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The fanaticism in the PD-1/PD-L1 field is a visible fact. Even clinical recruiters jokingly said that patients were not enough soon enough….
Is there any chance for latecomers in this field? The reporter recently also interviewed experts in this area.

Intense competition

Currently, there are 5 PD-1/PD-L1 inhibitors in the world listed in dozens of countries in Europe and the United States, Hong Kong and Macao, China, including two PD-1 antibodies and three PD-L1 antibodies: Nivolumab (Opdivo), Pembrolizumab (Keytruda); Atezolizumab (Tecentriq), Avenumab (Bavencio), Durvalumab (Imfinzi). The listing of generic drugs did not hinder the research process of combination therapy and new drug candidates.
More than 100 PD-1/PD-L1 projects have been tracked worldwide.

Nivolumab and Pembrolizumab have also submitted a listing application to the National Drug Administration of China several months ago. Not surprisingly, these two drugs will be approved for listing in China this year. In addition, three Chinese domestic companies also submitted PD-1 drug listing applications.

Mabos submitted its clinical trial application for the first PD-L1 project MSB2311 injection to CDE in November 2017 and is currently in the “in review and approval” state. Phase I clinical trials in the United States have already started. Wan Yuntao, the person in charge of the company’s clinical development and operations, told reporters that as of May 2017, there were only 268 clinical trials conducted by Keytruda and Opdivo reached 242. Today, the number of clinical trials for these two popular drugs exceeds 300 (Keytruda is close to 400), and competition in clinical trials is fierce.

Shen Lin, the dean of Cancer Hospital of Peking University in China, is a well-known expert in the field of cancer. Her major projects are focused on high incidence of gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, gastrointestinal stromal tumor, and digestive system in domestic patients. Neuroendocrine tumors and other digestive tract tumors. She said that from the perspective of disease indications, the most intensely competitive battlefield is the lung cancer field, especially the opportunity to snatch first-line treatment.

Sansei Pharmaceuticals Chief Scientific Officer (CSO) Zhu Yuping is cautious about the numerous clinical trials of PD-1/PD-L1. He recalled that oncologists had dared to try clinical trials for more than 30 years, and they also rapidly promoted the rapid development of chemotherapy technology. However, in his opinion, when the pharmaceutical industry also focused on the PD-1/PD-L1, it is not a good phenomenon for the entire medical development. A large number of PD-1/PD-L1 clinical trials will occupy More clinical resources have even led some innovators to dare not try other emerging targets.

Differentiation of technology

If the competition in the PD-1/PD-L1 field has become heated, it has not stopped investors’ enthusiasm. Earlier this month, Cornerstone Pharmaceuticals obtained 260 million U.S. dollars in financing. At the same time, Maibos also completed 40 million U.S. dollars in Series B financing.

Shen Lin confirmed the rapid progress of tumor immunotherapy, and also pointed out that the development and application of PD-1/PD-L1 in the digestive system tumors such as gastrointestinal tract is relatively lagged. Although Opdivo and Keytruda have been approved for the third-line treatment of gastric cancer in Japan and the United States, the subsequent use of these two drugs alone in the second-line treatment of gastric cancer is not as effective as chemotherapy. She pointed out that although everyone’s ultimate goal is to achieve first-line treatment, it is also necessary to recognize the fact that current treatments cannot affect all tumor types.

Ji Dongmei, who is working at the Phase I clinical trial center of China’s Fudan University Affiliated Cancer Hospital and an early clinical study of new anti-tumor drugs, said that from the perspective of indications, only non-Hodgkin’s lymphoma has more than 100 subtypes. Many existing companies focus their PD-1/PD-L1 indications on large B-cell lymphomas, while NK cell lymphomas and T-cell lymphomas are less likely to be used. In addition, the beneficial effects of nasopharyngeal carcinoma on head and neck tumors can reach 30%, and in other parts of the head and neck tumors, the existing PD-1/PD-L1 drug effects are not optimistic. It is also worth digging.

Wang Zaiqi, who is currently head of the Roche Shanghai Innovation Center in China, was responsible for Keytruda’s registration and clinical trials in Merck East. He told reporters that in certain refractory cancers, 90% progress will be achieved through chemotherapy, and even if PD-1/PD-L1 is added, there is still 75% progress. This shows that the current effectiveness of the joint application does not make people very satisfied. This shows that “There are still many opportunities for improvement in oncological treatment.”

How to improve this process is when the benevolent sees wise men. For R&D companies, the best way is to do their best to optimize their products.

Wan Yuntao revealed that Maibos has developed the second-generation humanized PD-L1 antibody. Unlike the PD-L1 antibody epitopes that are currently approved for marketing, the binding of this antibody to PD-L1 is uniquely pH-dependent and facilitates the recovery and penetration of antibodies in tumor tissues, with equivalent doses in animal models. Shows better results.

Xu Wei, chairman/CEO of Corning Jerry, a competitor and partner of China Meibuse, told reporters that their PD-L1 was screened out through a camel immunization library and currently shows high water solubility, high expression levels, and high thermal stability. Sex and many other advantages. In January last year, the clinical trial of the PD-L1 single-domain antibody KN035 was approved by the State Food and Drug Administration. The fastest-growing indication has reached phase III.

Diversification of strategy

In general phase I clinical trials, different types of tumors are usually selected for testing, and even if based on some animal studies that do not fully predict the results of human trials, the study drug may become a new treatment. For oncologists such as Shen Lin and Ji Dongmei who are cultivating on the first line, their view is that even if there is only a very small number of benefits, it will be the last “sweet straw” for patients, and naturally they will not give up each of them. A potential therapy.

It is reported that 60% of clinical trials are not initiated by companies, but initiated by oncologists with clinical trial qualification hospitals, and they hope to try more treatment possibilities.

In gastrointestinal cancers, PD-1/PD-L1 does not “strive for stability” in the third-line, second-line, and first-line like the treatment of non-small cell lung cancer, even at a relatively late level. Shen Lin told reporters that this was largely related to the pace of the entire field, and did not carefully study the characteristics of digestive diseases. At present, the benefit in the field of gastrointestinal cancer is less than one-third, but once it benefits, it will significantly prolong survival. She also asked in the opposite direction: Is it possible to identify the people most likely to benefit by improving the trial’s effectiveness evaluation strategy or by biomarker screening?

Wang Zaiqi told reporters that Merck’s domestic application of Keytruda’s clinical strategy was completely different from the international market. According to his experience, it is on the one hand to consider the conditions of the disease in China, but also consider future joint treatment, even the survival of patients, the proliferation of tumor cells and so on.

Wan Yuntao said that the efficacy of PD-1/PD-L1 monotherapy is limited, and the possibility of combination therapy is limitless. The objects that can be combined are all over immunotherapy, small molecule therapy, chemotherapy/radiotherapy, and cancer vaccine. , oncolytic viruses and other fields in many forms. He speculates that multinational drug companies consistently have a layout that they can think of. If start-ups want to counteract large drug companies in clinical strategies, it is obviously a huge challenge for products that do not have superior efficacy or other differentiated features.

In Ji Dongmei’s view, the combination therapy should follow three principles: single drug is effective; the mechanism of action, time, and space do not work; there is a synergistic or additive effect rather than an antagonistic or subtractive effect.

Xu Wei added that they are not only considering combination therapy of multiple drugs, but also developing dual target antibody drugs, and even doing some sponsor joint research projects with PI to try more treatment possibilities.

Latecomers first?

The reporter was informed that new anti-tumor antibody antibodies against targets such as PD-1/PD-L1 and CTLA-4, used alone or in combination with other therapies, have been approved for malignant melanoma, non-small cell lung cancer, and renal cancer , bladder cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, Merkel skin cancer, Hodgkin’s lymphoma, and all microsatellite highly unstable solid tumors.

However, through dialogues with some experts, it is found that although it is not appropriate to use the term “competitors come first” to describe them, it is not necessarily impossible to go beyond them. Will there be better next-generation PD-1/PD-L1 products? The answer is obviously not negative.

Shen Lin said that for currently available drugs, existing PD-1 drugs can be used for PD-L1 positive or TMB high esophageal cancer; however, existing combination therapy is not very sensitive to current gastroesophageal cancers. There may be a major adverse reaction.

Ji Dongmei, for example, told reporters that even with the already-marketed PD-1/PD-L1 drugs, some unexpected adverse reactions may occur. For example, she has found in clinical practice that a patient with nasopharyngeal carcinoma treated with PD-L1 monoclonal antibody that has been on the market has well-controlled tumor cells, but the phenomenon of conjunctival irritation after the tenth infusion; There was also a patient with esophageal cancer receiving PD-L1 monoclonal antibody. After two courses of treatment, the tumor regressed obviously but shingles developed. They also discovered later by examining the data that PD-1/PD-L1 brought about an immune reconstitution process and produced side effects of shingles.

Guo Wei, Vice President of Business Development at IQVIA Greater China, reminded that in the I-O era, the deceased will not be able to decide prematurely. However, for the latecomers, there is no doubt that major phase III clinical trials that require more financial resources to compete with marketed drugs. At the same time, there are not enough data to prove that the single drug is effective or that the combination of the two drugs will achieve the effect of 1+1≥2, which is a challenge to the regulatory agencies and statisticians. As a statistician, he is conservatively hoping that everyone’s steps will be slower, so that the experimental design will be more complete, and the progress in the I-O field will be more steady.

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