cell lung cancer (NSCLC), the overall response rate (ORR) was 22.6% in PD-L1-positive patients (PD-L1 ≥1%) and 33.3% in patients with high PD-L1 expression in the 500 mg dose cohort. In the 1200 mg dose cohort, the ORR reached 40.7% in PD-L1-positive patients (PD-L1 ≥1%) and was as high as 71.4% in patients with high PD-L1 expression. This performance was significantly superior to that of PD-1 antibodies in similar patient populations.

Source: Compiled from public information

Multiple Investigational Indications: Head-to-Head Comparative Studies with Keytruda

Currently, Merck KGaA has initiated multiple clinical trials for M7824, implementing a multi-faceted development strategy. The indications under investigation cover non-small cell lung cancer, colorectal cancer, esophageal cancer, gastric cancer, recurrent respiratory papillomatosis, gallbladder cancer/cholangiocarcinoma, prostate cancer, and various HPV-associated malignancies.

Notably, in the Phase II clinical trial (NCT03631706) evaluating first-line treatment for non-small cell lung cancer, Keytruda was designated as the control arm, with Merck conducting a head-to-head comparative study of M7824 versus Keytruda. The trial was initiated in mid-October 2018 and is currently in the recruitment phase, aiming to enroll 300 participants. The final results are highly anticipated.

In the Chinese market, Merck KGaA has submitted multiple clinical trial applications for M7824 since November 2018. Two clinical studies have been conducted in China: one is a Phase II clinical trial of M7824 monotherapy for locally advanced or metastatic cholangiocarcinoma (CTR20191364), and the other is a comparative study of M7824 combined with pembrolizumab as first-line treatment for PD-L1-positive advanced non-small cell lung cancer (CTR20190305).

The clinical trial application mentioned at the outset is the fourth such submission by Merck KGaA for M7824 in the Chinese market, highlighting Merck’s strategic layout in China.

Domestic Similar Drugs

In China, Hengrui Medicine has strategically positioned itself with a bifunctional antibody targeting PD-L1 and TGFβ.

In February 2019, SHR-1702 injection, an investigational new drug under development by Hengrui Medicine, advanced into Phase I clinical trials. Currently, this clinical trial (CTR20190638) is ongoing, with plans to enroll 54 to 78 participants in China. The primary objective is to determine the dose-limiting toxicities and maximum tolerated dose of SHR-1702 as a monotherapy or in combination with camrelizumab in patients with advanced solid tumors.

In the field of bispecific antibodies targeting PD-L1 and TGFβ, Hengrui Medicine is leading the development race among domestic pharmaceutical companies.

Original Title: Antibodies | New Clinical Trial Application in China: Merck’s Upgraded PD-1 Antibody Is Here Again!