Caspofungin is a lipopeptide compound developed by Merck’s semi-synthetic technology for fermentation. It inhibits the synthesis of β(1,3)-D-glucan, the basic component of many filamentous fungi and yeast cell walls, and thus acts as an antifungal. The role. It can be used to treat invasive Aspergillus infections, Candida bacteremia and other Candida infections, esophageal candidiasis, and fungal infections in patients with febrile neutropenia who cannot tolerate other antifungal drugs.
Caspofungin acetate for injection is currently the antifungal infection recommended by national clinical guidelines. For example, the American Society of Infectious Diseases (IDSA) guidelines issued in December 2015 recommended the use of echinocycline drugs (such as caspofungin) instead of fluconazole as a first-line treatment for candidemia. The “Guidelines for the diagnosis and treatment of invasive fungal infections in critically ill patients” developed by the Chinese Medical Association Critical Care Medicine Branch also recommended caspofungin as a preventive drug for invasive fungal infections and as a target treatment after infection.
Caspofungin acetate structure
Caspofungin acetate for injection (freeze-dried powder injection) was first approved by the FDA in January 2001. The trade name Cancidas is the first echinocandin antifungal agent listed worldwide. Cancidas’ sales performance after listing was very stable, with annual sales peaking at US$660 million and cumulative sales revenue of US$8.32 billion for Merck.
The original research Caspofung has been listed in China, with sales in China of approximately US$75 million in 2015. Despite the high clinical status of caspofungin, patent protection has expired in 2014, but there are fewer players in China involved in the development of this generic drug.
Caspofungin preparations Currently only China’s Merck’s Cancidas (Cousses) and Hengrui’s generic products are on the market, and the raw materials are only produced by Jiangsu Shengdi, a subsidiary of Hengrui. Among them, Hengrui was the first company to submit a declaration, and its imitation application (CYHS1201509) was approved for approval in January 2017 through the priority review method (the priority of the review was “patent expiration”).
In addition to Hengrui, there are no more than 10 companies in China that declare Kabofenjing. Among them, Borui Bio, Zhengda Tianqing, Huadong Medicine, Osei Kang, and Shanghai Tianwei Biopharmaceuticals have simultaneously declared raw materials and preparations. . From the time of filing, Borui Bio/Xintai Pharmaceutical is the top one in the research enterprise.
Judging from the bid and price, Merck’s 50mg and 75mg two specifications of caspofungin won more than 20, the median price of the winning bid is 1743.96¥/inject and 2727.08¥/inject. The Hengrui 50mg specification has covered 9 regions after the listing, and the median price of the winning bid is 1485.25¥/inject.
On the one hand, the data of each dimension suggests that the market competition pattern of caspofungin is very good; on the other hand, it also shows that for a high-tech barrier such as caspofungin, generic companies can enjoy good prices. And profit margins.
Why does Caspofung appear to be a very imitation of a market space, and the patent has expired for a long time, but few players in China have taken part in the market? This is to start with “fermentation semi-synthesis”.
Industrial value of fermented semi-synthetic technology platform
When it comes to the application of microbial fermentation in the pharmaceutical industry, everyone knows more or less. For example, the story of industrial production of penicillin reducing the number of casualties in the Second World War has become a well-known historical story. The application of microbial fermentation in the pharmaceutical industry is not limited to the field of antibacterial. The macromolecules such as growth factors, recombinant human cell stimulating factors and interferon expressed by various genetic engineering bacteria have greatly satisfied the clinical needs of humans against various diseases. .
Compared with penicillin, the bacterial culture medium is separated and purified to obtain the whole fermentation drug of the target component, and caspofungin is a fermented semi-synthetic drug. It is necessary to obtain a crude product by a fermentation technique, and then obtain an intermediate product by separation and purification. Then the intermediate product is used as the starting material, and the side chain splicing is completed by the synthesis technology, and finally the target component is obtained. Because the “fermentation and semi-synthesis” products need to undergo fermentation, separation, purification, synthesis and other technical links, the technical route and process parameter control is very complicated.
The regulatory requirements for the registration of a fermented semi-synthetic product such as caspofungin are also extremely high. The declaration documents need to start from the source of fermentation. It is necessary not only to systematically study the cultivation of bacteria, the fermentation process, the purification process, but also to explore the routes and conditions of the synthesis. And in the process of controlling impurities, because its final product is quite fragile, a little careless will be abandoned, technical difficulty and high cost. According to Hengrui’s announcement, the R&D investment in this generic drug variety reached 30.54 million yuan. Even if you look at the international market, the development of Caspofung’s generic drugs is not something that a generic drug company can participate in.
In fact, most of China’s generic pharmaceutical companies or R&D institutions are good at developing chemically synthesized generic drugs. Only a small number of enterprises with fermentation technology have certain scarcity. In comparison, the technical and hardware thresholds for chemical synthesis are relatively low. There are raw material reagents, reaction kettles, and ventilation equipment, which basically have the conditions for start-up. The pharmaceutical industry also has a large reserve of chemical talents.
For the semi-synthesis of fermentation, all the production processes involve more technical links and more hardware equipment. The initial hardware investment intensity is very high. At the technical level, it is only a major problem to optimize the breeding of strains at the source. Most fermenting companies can only develop some strains and develop them directly. They have no ability to further cultivate and optimize. In addition, the fermentation process (temperature and humidity control), fermentation equipment (oxygenation mode), disinfection, separation and purification will affect the stability and yield of the product. From the perspective of industrial talents, compound talents who understand both fermentation and synthesis are also more scarce.
Overall, due to the high threshold, high investment intensity, high technical and talent barriers, the industrial value of the fermented semi-synthetic technology platform is still very obvious, and the product development layout around the high barrier technology platform is also a competitive strategy worth learning.