On January 9th, the official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration announced that the application for the listing of SHR4640 tablets, a Class 1 new drug of Hengrui Pharmaceutical, has been accepted. SHR4640 tablets are a highly selective small molecule inhibitor developed by Hengrui Pharmaceutical for the specific expression of UraT1 (urate transporter) in renal tubular epithelial cells. It is a class 1 anti gout drug independently innovated by Hengrui Pharmaceutical and the first UraT1 inhibitor to be applied for market in China. As of now, a total of approximately 279.87 million yuan has been invested in research and development projects related to SHR4640 tablets.

01. Breaking the monopoly of imported drugs?
Since the 1970s, the development of URAT1 inhibitors has been quite bumpy. In the nearly 50 years since its first appearance on the historical stage, multiple products have repeatedly gone through listing and delisting.

In 1971, the first URAT1 inhibitor, benzbromarone, was approved in Germany, and safety concerns have been associated with URAT1 inhibitors ever since. In 1994, the Netherlands was the first to announce incidents related to the hepatotoxicity of benzbromarone; Subsequently, in 2000, Japan reported three more cases of liver failure caused by benzbromarone; In 2003, it was delisted due to an outbreak of liver necrosis in Europe.

In response, the US FDA, as a global benchmark for drug review, has consistently refused to approve this drug due to the serious risk of liver damage. After the delisting of benzbromarone, URAT1 inhibitors also fell silent; The xanthine oxidase (XO) inhibitor febuxostat has become a hot topic for some time.

As a typical drug of xanthine oxidase (XO) inhibitor, febuxostat, which is suitable for long-term treatment of hyperuricemia in gout patients, has a high market share in China.

After being approved in 2013, the market performance of this drug remained "evergreen" until it encountered centralized procurement in 2020, and the price dropped from around 10 yuan per tablet (40mg specification) to around 1 yuan, directly causing the market to "shrink".

According to data from the Zhongkang Kaisi system, the sales revenue of non busostat in grade hospitals reached 1.532 billion yuan in 2019; In 2020, the year-on-year decline was 10.4%, reaching 1.372 billion yuan; Subsequently, in 2021, it sharply declined to 406 million yuan, a year-on-year decrease of 70.4%; In the following years, the sales revenue did not exceed 500 million yuan; In the first three quarters of 2024, it will only reach 384 million yuan.

After a significant drop of 75.1% in price in 2020, the average unit price of febuxostat decreased from 92.6 yuan/box to 23 yuan/box, and continued to decline for four consecutive years thereafter. However, in terms of sales volume, although the sales volume in 2021 decreased from 1.372 billion yuan to 406 million yuan, its sales volume increased by 19% year-on-year and maintained a positive growth trend for four consecutive years.

However, internationally, the risk of cardiovascular disease associated with febuxostat has also been blacklisted by the FDA. After decades of silence, the emergence of the second URAT1 inhibitor, Resveratrol, once gave people hope. Due to its publication in Phase II clinical data, Rescinamide has shown significant efficacy and good safety, and can even be used for patients with renal failure.

This clinical data prompted AstraZeneca to acquire Ardea Biosciences, the original research company of Rescind, for $1.26 billion. AstraZeneca has high hopes for it, believing that Rescind's sales can easily exceed $1 billion.

AstraZeneca's big move quickly attracted people's attention, and Ressinad became the hope of URAT1 target. Followers at home and abroad followed Ressinad's route. With the FDA approval of Resveratrol in 2015, this wave reached its peak, ushering in another spring for URAT1 inhibitors.

According to statistics, more than 10 domestic companies have participated in the layout of Resveratrol Me Too drugs since Resveratrol, among which the fastest is Hengrui Pharmaceutical SHR4640. However, the progress of Hengrui has not been smooth sailing. Although SHR4640 entered phase III clinical trials in 2019, the clinical results have not been announced yet. And in 2022, it began phase II clinical trials in combination with febuxostat, possibly due to safety issues with monotherapy, and instead pursued combination therapy.

The application for the listing of SHR4640 has been accepted, and Hengrui Pharmaceutical has become the first domestically produced URAT1 inhibitor to stand out from the competition. Based on previous results, the high-dose group showed a more significant uric acid lowering effect compared to benzbromarone, and SHR4640 is expected to become the first domestically marketed URAT1 inhibitor.

02. Gout 10 Year End "New Release". Is there a change in the order of the URAT1 inhibitor market?
From a global perspective, there are currently over 40 types of URAT1 drugs available worldwide, but the main ones approved for use include benzbromarone, probenecid, remifentanil, and domperidone. In the Chinese market, URAT1 inhibitors that have been launched include benzbromarone, probenecid, and the recently approved Doxostat tablets.

On December 9th, Eisai China announced the launch of its new urate reabsorption inhibitor, Doxostat Tablets (trade name: Ulex) ®） It has been approved by the National Medical Products Administration (NMPA) in China for the indication of gout with hyperuricemia.

It is reported that it has been 11 years since febuxostat was approved for marketing in China in 2013, and no new drugs for treating gout have been approved. From the perspective of safety improvement and efficacy enhancement, there is still a great unmet clinical demand in the gout medication market.

According to Frost&Sullivan's prediction, the number of people suffering from hyperuricemia and gout in China will reach 240 million by 2030, and the domestic gout drug market will grow from 900 million yuan in 2016 to 2.8 billion yuan in 2020, and is expected to grow to 10.8 billion yuan by 2030.

Due to the large number of domestic patients and unmet clinical needs, there is an urgent need for the research and development of new gout drugs in China. Duotenorel is a highly selective urate transporter (URAT1) inhibitor. It effectively inhibits the function of renal proximal tubule URAT1, promotes the excretion of uric acid from the kidneys, and thus reduces blood uric acid levels.

Compared to the currently marketed benzbromarone, the metabolites of Doxolone do not contain "p-benzoquinone" or similar substances, which can avoid the hepatotoxicity of benzbromarone. Long term use has no significant impact on kidney function and liver function. In addition, it also has significant high selectivity and efficiency in targeting. Duotenorel selectively inhibits URAT1 without affecting other uric acid transporters, improving the efficiency of blood uric acid lowering.

According to a research report by Ping An Securities, there are currently at least 20 small molecule drugs under development worldwide for the treatment of hyperuricemia/gout, with URAT1 inhibitors being the main ones. Among domestic enterprises, the leading companies in the research and development of URAT1 inhibitors include Hengrui Pharmaceutical SHR4640 (Phase III in China), Yingli Pharmaceutical YL-90148 (Phase III in China), Xinnuowei XNW3009 (Phase III in China), and New Element Pharmaceutical ABP-671 (Phase IIb/III in China).

From the perspective of domestic R&D pipelines, the AR882 of poinsettia is particularly noteworthy, as it has the potential to be the best in its class. Currently, it has entered Phase III clinical trials overseas. Previous clinical data shows that compared to existing therapies, AR882 has better efficacy and higher safety in treating gout patients. AR882 can not only reduce serum uric acid (sUA) in gout patients, but also significantly reduce gout stones, alleviate uric acid crystal burden, and decrease the trend of acute gout attacks.

According to the drug clinical trial registration and information disclosure platform under the National Medical Products Administration, this year, the Yifengxin AR882 capsule launched a multicenter, randomized, double-blind, parallel controlled, phase II/III clinical trial to compare the efficacy and safety of febuxostat tablets in the treatment of patients with primary gout and hyperuricemia.

Conclusion
Due to the difficulty of drug development and other reasons, only a small number of URAT1 inhibitors have been approved for market. The application for the first class new drug SHR4640 tablets from Hengrui Pharmaceutical has been accepted and is expected to stand out in fierce competition, becoming the first domestically produced URAT1 inhibitor to be launched, benefiting Chinese patients with hyperuricemia and gout.

Source: https://pharm.jgvogel.cn/c1481546.shtml