Anti-PD-1/PD-L1 Monoclonal Antibodies: Not Easy to Let Go (2)

1. Players rushing on like a swarm of hornets

2. Whether products have unique advantages?

Whether products have unique advantages is a criterion for considering whether they can be further advanced. Most "innovation points" of products in development at present are: new antibody sequence (for patent application, but seemingly no improvement to product quality), "optimization" of Fc region (there is also Fc optimized product among the marketed products), nanobody, raising of affinity, and working in the local tumor microenvironment, etc. Manufacturers themselves may be well aware of how many subversive advantages the above will bring clinically!

It's hard to predict what adverse reactions will happen after drugs enter clinical trials. Even Hengrui, the number one among the Chinese pharmaceutical enterprises, may also face tough decision regarding its anti-PD-1 monoclonal antibody product. According to the adverse reaction situation of 58 patients published in the article Phase I study of the anti-PD-1 antibody SHR-1210 in patients with advanced solid tumor in ASCO (American Society of Clinical Oncology) last year, 79.3% subjects had symptoms of reactive capillary hemangiomas; there was no detailed report on other adverse reactions, however, the drug should also show the adverse reactions showed by Opdivo (BMS) and Keytruda (MSD). Therefore, even if Hengrui managed to market the drug, what could it rely on to persuade doctors and patients to rest assured to use own drug in the future market competition?

3. Influences China’s national macro-policies may bring in the future

In the face of the current situation of flocking to applying for drugs for a target, the Chinese government has mentioned in the Administrative Measures for the Disclosure of Information on the Drug Review and Approval (Draft for Comment), "List of pharmaceutical products with more than 3 enterprises applying for the same varieties will be disclosed, to guide applicants to conduct orderly R&D and rational application." According to my bold guess, what is implied in this sentence is that: for a variety with too many applicants, later applicants for such variety should stop the application, otherwise, they would be guided to quit.

Premier Li Keqiang further stressed the implementation of "zero tariff for imported cancer drugs" proposed during the two sessions in the recent executive meeting of the State Council of China, deciding to fulfill this promise from May 1 this year. What should be vigilant against is that products that have been filed the marketing application in China include Keytruda and Opdivo, meaning that the situation of bringing "wolves into the house" has formed.

Looking beyond: the argument on intellectual property is the priority among priorities in the trade war between the U.S. and China, to protect Chinese enterprises. However, the antibody drug patent protection in China still has a gap with that of the Europe and America, and most notably, Chinese enterprises are still unable to conduct patent protection of antibody/antigen action sites. The patent dispute of Amgen and Sanofi over the action site of PCSK9, and the case in which BMS accused MSD’s Keytruda of patent infringement in terms of treatment of metastatic melanoma might happen in China in the future. Latecomers will inevitably be confronted with the patent barriers set up by the opponents ahead.

Summary: It's generally believed that for the same target, the first three marketed products can almost occupy the entire market, and the fourth and fifth marketed products can lose no money or earn a little if the enterprises thereof have prodigious financial resources and selling channels, while the rest will only lose money, therefore, they would be irrelevant even if the market was worth tens of billions of USD! Companies that have yet applied for clinical trial or that are the bottom 20 players in Fig. 1 can think about how much are the innovation advantages of own products to subvert products above in the list; whether they have made solid basic research on safety and effectiveness of own products; how much capital they have to back their clinical and market competition in the future; and also unknown factors like policy regulation and intellectual property tightening. In the face of the possible nothing to harvest, letting go anti-PD-1/PD-L1 monoclonal antibodies and choosing others may be the better selection. The reason that many players cannot bear to let go may be the fear of being abandoned by the times of tumor immunotherapy that has come, however, when the wind rises, it will take away more than a leave.

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