The Pharmaceutical Industry at a Glance Trends in Clinical Development of New Drugs by Chinese Pharmaceutical Companies

Tomoyuki Shibukuchi, Senior Researcher, Pharmaceutical Industry Policy Institute

In November 2019, the FDA expedited approval of ^BrukinsaTM (generic name: zanubrutinib), a BTK inhibitor developed by Beigene of China, for the treatment of mantle cell lymphoma (MCL) with at least one prior therapy. Chinese pharmaceutical companies have been involved in the manufacture and sale of generic drugs to date, but in recent years they have become more actively involved in new drug development, and as mentioned above, some new drugs are beginning to be approved in the United States. This paper reports on the annual changes in the number of clinical development items and a summary of the characteristics of these items.

Research Methods

The analysis was conducted using Informa's Pharmaprojects® (see "Research and Development of Small Molecular Drugs and Biopharmaceuticals" in Policy Research Institute News No. ⁴⁴¹⁾, using trend data before 2019 and data as of May 2020 for 2020. New chemical entities (NCEs), synthetic nucleic acids, synthetic peptides, and biopharmaceuticals were selected for the compilation of new active ingredients for new drug launches, while biosimilars, new dosage forms, and fixed-dose combinations were excluded. Biosimilars, new dosage forms, and fixed-dose combinations were excluded.

Annual Trends in the Number of Items in Clinical Development

Figure 1 shows the number of new active ingredients developed by Chinese pharmaceutical companies as "Originators" in each stage of clinical development over the 10-year period from 2011 to 2020. The development stage is the most advanced stage for each ^product4). Figure 1 (left) shows that the number of products has increased about 25-fold over the past 10 years, with 614 products in clinical development as of 2020. On the other hand, not all of them are aiming for global development. As shown in Figure 1 (right), 93 of the 614 drugs in 2020, or about 15%, are being developed in North America, Europe, or Japan, and are considered to have global development in mind.

Figure 1: Annual Trends in the Number of Products in Clinical Development by Chinese Pharmaceutical Companies

Figure 2 shows the breakdown of countries where clinical development is conducted. 463 out of 614 products (75% of the total) were developed only in China in 2020. Others" include Australia and Singapore. In general, R&D for products being developed outside of China was also being conducted in China.

As for the stage of development, the percentage of Phase II or later products was higher for those being developed in North America, Europe, or Japan, suggesting the possibility that products whose safety has been confirmed are being developed outside of China.

Figure 2 Breakdown of Countries Conducting Clinical Development

Characteristics of Products Developed Globally

As noted in the previous section, the clinical development of products created by Chinese pharmaceutical companies is mainly conducted in China, with a small portion being developed outside of China. In this section, we summarize those products that are being developed in North America, Europe, or Japan (hereafter referred to as "globally developed products"), and in the next section, we summarize those products that are being developed only in China.

The characteristics of globally developed products are summarized in Figure 3. The most common drug ^{classifications5)} and 6 are antitumor agents, accounting for nearly 70% of the total. This is followed by gastrointestinal and metabolic agents and anti-infectives. Among modalities, low molecular weight drugs accounted for nearly 60% of the total, and biopharmaceuticals such as monoclonal antibodies accounted for about 40%.

Fig. 3 Characteristics of products under global development (2020, 93 products)

Among biopharmaceuticals, monoclonal antibodies and other antibody drugs accounted for nearly 70%, while chimeric antigen receptor-expressing T-cell therapy (CAR-T cell therapy), which is being actively developed in China as described below, accounted for only two products. Monoclonal antibodies (including other antibodies) include many immune checkpoint inhibitors targeting PD-1/PD-L1.

Among these 93 drugs, 14 were designated as Orphan Drugs in the U.S. and Europe, and six were designated as Breakthrough Therapy or Fast Track by the FDA or PRIME by the EMA (Table 1). ⁷⁾. NEUCARDIN® is a recombinant human neuregulin-1 fragment that acts as an agonist at the ErbB4 receptor. Both LCAR-B38M and CT-053 are CAR-T cell therapies targeting the B-cell maturation antigen (BCMA) and have received special measures from both the FDA and EMA. LCAR-B38M is being co-developed with Janssen and is being developed outside China by Janssen as JNJ-4528. albuvirtide in combination with 3-BNC117 has Fast Track designation for multidrug-resistant HIV infection. Albuvirtide is a synthetic peptide developed by Frontier Biotechnologies that acts as a gp41 antagonist of the HIV envelope, and 3-BNC117 is a neutralizing antibody (monoclonal antibody) against HIV developed by Rockefeller University. HTD-1801 is a small molecule drug with FDA Fast Track designation for primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH). Unfortunately, the mechanism of action was not clear. ORIN-1001 has a Fast Track designation for relapsed/refractory metastatic breast cancer, but again, the mechanism of action was not disclosed.

Table 1: Products created by Chinese pharmaceutical companies that have received special regulatory treatment overseas (selected products)

Table 2 summarizes the background of the companies listed in Table 1, including the location and year of establishment, etc. Some companies, such as Shanghai Fosun Pharmaceutical, which were mainly engaged in the manufacture and sale of generic drugs, have expanded into the new drug development business, while others were established after 2000. Zensun Shanghai Sci & Tech, CARsgen Therapeutics, and Frontier Biotechnologies have been engaged in drug discovery targeting specific disease areas based on the results of research conducted at domestic and overseas research institutions. Zensun Shanghai Sci & Tech, CARsgen Therapeutics, and Frontier Biotechnologies seem to be engaged in drug discovery targeting specific disease areas based on the results of research conducted at domestic and overseas research institutes. In the case of Nanjing Legend Biotech, the parent company, GenScript, possesses gene synthesis technology closely related to CAR-T cell therapy development, and the company appears to be developing its business by utilizing its own technology.

Table 2 Companies that created the products listed in Table 1

Characteristics of Products Developed Only in China

Figure 4 summarizes the characteristics of products being developed only in China. As with globally developed products, anti-tumor drugs are the most common, accounting for more than 50% of the total. This is followed by anti-infectives and gastrointestinal and metabolic drugs. As for anti-infectives, the global epidemic of COVID-19 continues, but there are three vaccines against it, and the data do not seem to indicate a specific increase in 2020.

As for modalities, the trend differs from that of globally developed products, with biopharmaceuticals accounting for a larger share than small molecule drugs. In particular, vaccines and CAR-T cell therapies accounted for a large proportion of the total. As for vaccines, 50 out of 55 products were against infectious diseases, and most of them were antiviral vaccines against influenza, hepatitis viruses, and other viruses.

CAR-T cell therapy

As indicated in the previous section, there are more CAR-T cell therapies in China than monoclonal antibodies. Especially in the past few years, not only the number of products has increased, but also new companies, mainly start-ups, have entered the market. As shown in Figure 5, as of May 2016, there were two products in clinical development and one company was identified for the first time, and since then the number of clinical development products as the number of new companies has been increasing every year. In particular, there were many companies based in Shanghai, Beijing, and Nanjing, indicating the formation of a bio-cluster.

Finally, Figure 6 shows the types of antigens targeted, with CD19 being the most common, followed by TNFRSF17 (B cell maturation antigen: BCMA). Although there were several other antigens targeting not only blood cancers but also solid tumors, many of them targeted the same antigens, and although the number itself is increasing, it is expected that the selection of items will continue to some extent as the development progresses in the future.

Fig. 5 Number of new CAR-T cell therapy products and new entrant companies

Fig. 6 Types of target antigens and number of items

Summary

As we have seen, new drug development by Chinese pharmaceutical companies is becoming more active, especially in the last few years, with the number of products increasing rapidly. The 13th Five-Year Plan for National Economic and Social Development (2016-2020), which involves science and technology innovation policy, and "China Manufacturing 2025," which describes the future development plan for the manufacturing industry, highlight biopharmaceutical development and manufacturing as one of the nation's key strategies, and the recent development and The recent increase in the number of products developed and manufactured in China, as shown in Figure 1, is thought to be partly due to these policies.

The majority of the products are anti-tumor drugs, and the development of biopharmaceuticals such as CAR-T cell therapy has been particularly active. Some of the products were designated as special measures by the FDA and EMA and have the potential for global development, especially by startups, confirming the improvement in drug discovery capabilities of Chinese pharmaceutical companies.

In the area of CAR-T cell therapy, for which R&D for commercialization is particularly active in China, startups are being established and entering the market one after another, mainly in Shanghai and Beijing, and it seemed as if there is an environment conducive to the formation of a bio-cluster. On the other hand, many of the target antigens have already been reported, and there are issues in terms of novelty.

As shown in Figure 2, most of the new drug development by Chinese pharmaceutical companies is conducted only within their own country, and there are not yet many products that can be developed globally, which may be due to the novelty of each product. Although each product needs to be examined closely, there is no doubt that new drug development is becoming more active, and it will be necessary to continue to monitor the trend closely in the future.

1) Number of reports and countries from which data was obtained

Pharmaceutical and Industrial Policy Research Institute. Status of Research and Development of Small Molecular Drugs and Biopharmaceuticals," Policy Research Institute News No. 44 (March 2015).
2)

The data were compiled based on the category "Originator" and its "Company HQ Country" in Pharmaprojects®.
3)

Unlike the "Nationality of the Originator" survey conducted by the National Institute for Policy Studies (NIPR), this survey does not examine the basic patents for each item. Therefore, it is possible that the parent company at the time of application may be a company with a different nationality.
4)

Drugs approved in one of the countries and under development in other countries or for other diseases are not included in this tabulation.
5)

Therapeutic Class and Modality are based on "Therapeutic Class," a category within Pharmaprojects®.
6)

An item may have multiple indications.
7)

For details of each special measure, please refer to the " New Drugs Approval in Japan, the U.S., and Europe " (Japanese only ). See Supplement to "Comparison of New Drug Approval Status and Review Periods in Japan, the United States, and Europe," Policy Research Institute News No. 58 (November 2019).
8)

RMAT (Regenerative Medicine Advanced Therapy): A system that stipulates that an expedited approval system, etc., may be applied to products used for regenerative medicine advanced therapy that meet specified requirements. The Act was enacted with the passage of the 21st Century Cures Act in 2016.

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