Chinese pharmaceutical companies represented by Hengrui Medicine and Ipomoea australis are actively planning the clinical development of URAT1 inhibitors. With the acceleration of the research process, a new generation of highly effective and low-toxic gout treatment drugs is expected to be quickly launched on the market, promoting innovation in the field of gout treatment.

Significant clinical need

Hyperuricemia is a metabolic syndrome caused by purine metabolism disorder. Its clinical diagnosis requires that the blood uric acid level of an adult exceeds 420μmol/L (7mg/dl) twice on different days. Gout is a crystal-related arthropathy. As a common metabolic rheumatic disease, its pathological basis is hyperuricemia - abnormal purine metabolism or reduced uric acid excretion causes increased blood uric acid, which in turn leads to the deposition of monosodium urate crystals.

The current treatment of chronic hyperuricemia and gout mainly revolves around two core mechanisms: inhibiting uric acid synthesis and promoting uric acid excretion. Drugs that inhibit uric acid production work by inhibiting the activity of xanthine oxidase, and representative drugs include allopurinol and febuxostat. Among uricosuric drugs, benzbromarone has a unique dual mechanism of action, which can simultaneously inhibit renal tubular uric acid transporter-1 (URAT1) and glucose transporter 9 (GLUT9), thereby reducing uric acid reabsorption, increasing excretion, and achieving a decrease in blood uric acid levels.

However, in addition to the effectiveness of existing therapies, safety issues still need to be focused on. For example, allopurinol may cause skin allergic reactions and liver and kidney damage. Febuxostat has a black box warning from the US FDA, and domestic guidelines recommend that elderly patients with cardiovascular and cerebrovascular diseases should start with a low dose and closely monitor the risk of cardiovascular events. Benzbromarone has not been approved by the FDA due to its potential hepatotoxicity and has been withdrawn from the European market since 2003.

The "Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout in China" lists the URAT1 inhibitor benzbromarone as the first-line drug of choice for the treatment of hyperuricemia and gout (1B recommendation). The guidelines also point out that liver function needs to be monitored regularly during clinical use, and for patients with concomitant chronic liver disease, benzbromarone should be used after careful evaluation.

Yaozhi data shows that domestic sales of benzbromarone continued to rise from 2016 to 2024, and the sales of the drug in domestic public medical institutions reached 425 million yuan in 2024.
According to a Frost & Sullivan study, in 2020, the number of people with hyperuricemia worldwide was about 930 million, and the number of gout patients reached 220 million. The "2021 China Hyperuricemia and Gout Trend White Paper" pointed out that the overall prevalence of hyperuricemia in my country is 13.3%, and the number of patients is about 177 million. This series of data highlights the increasingly severe disease burden of hyperuricemia and gout in my country and even around the world.
New generation of URAT1 inhibitors

In the field of research and development of drugs for the treatment of hyperuricemia, URAT1, as a key transporter for uric acid reabsorption in the kidney, plays a core role in regulating uric acid homeostasis in the body. The uric acid excretion process can be directly regulated by inhibiting URAT1. Compared with other mechanisms of action, this targeted intervention in uric acid excretion is considered to be a more precise and clinically promising treatment path, thus attracting many pharmaceutical companies to develop it.

Dotinurad, developed by Eisai, is the world's first new-generation URAT1 specific inhibitor and the only URAT1 inhibitor approved for marketing in China. The drug selectively inhibits the renal proximal tubule uric acid transporter URAT1, blocking urate reabsorption, thereby effectively reducing blood uric acid levels without affecting the functions of uric acid excretion factors ABCG2 and OAT1/3, making it more efficient in lowering uric acid. At the same time, since it does not inhibit ABCG2 in the intestine and does not affect intestinal uric acid excretion, it can reduce the burden on the kidneys. In addition, the drug does not increase the accumulation of uremic toxins and may help reduce the risk of chronic kidney disease (CKD) and cardiovascular disease (CVD).

In the global approval process, Dotinorel was first approved in Japan in January 2020 and approved for marketing in China in December 2024. Its indications are gout and hyperuricemia. In terms of market performance, sales of Dotinorel reached 2.2 billion yen in 2022 and increased to 3.3 billion yen in 2023.

A phase 3 study conducted in China showed that after 24 weeks of treatment with 4 mg of dotinoret, the proportion of patients with blood uric acid ≤ 6 mg/dl (360 μmol/L) was 73.6%, significantly higher than the 38.1% in the 40 mg febuxostat group.

In a Phase 3 study conducted in Japan, the use of dotinoreplast for 58 weeks had no significant effect on liver and kidney function, and the uric acid compliance rate reached 100% at a dose of 4 mg; no dose adjustment was required in patients with mild to moderate renal insufficiency, and no serious adverse cardiovascular reactions were found in multiple clinical studies, showing good safety and tolerability.

AstraZeneca developed the world's first new selective URAT1 inhibitor, Resinade, which was approved by the FDA in 2015. However, due to its limited pharmacodynamic activity, it needs to be used in combination with allopurinol in clinical practice to enhance the acid-lowering effect. In terms of safety, the FDA issued a black box warning for the risk of acute renal failure and the drug was withdrawn from the US market in 2019.

Dotinorex developed by Eisai exhibits a different safety profile. Most adverse events during treatment are mild, and the drug is highly selective for URAT1, with little inhibitory effect on other urate transporters.

Hengrui leads the way

In the field of global gout treatment drug research and development, the URAT1 target continues to lead the research and development. At present, many new URAT1 inhibitors have entered the middle and late stages of clinical development. This type of drug is expected to break through the limitations of existing therapies and bring safer and more effective solutions to gout treatment.

Hengrui Medicine's Ruzinurad (SHR4640) is the URAT1 inhibitor with the fastest clinical progress in its pipeline. In January 2025, the drug candidate's application for marketing approval for the treatment of primary gout with hyperuricemia was accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration. If approved, SHR4640 will become the first domestically produced highly selective URAT1 targeted drug.

Its Phase 3 clinical data showed that compared with the first-line drug allopurinol, the drug achieved statistically and clinically significant dual superiority improvements in the primary endpoint indicators, and had excellent safety and tolerability, providing a potential option for the treatment of gout.

AR882 is a URAT1 inhibitor developed by Iris and Arthrosi and has entered Phase 3 clinical trials in the U.S. The candidate drug achieves metabolic optimization through a unique molecular design: four deuterium atoms and one hydroxyl group are introduced into the structure of benzbromarone to change the metabolic pathway to reduce the risk of hepatotoxicity, while achieving 24-hour continuous acid suppression through long-term binding to uric acid transporters.

The global multicenter 2b trial showed that 82% of patients in the 75mg dose group had their blood uric acid levels dropped below 5mg/dL. Compared with existing treatment options, AR882 has shown more significant efficacy and higher safety in gout patients. The drug can not only effectively lower blood uric acid levels, but also significantly reduce tophi formation, reduce the burden of uric acid crystal deposition, and reduce the frequency of acute gout attacks.

Another Phase 2/3 trial comparing febuxostat (febuxostat is the first-line uric acid-lowering drug for gout patients recommended in the "Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019)") showed that AR882 showed excellent efficacy at 6 weeks of treatment, and 75mg AR882 showed superior efficacy compared to febuxostat (p<0.001). At the same time, AR882 showed good tolerability, without any severe adverse reactions, and had significant safety advantages.

Yingli Pharmaceutical's YL-90148 is conducting Phase 3 clinical trials simultaneously in China and the United States. Phase 1 data showed that it has good pharmacokinetic properties, can significantly increase the renal clearance of uric acid, reduce serum uric acid levels, and has excellent safety characteristics, laying the foundation for subsequent development.

Sinovent's XNW3009 tablets are a new type of small molecule URAT1 inhibitor. The URAT1 inhibitory activity (IC50 value) is more than 40 times higher than that of benzbromarone. It also has the potential to inhibit xanthine oxidase, forming a dual-effect uric acid-lowering mechanism of "reducing production + accelerating excretion". It has significant advantages over traditional single-mechanism drugs (such as febuxostat and benzbromarone) and is currently in the Phase 3 clinical stage.

New Element Pharmaceuticals' ABP-671 is currently conducting Phase 2b/3 clinical trials for gout in China and abroad. Two Phase 2 trials showed that the efficacy of a 2 mg dose once daily was equivalent to or superior to the highest dose of benzbromarone and febuxostat (80 mg), and 100% of patients in the 6 mg and 8 mg dose groups had sUA < 6 mg/dL. In terms of safety, the incidence of adverse events was comparable to that of placebo, all of which were mild and without serious events. In December 2024, China Medical System reached an agreement with New Element to obtain its exclusive commercialization rights in mainland China, Hong Kong and Macau, accelerating the product's landing process.

D-0120 is a URAT1 inhibitor independently developed by Infinobio, and its indications are hyperuricemia and gout . Currently, the drug has completed Phase 2a clinical trials in China, and data show that the rate of patients' blood uric acid reduction reaching the target is as high as 80%, highlighting the excellent uric acid-lowering ability and clinical application potential of D-0120.

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