In depth report: recombinant protein drugs, EPO market under domestic monopoly

There are many patients with chronic kidney disease and cancer in China Erythropoietin (EPO) is the most important hematopoietic growth factor for the proliferation and differentiation of erythrocytes in vivo and the maintenance of the normal number of peripheral circulation erythrocytes It is mainly used in clinical: anemia caused by renal insufficiency, anemia caused by chemotherapy for non bone marrow malignant tumors The number of patients with chronic kidney disease (CKD) in China is estimated to be about 120 million, among which renal anemia is the most common complication affecting the quality of life of CKD patients The number of new cancer cases in China is about 3.12 million every year, and about 50% of chemotherapy patients will have anemia After the global EPO market peaked in 2006, it declined year by year Since Amgen listed its first rhEPO product in 1989, rhEPO drugs have been growing rapidly because of its good anti anemia effect By 2006, the global rhEPO drug sales reached a peak of 12.6 billion US dollars, becoming the most successful genetic engineering biological products at that time After that, due to the competition of generic drugs and the decline of product prices, the market size slowly dropped to 6.9 billion US dollars in 2013 Amgen has more than half of the market share In 2013, in the global EPO market, Amgen company accounted for nearly 56% of the market share with us $3.86 billion and was in the absolute leading position in the market; the procrit products of ortho biotech, a subsidiary of Johnson, had a sales volume of US $1.36 billion and a market share of about 20%; Kyowa Hakko Kirin's NESP / ESPO product sales volume is 620 million US dollars, with a market share of about 9%; Roche's rhEPO product sales volume is 1.05 billion US dollars, with a market share of 10.5% At present, long-term and short-term EPO products coexist in European and American markets The representative products of long-term EPO include Aranesp (once a week) of Amgen and mircera (polyethylene glycol betaine) of Roche In 2005-13, the domestic rhEPO market CAGR was 14% The domestic rhEPO market started from the imported drugs in 1992 Due to the excellent effect of rhEPO in the field of anemia and the promotion of professional chemistry in foreign pharmaceutical enterprises, the clinical application rate of rhEPO has increased steadily In 1998, the first domestic EPO Shenyang Sansheng pharmaceutical "ibio" was listed on the market From 2005 to 2013, the sales volume of rhEPO increased from 120 million yuan to 330 million yuan, with a compound annual growth rate of 14% Domestic products monopolize the domestic EPO market Domestic rhEPO rapidly occupied 90% of the market of domestic hospitals with obvious price advantage Shenyang Sansheng's rhEPO product "ibio" has occupied half of the market of domestic sample hospitals since 2005, and its share has been expanding in the following years By 2013, the share of "ibio" in domestic sample hospitals reached 65.6%, which is absolutely in the leading position in this field Leebo, the rhEPO product of Japan union Kirin company, has always been in the second place in the domestic sample hospital market, but its share is constantly decreasing Its share in the domestic sample hospital dropped from 34.2% in 2005 to 11.5% in 2013 1、 Overview of erythropoietin 1 Brief introduction of EPO Erythropoietin (EPO) is the most important hematopoietic growth factor, which can inhibit the apoptosis of erythroid progenitor cells, stimulate the release of reticulocytes into the blood circulation, and stimulate the synthesis of proteins in the cells In the early stage of embryo, fetal liver is the main source of fetal EPO After birth, EPO synthesis changes from liver to kidney The EPO of adult body mainly comes from the synthesis and secretion of renal tubules, capillary endothelial cells and interstitial cells However, about 10-15% of EPO comes from the outside of kidney The main synthetic organ is liver, which is produced by hepatocytes and Kupffer cells around the central vein of liver In addition, it has been found that macrophages in bone marrow and astrocytes in central nervous system may be nearby EPO can also be synthesized by secretion 2 The physiological function of EPO the most important function of EPO is to promote the survival, proliferation and differentiation of erythroid progenitor cells in bone marrow to regulate the generation of erythrocytes In addition, EPO has a variety of non hematopoietic functions, such as organ protection, promoting the proliferation, differentiation and maturation of progenitor cells, regulating some functions of neurons, regulating intracellular calcium concentration and immunoregulation 3 The development process of EPO drugs has been from the discovery of EPO by French scientists Carnot and defrandre in 1906 People have been deeply understanding EPO in this century and have made a lot of great achievements In June 1989, Amgen company successfully developed and launched the world's first recombinant human erythropoietin (rhEPO) product, Epogen (afaepatin), mainly in the treatment of renal anemia, anemia caused by radiotherapy and chemotherapy of malignant tumors and other symptoms In September 2001, arnesp, a "high glycosylated" long-term recombinant erythropoietin product of Amgen company, was approved by FDA and officially launched in 2002 In November 2007, Roche launched another long-term recombinant erythropoietin product, mircera (PEGylated betaine) 4 Clinical application of rhEPO 5 There are many patients with chronic kidney disease (CKD) and cancer in China In recent years, the prevalence of CKD in China has increased year by year, which has become one of the problems affecting public health According to the survey data of Peking University and Zhejiang University, the total prevalence of CKD is 10.8% (10.2-11.3) Therefore, the number of patients with chronic kidney disease in China is estimated to be about 115.5 million (112.9-125 million), of which renal anemia is the most common complication affecting the quality of life of CKD patients Some studies have shown that the incidence of anemia increases with the decrease of renal function (the increase of CKD stages) Among them, nearly half (49.9%) of ckd3 patients have anemia, and the incidence of anemia in hemodialysis patients is at least 10 times higher than that in non CKD patients According to the 2012 annual report of China cancer registration issued by the National Cancer Registration Center, the number of new cancer cases in China is estimated to be 3.12 million every year, with an average of 8550 people per day Six people are diagnosed as malignant tumors every minute Chemotherapy is still the most important means of cancer treatment, about 50% of chemotherapy patients will appear anemia 2、 The global rhEPO market shrank year by year 1 The global rhEPO market peaked in 2006 and then declined year by year Since the first rhEPO product was listed by Amgen company in 1989, rhEPO drugs have been growing rapidly because of its good anti anemia effect By 2006, the global rhEPO drug sales reached a peak of 12.6 billion US dollars, becoming the most successful genetic engineering biological products at that time During 2001-2013, the global sales of rhEPO increased from 6.3 billion US dollars to the peak of 12.6 billion US dollars in 2006, and then the market scale slowly dropped to 6.9 billion US dollars in 2013 due to the competition of generic drugs and the decline of product prices 2 Market share of Amgen company is more than half In 2013, in the global rhEPO market, Amgen company accounted for nearly 56% of the market share with us $3.86 billion, and was in an absolute leading position in the market Although its short-term product Epogen has been on the market for 25 years, its sales volume still reached US $1.95 billion, with a market share of 28.3%, becoming the first drug to be sold for this single product; followed by its long-term product Aranesp, with a sales volume of US $1.91 billion, accounting for about 27.7% 7% market share; the third is procrit products of ortho biotech, a subsidiary of Johnson, with sales of US $1.36 billion and market share of about 20%; Kyowa Hakko Kirin's NESP / ESPO product sales volume is 620 million US dollars, with a market share of about 9%; Roche's rhEPO product sales volume is 1.05 billion US dollars, with a market share of 10.5%, among which Chugai Pharm's rhEPO product epogin / neoreformon sales volume is 580 million US dollars, and mircera, a new generation of polyethylene glycol long-term EPO product That's $470 million 3 Sales of major rhEPO products in the world 1 Epoetin alfa (epoetin alfa) of Amgen company is the first rhEPO - α product in the world which was listed by Amgen company in June 1989 It is mainly used to treat anemia caused by chronic renal failure and anemia symptoms caused by radiotherapy of malignant tumors, and has obtained good market response Related background introduction: at the beginning of the company's establishment, Amgen sold Epogen's market right in Asia to Japan union Kirin company for us $300 million in cash, and then authorized Epogen to Johnson & Johnson company Johnson & Johnson can sell rhEPO in the United States, but only for anemia symptoms (mainly cancer) other than renal anemia, but there is no symptom limit in the European market Johnson & Johnson paid Amgen millions of dollars and promised to pay royalties in the future Ortho biotech, a subsidiary of Johnson & Johnson, promoted the drug as procrit Amgen's Epogen sales were $506 million in 1992 and peaked at $2.6 billion in 2004 Epogen's sales in 2013 were $1953 million 2 Aranesp of Amgen Alfa) is a kind of "high glycosylated" long-acting rhEPO - α product approved by the FDA in September 2001 The long-acting principle is that the amino acid sequence of human erythropoietin is partially modified and a new sugar chain is added to its molecule, so that it has a longer half-life of serum and a sustained activity of erythropoiesis Therefore, it has the ability to promote erythropoiesis It is much better than the first generation rhEPO Arnesp's sales volume in the year of listing was US $41.5 million, but it reached US $420 million in 2002, which increased by nine times in one year, proving its popularity in the market Arnesp's sales volume peaked at US $4.12 billion in 2006 In 2007, Aranesp was shown to promote tumor growth and increase the risk of death in cancer patients in a series of studies American insurance companies and Medicare have successively withdrawn Aranesp (cancer chemotherapy) from the reimbursement list, but subsequent research shows that Aranesp will not accelerate the death of cancer patients In 2013, arnesp's sales fell to $1911 million 3 Johnson & Johnson's procrit / eprex / erypo procrit / eprex / erypo (epoetin alfa) is the rhEPO - α product that ortho biotech (a subsidiary of Johnson & Johnson) obtained by paying millions of US dollars patent fee after Amgen launched the new drug Epogen, and ortho biotech named the drug procrit for promotion However, according to the agreement, the indications sold by procrit / eprex / erypo in the United States can only be used for other diseases (mainly cancer) other than renal failure, and there is no restricted use in Europe Since procrit / eprex / erypo was listed in the same time as Epogen in June 1989, it brought considerable returns to ortho biotech (a strong subsidiary) in the following 20 years Due to the relatively complete sales network of Johnson & Johnson, the sales revenue of procrit / eprex / erypo in 2001 was 3.43 billion US dollars, even higher than that of Epogen of Amgen at that time, which was 2.11 billion US dollars Procrit / eprex / erypo's revenue remained above $3 billion in 2001-2006 and peaked at $4.27 billion in 2002 In 2013, the global sales revenue of procrit / eprex / erypo was US $1.37 billion 4 The ESPO / NESP ESPO (epoetin alfa) of Kirin Concorde is the first generation rhEPO - α developed and listed by Kyowa Hakko Kirin (Japan Concorde Kirin pharmaceutical company), which is the only imported drug that can occupy a place in the domestic rhEPO market NESP (afadabep