From atorvastatin to apixaban
Release Time: 2020-12-29 11:41:44 Visited: 1213 times
From atorvastatin to atorvastatin
After the expiration of global "heavyweight" drug patents, the rapid development of generic drugs will bring explosive growth in demand for APIs and intermediates. For example, omeprazole and other products that began to sell well in the 1990s will bring huge profits to Indian pharmaceutical companies and form the concept and mode of "characteristic APIs".
In recent years, among the world's heavyweight drugs, most of the top sales are biological products, and the high price is an important factor leading to this result. However, in terms of quantity, small molecule drugs based on chemical synthesis are still the largest main products in the world. Among them, there are many small molecule drugs that are newly developed and marketed, and the sales amount is growing rapidly, reaching the "heavyweight" scale.
In fact, from omeprazole in the 1990s to statins with the longest duration of fever after 2003, as well as clopidogrel, sofibuvir, lenalidomide, "tinib" and "Saban", star products have emerged constantly. Each star product is leading the development of clinical medicine, and after the expiration of the patent, the market scale of its generic drugs expands rapidly, becoming a drug with a wider range of use and stronger vitality. Among them, atorvastatin, clopidogrel and apixaban are the representative products with a scale of more than 10 billion US dollars.
In the 21st century, the strength of China's pharmaceutical industry has improved rapidly. Around statins, prils, sartans, penem and other products, a number of representative characteristic API manufacturers such as Haizheng pharmaceutical and Huahai pharmaceutical have emerged. With the expansion of the scale of the "old generation" classic "characteristic API" products such as statins and sartans, and gradually fading the characteristics of high added value, the emerging star products such as "tinib" and "Saban" are attracting people's attention.
Atorvastatin: a classic
The regulation of blood lipid, prevention and treatment of cardiovascular disease are the research and application hotspots in the field of global medicine in recent 30 years. Cholesterol lowering drugs have long been the treatment category with the largest sales in the global market. The advent of statins is known as another milestone in the development history of cardiovascular drugs in the late 20th century. At the forefront of global pharmaceutical research and development, research on various new targets and mechanisms of action is in full swing, but statins are still the main varieties at present and for a long time in the future. In particular, atorvastatin, a fully synthetic product, has become the focus of generic drug manufacturers in the world.
Atorvastatin is a kind of statin lipid regulating drug jointly developed by Warner Lambert company and Pfizer company of the United States. It was first listed in the UK in 1997. It is the first drug with single product sales of more than 10 billion US dollars in history, and it has maintained an annual sales performance of more than 10 billion US dollars for seven consecutive years. After its global patents expired in 2009, the sales volume of the original research drug was quickly replaced by generic drugs. At present, it is still the largest lipid regulating drug in the world, and its global demand for API reaches thousands of tons.
After the global patent of atorvastatin expired in 2009, the API and intermediate industry of atorvastatin in China ushered in a period of rapid development. The production scale increased rapidly, and the export products were mainly intermediates. The export scale rapidly exceeded 100 tons, reaching more than 200 tons in 2011, 600 tons in 2014, 800 tons in 2015, and the total export of various API and intermediate exceeded 1000 tons in 2018, The amount of exports reached more than US $100 million, basically unchanged in 2019 and 2018.
Although the total export scale of API and intermediates of atorvastatin in China has exceeded 100 million US dollars, and it is mainly exported to India, correspondingly, the export scale of API alone of atorvastatin in India has reached 126 million US dollars, and the export of preparations has reached 160 million US dollars. At present, the product market has been in a stable period. For Chinese enterprises, the future opportunities mainly lie in tapping the development potential of downstream preparations and improving the added value of products.
Clopidogrel is an oral anticoagulant jointly developed by Sanofi and BMS and approved for marketing. Its mechanism of action is to inhibit ADP induced platelet aggregation. It was launched in the United States and Europe in 1998, and its trade name is Plavix. In the third year of its launch (2000), its sales volume exceeded US $1 billion. With the subsequent surge, it has become another US $10 billion variety in acute coronary syndrome（ ACS and other related disease treatment field has a solid position.
The patent of clopidogrel expired in 2012, and Indian enterprises have obvious advantages in the global generic market of clopidogrel. India's exports of clopidogrel preparations and APIs will reach US $130 million in 2019 and nearly US $120 million in the first nine months of 2020. China's exports of this product are mainly concentrated in APIs and intermediates, but the scale is small, with a total of more than 31 million US dollars, which has a large growth space in the future.
From the perspective of similar products, the main competitive alternative product of clopidogrel is ticagrelor. Ticagrelor is a new and selective small molecule anticoagulant developed by AstraZeneca.
Ticagrelor was approved by the European Union in December 2010, and was approved by the US FDA on July 20, 2011, with the trade name of bril inta. On November 22, 2012, it was approved to be listed in China, with the trade name of Belinda. The compound patent in China will expire in 2019, and the crystal patent will expire in 2021. Shenzhen xinlitai has successfully challenged the patent and listed generic drugs in China. At present, ticagrelor has entered a period of rapid development of generic drugs, and China's APIs and intermediates have rapidly entered the global market.
Ticagrelor has been recommended by European Society of Cardiology (ESC) guidelines and American Society of Cardiology guidelines for the treatment of ACS patients. Among them, ESC has listed the recommended level of ticagrelor before clopidogrel in recent two years, that is, clopidogrel can only be used in patients who cannot use ticagrelor. It can be predicted that ticagrelor has formed a challenge to the clinical application and market position of clopidogrel, and the substitution trend is obvious, which is expected to become the next generation of star products.
Apixaban: new expectation
"Sarbanes" drugs are a series of highly effective anticoagulants developed for coagulation factor Xa. As of May 2018, the US FDA has approved four "Sarbanes" drugs on the market. Among them, the global market performance of apixaban is growing rapidly, breaking through the $10 billion mark in 2019, ranking second in the overall ranking, becoming another small molecule chemical with sales exceeding $10 billion after atorvastatin and clopidogrel. Rivaroxaban, which went on the market earlier, ranked tenth with a performance of US $6.8 billion (ranked fourth among small molecule chemicals).
Apixaban was jointly developed by BMS and Pfizer, with the trade name of elotal. It was approved by FDA in December 2012, entered the Chinese market in 2013, and entered the medical insurance drug catalog in 2017. Apixaban is mainly used in adult patients undergoing hip or knee arthroplasty to prevent venous thromboembolism. The patent of this product will expire in 2022, but after its Chinese patent is determined invalid in 2019, the generic drugs of Jiangsu Haosen (first generic), Zhengda Tianqing and other enterprises will be approved and listed soon. As of November 2020, six institutions have obtained generic drug approval.
Different from the international market, the sales scale of apixaban has not increased greatly since it was listed in China, and it has been suppressed by rivaroxaban. After entering the market in 2019, domestic brands will grow rapidly, which has completely surpassed the original research drugs and become the main driving force of the market growth. Similarly, the development of apixaban intermediates in China is also rapid. It is an inevitable first step to continue the previous mode of supplying intermediates to India. However, different from the previous statins, the quality and efficacy consistency evaluation of generic drugs in China has been carried out, especially after purchasing with quantity, the quality and price competitiveness of domestic preparations have been greatly improved; the domestic patent challenge of apixaban has been successful, and it has won the advantage of time, bringing more optimistic expectations for domestic apixaban preparations to enter the international market.
According to the export statistics of apixaban in India, its market scale is still very small, less than US $2 million in the first nine months of 2020; the export scale of intermediates and APIs in China is more than US $10 million, and the key production enterprises include kailaiying, Jiangxi Tonghe, Zhejiang Aoxiang and Zhejiang Tianyu.
After the expiration of "heavyweight" drug patents, India has always focused on seizing the international mainstream market in terms of generic drugs and APIs, while in terms of intermediates, Chinese pharmaceutical companies often become the main suppliers at the first time. From the perspective of specific manufacturers, for atorvastatin and clopidogrel, Indian enterprise Dr. Reddy's has outstanding performance in APIs and preparations; Chinese enterprise Zhejiang Lepu Pharmaceutical Co., Ltd. has the most complete atorvastatin industry chain and the largest scale of domestic and foreign sales, and Minolta has greater advantages in clopidogrel APIs.
In the domestic market, Shenzhen xinlitai first launched clopidogrel in 2000 and quickly occupied the market, and its products passed the EU certification. In addition, it was approved by FDA and clopidogrel group.
With the implementation of policies such as quality and efficacy consistency evaluation of generic drugs and procurement with quantity, Chinese pharmaceutical enterprises have certain advantages in the quality, price and cost of characteristic APIs and preparations, and their competitiveness in the international market has been greatly improved.