Since its approval as the first PD-1/PD-L1 inhibitor, on September 4, 2014, Keytruda has stood on the top of the heap and dominated attention across the spectrum of industry watchers. At present, the competition in this field is especially fierce. All five PD-1/PD-L1 inhibitors on the market are actively expanding their territories and rapidly pushing forward their clinical trials in a number of applications. According to people familiar with this matter, their total market value is expected to peak at $35 billion. Furthermore, Sinohealth has predicted that Opdivo and Keytruda will become the second and third best-selling anti-cancer drugs in the next five years, amounting to a total of $43.3 billion and $41.3 billion respectively.
On the other side of the globe, the PD-1/PD-L1 market in China is also intensely hot and has made a series of headways. The Chinese anti-cancer and immunomodulator markets are expected to maintain rapid growth in the coming years. In 2016, its total market size reached $20.52 billion, an 11.4% increase over that in the year of 2015. In the meantime, the market potential of immunotherapy for late-stage cancers in China is huge, primarily thanks to the low awareness and prevalence of early cancer screening, the high proportion of patients diagnosed with advanced cancers, and its large population base. Deutsche Bank has predicted that the total Chinese market for PD-1/PD-L1 will rise to $4 billion in 2025.
As yet, none of the five US listed PD-1/PD-L1 inhibitors has made their way into the Chinese market. However, all of them have pegged promise on it. Opdivo and Keytruda are leading the way; both have already submitted their listing applications to the Chinese FDA. Meanwhile, in the face of the market void, along with the huge unmet need, a slew of Chinese domestic pharmas is stepping up their efforts. The competition is unprecedently intense. As of the publication of this article, 25 Chinese PD-1/PD-L1 inhibitors have submitted a registration application in China. And there are more under way.
The domestic PD-1/PD-L1 competition in China
At present, China’s domestic pharma companies mainly rely on copying the development of leading PD-1/PD-L1 antibodies in the global market. That is, generating mouse antibodies through hybridoma and then humanizing the lead candidates. However, there is no shortage of innovation.
Beigene’s BGB-A317 has managed to reduce the ADCC effect through Fc engineering, in an attempt to decrease its impact on T cell functions. Worth mention is that on July 5, 2017, the company penned a strategic collaboration with the pharma giant Celgene to co-develop and commercialize BGB-A317 in the treatment of solid tumors. Mabspace Biosciences’ MSB2311 has applied immune tolerance breaking technology, targets at a new PD-L1 antibody epitope, and binds in a PH-dependent manner. Overall, these characteristics have helped it to enhance its recovery, infiltration, and enrichment in tumor tissues down the line. Alphamab’s KN035 is based on the application of Nanobody-Fc fusion proteins. This enables it to be prepared into a room-temperature stable formula, making it the first subcutaneous injectable PD-1/PD-L1 antibody.
What is more, a number of Chinese pharmas have even abandoned the traditional hybridoma technology and adopted the latest fully human antibody platforms from abroad. For example, Innovent Biologics has introduced the yeast display technology from Adimab to develop its fully human antibody IBI308; Zhaoke Pharm has brought the fully human PD-L1 antibody from Sorrento; and WuXi Biologics has incorporated the OMT transgenic platform from OmniAb.
2. Clinical trials
Beigene, Hengrui Medicine, Junshi Biosciences, and Innovent Biologics are leading the PD-1/PD-L1 development in China, with Phase III clinical trials ongoing. Among them, Beigene and Henguri Medicine have a clear leg-up against the competition. Overall, their pipelines are widespread and reasonable; their Phase III trials have covered a number of popular indications, including liver cancer, non-small cell lung cancer, esophageal cancer, etc. And then there is Innovent Biologics, currently with one Phase III clinical trial on non-small cell lung cancer and three Phase II clinical trials, including esophageal cancer, Hodgkin’s lymphoma, and NK/T-cell lymphoma. Junshi Biosciences’s studies are more concentrated in Phase I clinical trials, with only one Phase III in melanoma in progress.
The second tier of the PD-1/PD-L1 competition in China is currently carrying out Phase I studies. This includes Gloria Pharmaceuticals, Bio-thera Solutions, Genor Biopharma, Tianyancha, Alphamab and Cstone Pharma.
The majority of companies are actively developing PD-1/PD-L1 against liver cancer, lung cancer, esophageal cancer, etc., due to their high incidence in China. However, some are on a different path. For example, Innovent Biologics has set their sights on the less popular target, Hodgkin’s Lymphoma. And currently, its IBI-308 is leading the Chinese PD-1 race in this sector. Another honorable mention is Hengrui Medicine. Starting as a small molecule provider, Hengrui has accumulated substantial knowledge and extensive expertise in this field. Coupled with its strong financial, the company has been aggressively pushing forward the research of its combination therapy with Apatinib, in an attempt to overcome refractory cancers, such as small cell lung cancer.
4. Chinese pharma’s adventure in the global market
With five listed contenders already in the scene, the global market competition is especially fierce. However, thanks to the differentiated characteristics, some China-developed PD-1/PD-L1 antibodies have already opened the FDA door. Until now, a total of seven candidates have submitted IND applications to the US. Among them, Beigene is the pioneer. As early as on January 8, 2016, its BGB-A317 passed FDA approval to treat relapsed or refractory solid tumors. Next are Hengrui’s SHR-1316, Livzon’s LZM-00, and Henlix’s HLX-10. They received approvals in January, July, and September of 2017 respectively. On January 9, 2018, Junshi Biosciences’ JS0001 was granted an IND right. On the heels of this approval, Alphamab’s KN035 and Mabspace Biosciences’s MSB2311 also joined the club, passing an FDA clinical trial application on February 16, 2018.
Major Chinese PD-1/PD-L1 pharmas
1. Hengrui Medicine
Among all the Chinese domestic pharmas, Hengrui holds the crown. Starting with chemical medicines, it has been actively plowing ahead in its research and development in innovative biologics in recent years. Currently, equipped with the largest R&D plant for anticancer and surgical drugs in China, Hengrui has already become one of the most innovative large-scale pharmaceutical companies across the globe. As of this week, its total market value reached $40 billion, exceeding Takeda, and the company became the largest pharma in Asia for the first time. Hengrui has also been actively deploying an increasing amount of R&D expense every year. In 2016, this reached a total of $184 million, accounting for about 10.6% of its revenue of that year.
At present, Hengrui’s PD-1/PD-L1 clinical trial arrangement is the most reasonable and risk resistant. It covers a wide range of implications, including several China’s most popular solid tumors, such as liver cancer and lung cancer, and already-approved cancer indications in the West, such as Hodgkin’s lymphoma and melanoma. At the same time, coupled with its strong financial and abundant reserve and experience in small molecules, Hengrui has dominated the progression of clinical trials in combination therapies.
Hengrui’s SHR-1210 is the second China-produced biologic and first China-produced monoclonal antibody granted with a generic name from WHO. From the published data of its Phase I clinical trial, the future of the drug is promising. In domestic studies, the ORR of esophageal squamous cell carcinoma from 29 patients was 34.48%; the ORR of 8 gastric cancer patients was 37.50%; 1 out 3 lung cancers responded; 1 out of 3 nasopharyngeal carcinomas responded; 1 out 3 liver cancers responded; 1 out of 3 bladder cancers responded. Overall, the response rate was about 31.0%. And the disease control rate was even higher; it has reached 46.5%. Meanwhile, its performance abroad is also bright, with a 43% disease control rate in a series of phase I studies. At present, SHR-1210 has started its Phase III clinical trials.
Other notable mentions from Hengrui Medicine include the G-CSF stimulant HHP-19K and C-Met ADC, the first Chinese ADC approved by FDA.
2. Innovent Biologics
Focusing on both follow-on drug and innovative drug R&D, Innovent Biologics has established 12 new medication varieties, covering four major disease fields, including cancer, fundus, autoimmune, and cardiovascular diseases. Among them, two have been selected into China’s major new drug innovation special project; nine are issued with global intellectual property rights.
In addition, Innovent Biologics has set up a large-scale production and manufacturing plant, equipped with two 1000L production lines (completed), six 3000L production lines (under construction), and four 15000L production lines (under construction). Particularly, the two 1000L production lines have passed the GMP audit by its partner in September 2016, officially becoming the first biopharmaceutical product line complying with the American FDA GMP standard in China.
Innovent Biologics’ road to list its PD-1 antibody (IBI308) has been full of twists and turns. On December 13, 2017, the Chinese Center for Drug Evaluation (CDE) officially accepted its application. Innovent Biologics became the first domestically developed PD-1 antibody applying for a listing in China. However, just two months later, it was rumored that the listing request was withdrawn. Innovent Biologics resubmitted its IBI308 and was again accepted by the Chinese CDE again on April 19, 2018. In the meantime, Innovent Biologics also presented its domestic clinical data to FDA for IND approval. Currently, it has been approved for Phase II/III clinical trials in the US, surpassing Phase I.
3. Junshi Biosciences
Junshi Bioscience, founded in 2012, is an innovation-driven pharma company, primarily focused on the discovery and development of monoclonal antibodies and therapeutic proteins. Equipped with 13 development projects, it has already established a robust and mature pipeline, covering a number of fields, including tumor, cardiovascular diseases, osteoporosis, etc.
Junshi’s PD-1 monoclonal antibody (JS001) got a head start over all the other competitors. It was the first to apply for a clinical trial in China and also one of the first approved for a clinical trial by the Chinese CDE. However, Junshi was not able to maintain its market lead in the hot PD-1 race; Hengrui has come from behind to snatch the number 1 position. Overall, JS001 has engaged in the most indications, including a total of seven, among all the contenders. In China, it has already entered Phase II clinical trials and is expected to make its way into the market in 2019.
Two sets of clinical trial data have been published so far. In one set, the overall effective rate was 40% and the disease control rate reached 73% among 15 patients. Particularly, one Hodgkin’s lymphoma had a complete remission; five patients reached partial remission (three Hodgkin’s lymphoma, one soft tissue sarcoma, and one diffuse large B-cell lymphoma); another five patients were stable (three non-small cell lung cancers and two head and neck squamous cell carcinomas). In the other set, among all 32 patients, one melanoma patient achieved a complete remission; six patients reached partial remissions (3 melanomas, two kidney cancers, one urothelial carcinoma); 10 patients had stable disease. Overall, the effective rate was 22% and the disease control rate was 53%.
Other notable drugs from Junshi include its PCSK9 biologics, already approved for clinical trials, and TNF- α monoclonal antibody, currently leading the R&D progress of BlyS mAb in China.
Beigene is a commercial-stage biopharmaceutical company, dedicated to the discovery, development, and commercialization of immuno-oncology drugs for cancer treatment. It is also the first Chinese innovative biopharma completed an IPO in the US. Focused on both small molecule-targeted chemical drugs and biologics, Beigene has developed more than 10 new drugs to date.
Its BGB-A317 is an immune checkpoint inhibitor against PD-1. From the preliminary analysis of its Phase I clinical trials, BGB-A317 was shown to be well tolerated and appeared to have initial anti-tumor activity in HCC patients. In experiments for gastric cancer and esophageal cancer, its control rate was 32%; for ovarian cancers, its control rate was 43%; and in head and neck squamous cell carcinomas, its effective rate was 50%. Additionally, Beigene has also launched a combination therapy clinical trial with its own PARP inhibitor. Among 16 tumors observed, seven were reduced by more than 30% (five cases of ovarian cancer, one case of uterine cancer, one case of pancreatic cancer); one ovarian cancer reached a complete remission; and another six patients achieved stable disease state for more than six months (including two pancreatic cancer patients). The total effective rate was 21.1% and the disease control rate was 36.8%.
Other candidates worth mentioning in Beigene’s pipeline include BGB-290, a potent and high selective PARP inhibitor, and BGB-283, a small molecule RAF inhibitor.
The PD-1/PD-L1 antibodies have brought new hope to cancer patients; at the same time, they present tremendous opportunities and great challenges for pharma companies. The US and Europe have been leading this field and have accumulated vast experience and knowledge over the years. Currently, they are actively exploring a number of new applications outside the traditional monotherapy, such as PD-1 companion diagnosis, PD-1/CTLA4, PD-1 antibody/new IL-2 (NKTR-214), and other combination therapies.
China is the newcomer in the scene. At present, it is still on the eve of its listing application. However, in the face of favorable government policies, strong financial support, and the influx of overseas talents, the Chinese PD-1/PD-L1 antibody developers are well equipped to make their way to the market, and further down the line this will benefit enormously patients across the globe.