By Zhixing

Anti-PD-1 monoclonal antibodies could be called springing up on overseas cancer drug market, and are very popular with pharmaceutical enterprises, however, it is hard to find such monoclonal antibody in China. This situation may be soon ended, as it has been reported recently that the Opdivo might become the first anti-PD-1 monoclonal antibody marketed in China, and be approved by CFDA in 2018 Q1 at the soonest. Furthermore, unwilling to lag behind, Chinese pharmaceutical enterprises have competed to conduct relevant phase III clinical studies, such as IBI308 of Innovent Biologics, BGB-A317 of BeiGene, and SHR-1210 of Hengrui Pharmaceuticals.

BMS -Opdivo

As the world’s first marketed anti-PD-1 monoclonal antibody, Opdivo (nivolumab) was first approved in Japan, and then approved by FDA in 2014 for melanoma, and has also been approved by FDA so far for non-small cell lung cancer (NSCLC), classical Hodgkin's lymphoma, head and neck squamous cell carcinoma, renal cell carcinoma, bladder cancer, colorectal cancer, gastric cancer, and hepatocellular carcinoma.

Generally, years after having been marketed overseas, new drugs will then be marketed in China, due to the strict drug policy and approval process in China, however, the opinions introduced last year will change this phenomenon. The State Council of China issued the Opinions on Deepening the Reform of the Review and Approval System and Inspiring Innovation of Drugs and Medical Devices in October 2017, which is of milestone meaning to the innovative development of China’s pharmaceutical industry, and clearly mentions that overseas clinical trial data are accepted for the imported innovative drugs. The introduction of the opinions will accelerate the marketing of new drugs on the Chinese market, and improve the Chinese cancer patients’ plight of long-term no access to drugs.

Not long after the introduction of the opinions, BMS filed the marketing application (JXSS1700015) for Opdivo as second-line therapy for NSCLC to the Center for Drug Evaluation of China Food and Drug Administration (CDE) in November 2017, which was included in the priority review by reason of "having significant therapeutic advantages compared to existing treatment means" in December 2017. Both the extensive indications and excellent clinical data of Opdivo are the evidence that it will be approved by CFDA, and Opdivo’s receiving of approval will only be a matter of time owing to the changes of relevant policy in China. It is believed that the approval will be granted in 2018 Q1. Let’s wait and see.

Hengrui Pharmaceuticals-SHR-1210

Early in April 2017, Hengrui Pharmaceuticals has announced the launch of the open-label, randomized, multicenter, Phase III clinical study of the anti-PD-1 antibody: SHR-1210 in combination with pemetrexed and carboplatin as first-line therapy in patients with advanced or metastatic non-squamous NSCLC, with the current status of in progress (recruiting), with 54 hospital institutions and 412 patients participating in the study, and primary endpoint of PFS, and secondary endpoint of ORR, DCR, and DoR, etc. In the same month, Hengrui Pharmaceuticals also launched the randomized, open-label, positive drug-controlled, multicenter, Phase III clinical study of SHR-1210 vs investigator’s choice of chemotherapy to treat advanced or metastatic esophageal cancer, with 44 hospital institutions and 438 patients participating in this study at present.

Hengrui Pharmaceuticals announced the launch of the randomized, double blind, placebo-controlled, multicenter, Phase III clinical study of SHR-1210 as second-line therapy in patients with advanced hepatocellular carcinoma (HCC) on December 22, 2017, with the primary endpoint of OS, and secondary endpoint of ORR, DoR, DCR, and TTP, etc., with the current status of in progress (having not recruited).

According to data of the Drug Clinical Trial Registration and Information Publicity Platform in China, other phase II studies of single SHR-1210 or its drug combinations include those relating to NSCLC, advanced liver cancer, classical Hodgkin's lymphoma, and NK/T-Cell lymphoma (nasal type). Furthermore, an exploratory trial of SHR-1210 targeting advanced solid tumor is being conducted.

Innovent Biologics-IBI308

Innovent Biologics publicized the launch of the phase III study of the anti-PD-1 monoclonal antibody IBI308 as second-line therapy of advanced or metastatic squamous NSCLC on the Drug Clinical Trial Registration and Information Publicity Platform in China on May 18, 2017, with the current status of in progress (recruiting), and with 42 hospital institutions participating in this study. The trial objective of this randomized, open-label, phase III study is to evaluate the safety and effectiveness of IBI308 vs docetaxel in patients with advanced or metastatic squamous NSCLC after failure of first-line platinum-based therapy, with the primary endpoint of overall survival (OS), and secondary endpoint of progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of objective response (DoR). Besides the above phase III clinical study, IBI308 has been conducted phase II clinical studies for other indications, such as esophagus cancer, classical Hodgkin's lymphoma, and NK/T-Cell lymphoma.

Dr. Yu Dechao, Founder, Chairman, and President of Innovent Biologics, said with confidence, "IBI308 is the fourth pharmaceutical product of Innovent that receives the clinical trial approval. According to the preclinical data, IBI308 has more significant efficacy than the current anti-PD-1 antibody drugs on the market".

BeiGene-BGB-A317

BeiGene publicized the launch of a phase III clinical study of the anti-PD-1 monoclonal antibody: BGB-A317 on the Drug Clinical Trial Registration and Information Publicity Platform in China on October 12, 2017. Like IBI308, its patients are the NSCLC population who have received platinum-based drug therapy, and it is used as the second-line or third-line therapy, with current status of in progress (having not recruited), and with 38 hospital institutions participating in this study. The main objective of this clinical trial is to evaluate the safety and effectiveness of BGB-A317 vs docetaxel, with the primary endpoint of OS, and secondary endpoint of ORR, PFS, and DoR, etc., with many similarities with the phase III clinical trial of IBI308 of Innovent Biologics.

Recently on January 3, 2018, BeiGene has announced the launch of a randomized, open-label, multicenter, Phase III study to compare the effectiveness and safety of BGB-A317 and sorafenib as first-line therapy in patients with unresectable hepatocellular carcinoma, with the primary endpoint of OS, and secondary endpoint of ORR, PFS, and DoR, etc., which has not started the recruitment and currently only has two hospital institutions participating. Besides, the underway phase II clinical studies of the biological product BGB-A317 include those relating to bladder urothelial carcinoma, Hodgkin's lymphoma, esophagus cancer/gastric cancer, or esophagogastric junction cancer. And certainly, BeiGene has not only conducted the single drug studies of BGB-A317, but also the drug combination effect studies.

The marketing application of the anti-PD-1 monoclonal antibody: Opdivo of BMS targets NSCLC, and likewise, the anti-PD-1 monoclonal antibodies of the above three Chinese pharmaceutical enterprises also started with the phase III clinical trials for NSCLC. As one of the most common cancers in the world, lung cancer has become the leading cause of death thereamong in China, and the NSCLC accounts for 80% of all lung cancers. The huge patient group provides sufficient volunteers for the conduct of clinical studies, and is also the problem needing prompt solution of China and its people.

Opdivo is not required to be conducted clinical study in China as its overseas clinical data are sufficient, and will soon become the first anti-PD-1 antitumor drug marketed in China. The antitumor effects of the anti-PD-1 tumor immunotherapy are incontrovertible. Comparing the above time of Hengrui Pharmaceuticals, Innovent Biologics, and BaiGene in launching phase III clinical trial, Hengrui Pharmaceuticals is quite likely to be earlier than the other two in obtaining CFDA’s approval, however, the problem of how to design the trial to obtain excellent clinical data is crucial. Sincerely hope that the pharmaceutical enterprises could produce the good medicines ASAP!

References:

1. Opdivo, Repatha and Lynparza likely among China’s 2018 blockbuster nods: report

2. Drug Clinical Trial Registration and Information Publicity Platform and websites of relevant pharmaceutical enterprises.