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Jin Zhang M.D., Ph.D is editor at The Pharmaceutical Consultant.
Both foreign and domestic pharmas are in a race to bring PD-1/PD-L1 inhibitors into China, writes Jin Zhang.
In recent years, the PD-1 inhibitor has emerged as a rising star in the field of oncology. Its main mechanism of action is to destroy cancer’s immune inhibition machinery and activate the recognition and attack of tumor cells by the human immune system at the same time. Since its first approval by FDA in 2014, it has been used a wide range of applications for various cancers. With an expected peak market size of $35 billion, it is on its way to replacing Humira to become the number 1 selling drug globally.
Riding on its rising economy, China is increasingly playing an important role in global drug competition. Both foreign and domestic pharmas are in a race to bring PD-1/PD-L1 inhibitors into China in an attempt to seize the market.
In 2018, BMS and Merck successfully received approvals for their PD-1 antibodies in China, becoming the first two players there. However, Junshi Pharma and Innovent Bio, two Chinese pharma companies, subsequently snatched greenlights from the NMPA (formerly the Chinese FDA) within less than half a year. Soon after, Hengrui Medicine became the third domestic pharma granted approval.
There is more to come. At present, BeiGene, Roche, and AstraZeneca are waiting for NMPA NDA approvals. In addition, more than 10 other companies, including Pfizer, Fosun Pharma, etc., are conducting clinical trials in hopes of getting a slice of this lucrative market.
Below is a list of leading PD-1/PD-L1 monoclonal antibodies in the Chinese market
Approval in China
Submitted for approval
Hodgkin’s lymphoma, previously treated or metastatic urothelial carcinoma
Table 1. Latest approval and development of PD-1/PD-L1 antibodies in China.
China’s cancer disease spectrum is very different from that of the West. At present, lung cancer, stomach cancer, liver cancer, and esophageal cancer are the four most prevalent solid tumors there. It is expected that the population most suitable for anti-PD-1/PD-L1 treatments is around 2.04 million. Therefore, clinical development in China should focus on first-line combined treatments for these four major indications. Less prevalent indications, such as melanoma, lymphoma, etc., also serve as a means to quickly access the market. Indeed, the four leading Chinese domestic pharmas, Hengrui Medicine, Innovent, BeiGene, and Junshi Pharma, are applying this approach. Their first approved indications are for these diseases, such as melanoma (Table 2) and Hodgkin’s lymphoma (Table 3).
Table 2. The comparison among approved PD-1 antibodies for Hodgkin’s lymphoma in China
Table 3. The comparison among approved PD-1 antibodies for melanoma in China
In terms of application coverage, Hengrui Medicine is currently leading the race among Chinese domestic pharma companies (Table 4). It is equipped with the most extensive pipeline, with multiple indications targeting China’s most popular tumors already in phase III studies. BeiGene, Innovent, and Junshi trail just behind.
Phase 3: Second line for liver cancer, first line for NSCLC, first line for late stage for esophageal cancer
Phase 2: second line for chemo and TKI failed NSCLC, relapse and refractory cHL, relapse and refractory NK/T lymphoma; first line and second line for late stage liver cancer, late stage NSCLC
Phase 1: liver cancer, late stage stomach cancer, late stage esophageal cancer, nasopharyngeal carcinoma, late stage solid tumor, late stage melanoma
Phase 3: second line for chemo and TKI failed NSCLC, relapse and refractory cHL, relapsed and refractory NK/T lymphoma; first line and second line for late stage liver cancer, late stage NSCLC, esophageal cancer, liver cancer
Phase 3: late stage or metastatic NSCLC, esophageal cancer, adenocarcinoma at the junction of stomach
Phase 2: late stage liver cancer, esophageal cancer, relapse and refractory classic Hodgkin’s lymphoma,
Phase 1: solid tumor
Phase 3: EGFR sensitive and EGFR-TKI failed late stage NSCLC, fourth stage or recurrent metastatic TNBC, untreated late stage or recurrent metastatic esophageal cancer, liver cancer, relapse or metastatic nasopharyngeal carcinoma, unremovable or metastatic melanoma
Phase 2: late stage or relapse EGFR sensitive T790M negative NSCLC, mucosal melanoma, bladder cancer
Phase 1: TNBC, endocrine tumor, kidney tumor, stomach cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell cancer
Table 4. The current development pipeline for PD-1 antibodies of leading Chinese pharma companies
Drug safety is as important as efficacy. To comprehensively evaluate a drug’s safety, multiple factors need to be considered carefully, including the past monoclonal antibody production experience, the ability to select the right patient population, and the quality control system. Based on these criteria, the four leading Chinese pharmas in this space are BeiGene followed by Hengrui Medicine, Innovent, and Junshi Pharma.
At present, the biggest shortcoming of Chinese pharmas is the lack of biopharmaceutical development and production experience, because of its late development. Overseas pharma giants, such as BMS, MSD, Roche, and AZ, have all accumulated years of experience in the industry and their development and production processes are more mature.
Furthermore, all of the foreign developed PD-1/PD-L1 antibodies are approved with their own companion diagnosis. So far, research suggests that the higher the PD-L1 expression, the more efficient the treatment. And according to preliminary standardization results of different companion tests, 22c8, 28-8, and sp263 are shown to be consistent.
None of the four Chinese pharma companies have so far developed related companion diagnosis. Thus, how to select the right patient population and avoid unsuitable ones will be a huge challenge for them in the future
As anti-PD-1/PD-L1 has become increasingly widely applied to different types of cancers, people’s perceptions about it have also begun to shift. However, the limited clinical use of immunotherapy alone has been bothering scientists across the industry. Increasingly, combination therapies with other drugs, such as chemotherapies and targeted therapies, have become an effective way to improve the response rate. All major PD-1/PD-L1 manufacturers are actively exploring this field. So far, a number of encouraging results have been achieved.
Toripalimab & albumin paclitaxel
Currently, Junshi is actively developing a combination therapy of toripalimab and albumin paclitaxel in triple negative breast cancer. This is a collaboration with CSPC, another Chinese pharma company.
The good news is that Roche’s PD-L1 combination therapy with albumin paclitaxel has already been approved by FDA for this indication. It is highly expected that the combination therapy of toripalimab (PD-1) and albumin paclitaxel will also work well.
Tislelizumab & bevacizumab/fruquintinib
In addition to studying tisleizumab as a monotherapy, BeiGene is also investigating a combination of its PD-1 inhibitor with the company’s PARP inhibitor, pamiparib, as well as with its BTK inhibitor, zanubrutinib.
Innovent Biologics and Eli Lilly jointly developed and received approval in China for its PD-1 antibody Tyvvt® (sintilimab injection) for relapsed or refractory classical Hodgkin's lymphoma (r/r cHL) and is currently in trials in the United States. Innovent’s IBI 305 is a recombinant humanized anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody for the treatment of non-small cell lung cancer (NSCLC), colorectal cancer and other malignant tumors and, as a biosimilar of bevacizumab, approved in January this year. Further, Innovent and Lilly are in trials for a combination of sintilimab and fruquintinib for advanced solid tumors.
Jin Zhang M.D., Ph.D is editor at The Pharmaceutical Consultant.