With annual sales of $1.4 billion, the race is on for the first copy of this innovative drug

When it comes to HIF-PHI drugs, chronic kidney disease anemia will come to mind without thinking. When it comes to HIF-PHI drugs approved in China, roxadustat comes to mind. Since its approval in China in December 2018, roxadustat has been the "only" drug in the field of HIF-PHI in China for five years.

Nowadays, with the rising sales of roxadustat in China, many pharmaceutical companies have taken a fancy to the "money scene" in the field of HIF-PHI drugs. Not only many pharmaceutical companies are engaged in the research and development of HIF-PHI innovative drugs, but also a large number of generic drug companies are gearing up for roxadustat.

The beginning of the first imitation dispute

In recent days, Roxadustat has become a small "fire".

On May 22, the marketing application of roxadustat capsule submitted by Nanjing Chia Tai Tianqing Pharmaceutical was accepted by the CDE, becoming the first domestic generic roxadustat. On May 23, the products of Jiangsu Wanbang Biochemical, Jiangxi Shanxiang Pharmaceutical and Chengdu Bette Pharmaceutical also submitted marketing applications and were accepted. This is the first time that a generic drug has been declared on the market since roxadustat was listed at the end of 2018, and four companies have reported production in two days, and a battle for the first copy of roxadustat has also been started.

Cp Tianqing Pharmaceutical Co., LTD was the first company to distribute generic roxadustat in China, and was also the first company to conduct BE research. At present, in addition to the four enterprises that have reported production, according to public data, more than a dozen domestic enterprises have carried out roxadustat BE research, including Qilu Pharmaceutical and Jichuan Pharmaceutical, which have completed relevant trials, and more enterprises will report production in the follow-up.

According to the CDE patent registration platform, the expiration time of the compound patent, composition patent, and pharmaceutical use patent of roxadustat is June 4, 2024, so the generic drug circuit of roxadustat is bound to be a fierce race in the next year or two.

The "paradoxical" roxadustat

Roxadustat, jointly developed by Astrazeneca and Fibrogen, is the world's first small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for the treatment of renal anemia.

Roxadustat is a small molecule hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI). Hypoxia-inducible factor (HIF) increases not only the expression of erythropoietin, but also the expression of erythropoietin receptors and proteins that promote iron absorption and recycling. Roxadustat mimics ketoglutarate, one of the substrates of prolyl hydroxylase (PH), to inhibit PH enzyme and affect the role of PH enzyme in maintaining the balance between the production and degradation rate of HIF, so as to achieve the purpose of correcting anemia.

In December 2018, roxadustat was the first in the world to be approved for marketing in China under the trade name of Eridro. It is the first HIF-PHI innovative drug developed by foreign pharmaceutical companies and completed the world's first in China, which has attracted much attention since its listing.

In August 2019, the indication for the treatment of anemia in patients with non-dialysis dependent CKD was approved by the NMPA. In November 2019, roxadustat was included in medical insurance through national medical insurance negotiations. In 2021, the price was reduced by nearly half through the negotiation of medical insurance price reduction. In 2022, roxadustat was listed as a national negotiated drug in the "dual channel" drug management.

It can be said that roxadustat has a sunny road in China, and its sales performance is also rising. According to the relevant financial reports of Fibrojin and Astrazeneca, after the negotiation of medical insurance price reduction, roxadustat's revenue for the whole year of 2021 was 1.327 billion yuan, an increase of about 12% year-on-year, and the sales volume increased by more than 80%. Sales volume increased steadily in 2022, with net sales of about 1.46 billion yuan, becoming a large single product with sales volume approaching 1.5 billion yuan.

Astrazeneca and Fibrogen will continue to invest in the Chinese market. On May 18, 2023, Fibrogen announced positive key data from another phase III study of roxadustat in China, which evaluated the efficacy and safety of roxadustat for the treatment of anemia in subjects with non-myeloid malignancies who were receiving chemotherapy.

In addition to China, Roxadustat's territory has been expanded to Japan, Chile, the European Union and other countries and regions. Japan was approved in 2019, and the European Union was approved in 2021.

Astellas and Fabrgen are jointly responsible for the development and commercialization of roxadustat in Japan, Europe, Turkey, Russia, the Commonwealth of Independent States (CIS), the Middle East and South Africa. Astrazeneca and Fibrotron are jointly responsible for development and commercialization in the United States, China, other markets in the Americas, Australia/New Zealand and Southeast Asia.

However, roxadustat, which has been on a smooth journey in many countries and regions around the world, has so far been unable to open the door of FDA, and the US market has become a "pain point" for roxadustat.

The biggest hurdle for roxadustat to pass the FDA is safety. On August 11, 2021, Fibrojin announced that it had received a complete response letter from the FDA regarding roxadustat's NDA for chronic kidney disease, in which the FDA made it clear that it would not approve the marketing application for roxadustat at this time and required Fibrojin to conduct additional clinical studies before resubmitting the marketing application.

Time may tell when Roxadustat, which has had a long road to market in the United States, will hit the market.

Progress in drug development of HIF-PHI

Hif-phi is a novel oral small molecule drug for the treatment of renal anemia. By inhibiting HIF prolyl hydroxylase, HIF-PHI stabilizes the level of HIF in vivo, and then regulates the transcription and expression of downstream target genes of HIF signaling pathway. HIF‐PHI promotes erythropoiesis by increasing endogenous EPO production and receptor expression, enhancing the expression of iron metabolism-related proteins, and reducing hepcidin level.

Chronic kidney disease (CKD) is a "silent killer" of human health. There are about 120 million patients with chronic kidney disease in China, and more than 50% of them are complicated with anemia, and the prevalence of anemia in dialysis patients is as high as 95%. Studies have found that erythropoiesis-stimulating agents (ESAs) and iron are the main drugs for the treatment of renal anemia in the past two to three decades, but they have certain limitations. On the one hand, high-dose ESA therapy can increase the risk of tumors, cardiovascular events and cerebrovascular events. On the other hand, patients with functional iron deficiency have a relatively high level of stored iron, and excessive iron treatment increases the risk of infection, allergy, and iron overload, which indirectly increases the risk of death.

Compared with traditional drugs for the treatment of renal anemia, HIF-PHI is more effective, and only requires oral administration, with high patient compliance. Once the drug is marketed, it is favored by patients.

Currently, there are six HIF‐PHI drugs approved in the global market. Other approved drugs include AkebiaTherapeutics' varadustat, JapanTobacco/ Synitech's Ennastat and Bayer's Molistat in Japan, GSK's Dappristat in the U.S. and Japan, and Kangzur's Dedustat in India.
Throughout the global HIF-PHI drug market, Japan is the country with the largest number of approved products. However, like roxadustat, although AkebiaTherapeutics' varadustat has been marketed in Japan due to safety issues, its marketing application in the United States has also been rejected by the FDA, becoming the second HIF-PHI drug rejected by the FDA. It can be seen that, FDA regulators pay attention to the safety of HIF-PHI drugs.

Although HIF-PHI drugs have repeatedly failed to pass the FDA, on February 1, 2023, with the approval of GSK's dapustat in the United States for the treatment of anemia (reduced red blood cell count) in adults with chronic kidney disease (CKD) who have received dialysis for at least 4 months, it became the first HIF-PHI drug approved by the FDA in the United States. At this point, the FDA dilemma of HIF-PHI drugs is solved.

Returning to the domestic market, the only HIF-PHI drug that has been listed in China is roxadustat of Astrazeneca/Fibrogen, which is the champion.

Among the investigational drugs, enastat of Xinlitai is currently in the marketing application stage; Dedustat from Kangzhe Pharmaceutical is in phase III clinical trial stage, HIF-117 from Sansheng Pharmaceutical is in phase II clinical trial stage, DDO-3055 from Hendray Pharmaceutical and HEC-53856 from Dongsunshine Pharmaceutical are in phase I clinical stage.
It is worth mentioning that the fastest progress is Sinitai's enastat, which has been listed in Japan in September 2020. In December 2019, Sinitai introduced enastat from Japan Tobacco (JT). In addition, the exclusive technology development, production, marketing and commercialization rights of the drug in the field of renal anemia in the Chinese market were obtained with the initial payment of US $22.5 million + the maximum R & D registration milestone payment of US $65 million + sales milestone payment and a certain percentage of sales share. In January 2022, Xinlitai has submitted the marketing application of enastat tablets, a new drug for renal anemia, and has been accepted by the CDE. At present, it is still in the application stage, which is expected to become the second HIF-PHI drug to be marketed after roxadustat.

Conclusion

In short, the current HIF-PHI drug field is not yet crowded, whether it is marketed or under development, but the rising sales and broad market prospects have led to the development of HIF-PHI innovative drugs. Now, with the competition of roxadustat generic drugs, the war has been burning from the innovative drug track to the generic drug track. The competition will get fiercer.