When it comes to metabolic diseases, conditions like diabetes and hyperlipidemia often dominate the conversation. Over recent years, pharmaceutical companies and investors have funneled substantial resources into these areas. Semaglutide, a blockbuster drug that has bolstered Denmark’s GDP, and inclisiran, a long-acting lipid-lowering drug priced at RMB 10,000 (USD 1,400) per dose and drawing 200 new patients daily, exemplify how these conditions have fueled the pharmaceutical industry’s growth.
Yet, in stark contrast, gout and hyperuricemia—long recognized as the second most prevalent metabolic diseases—have seen nearly a decade without the introduction of new drugs.
A report by Ping An Securities highlights a concerning trend: shifts in dietary habits and lifestyles are driving a steady increase in gout prevalence across China. In 2020, approximately 180 million people in the country were living with gout and hyperuricemia. This figure is projected to reach 240 million by 2030. Alarmingly, the average onset age for the disease is becoming younger.
Despite the high prevalence, gout is not inherently untreatable. The challenge has often been the side effects associated with existing medications. However, a breakthrough has emerged: Eisai’s dotinurad tablets have been approved in China for the treatment of gout with hyperuricemia, ending a decade-long stagnation in new drug development for this condition.
Gout medications: A decade-long stagnation
Once regarded as a “disease of the affluent,” gout has shed its stereotype as dietary habits shift alongside rising living standards. Foods and beverages like barbecue, beer, and sugary drinks have become everyday indulgences, making gout a growing concern across all demographics and age groups.
At its core, gout is caused by the deposition of uric acid crystals, which activate the body’s immune defenses. White blood cells engulf these crystals, releasing inflammatory chemicals that trigger painful symptoms. Consequently, inhibiting uric acid production has become a cornerstone of gout treatment, leading to the development of xanthine oxidase inhibitors (XOIs).
Febuxostat, the most widely used XOI in China, was approved in 2013 and saw steady market performance until 2020, when centralized procurement programs reduced its cost significantly—from approximately RMB 10 (USD 1.4) per 40-milligram tablet to RMB 1 (USD 0.14). While this price drop benefited patients, it halved the drug’s market value, with sales in secondary and tertiary hospitals falling from RMB 400 million (USD 56 million) in 2020 to just over RMB 100 million (USD 14 million) by 2021.
Despite its affordability, febuxostat has shown suboptimal efficacy, with studies indicating that 40–60% of patients fail to achieve effective uric acid control. Moreover, safety concerns have plagued the drug. In 2019, the US Food and Drug Administration (FDA) issued a boxed warning highlighting the risks of cardiovascular death, gout flares, liver toxicity, and severe skin reactions. For patients, this presents a difficult choice: take the drug and risk liver damage, or avoid it and face potential kidney damage.
Eisai’s introduction of dotinurad brings new optimism for gout treatment. In a Phase 3 clinical study conducted in China, 451 gout patients were randomly assigned to receive either dotinurad (4 mg) or febuxostat (40 mg). After 24 weeks of treatment, 73.6% of patients in the dotinurad group achieved serum uric acid levels of 6 mg per deciliter or lower, compared to only 38.1% in the febuxostat group.
A similar Phase 3 study in Japan demonstrated even more promising results: after 58 weeks of treatment, 100% of hyperuricemia patients (with or without gout) achieved target serum uric acid reductions. Additionally, long-term use of dotinurad showed no significant impact on kidney function and no clinically relevant effects on liver function.
The market for gout medications has long been constrained by a lack of effective and safe treatments. Dotinurad’s ability to deliver superior uric acid reduction while addressing safety concerns positions it as a standout candidate in this space. Its strong efficacy and improved safety profile could fulfill the unmet needs of millions of gout patients while unlocking new potential in the broader metabolic disease market.
As safety remains a critical consideration for new drugs, dotinurad’s performance to date suggests it may be well-poised to redefine gout treatment standards and capture a significant share of this long-overlooked segment.
Tracing dotinurad’s 50-year journey
What gives dotinurad its breakthrough therapeutic efficacy? The answer lies in its unique mechanism of action.
While both dotinurad and febuxostat aim to lower uric acid levels, they operate through distinct pathways. Febuxostat and other xanthine oxidase inhibitors (XOIs) prevent uric acid production at its source. In contrast, dotinurad, a uricosuric agent, focuses on reducing existing uric acid levels in the body by enhancing its excretion.
Dotinurad achieves this by selectively inhibiting urate transporter 1 (URAT1), a protein in the kidneys that reabsorbs uric acid. By blocking URAT1, dotinurad reduces uric acid reabsorption, effectively lowering serum uric acid levels. Originally developed by Fuji Pharma, dotinurad’s rights for development and commercialization in China were acquired by Eisai in 2020.
URAT1 is pivotal in reabsorbing up to 90% of uric acid in the kidneys. Its high affinity and efficiency make it a prime target for hyperuricemia and gout therapies. A research report from Zheshang Securities notes that over 30 URAT1-targeting drugs are currently under development or have been approved, underscoring the transporter’s significance in gout treatment innovation.
Despite dotinurad’s prominence today, the 50-year history of URAT1 inhibitors has been marked by setbacks, particularly concerning safety.
The first URAT1 inhibitor, benzbromarone, was approved in Germany in 1971. However, reports of liver toxicity emerged in countries like the Netherlands and Japan, leading to its withdrawal from the market by the early 2000s. The US Food and Drug Administration (FDA) consistently rejected benzbromarone due to these severe safety concerns.
This gap in the market allowed XOI drugs to dominate gout treatment. However, in 2015, the introduction of lesinurad, the second URAT1 inhibitor, renewed interest in the category. Clinical trials showed lesinurad’s efficacy and safety, even in patients with kidney failure, prompting pharmaceutical giant AstraZeneca to acquire its original developer for nearly USD 1.3 billion.
Despite its initial promise, lesinurad also encountered safety issues, earning an FDA-mandated boxed warning. During this period, researchers revisited benzbromarone’s toxicity, uncovering the causes of its liver-related side effects. This insight paved the way for safer alternatives.
Dotinurad represents the culmination of decades of research and refinement in URAT1-targeting therapies. By addressing the safety concerns that plagued earlier inhibitors, dotinurad has revitalized the category, offering a more effective and safer option for gout treatment.
The rise of new URAT1 inhibitors
While earlier challenges with URAT1 inhibitors have largely been addressed, research into this target remains robust, with Chinese pharmaceutical companies now taking a leading role in advancing innovation.
According to a report by Zheshang Securities, more than 20 small-molecule drugs targeting hyperuricemia and gout are under development globally, the majority of which are URAT1 inhibitors. Leading contenders from China include Hengrui Medicine’s SHR4640 (Phase 3 trials in China), Yingli Pharmaceutical’s YL-90148 (Phase 3), Sinovio’s XNW3009 (Phase 3), and Atom Bioscience & Pharmaceutical’s ABP-671 (Phase 2b and 3).
These candidates build on the groundwork laid by earlier URAT1 inhibitors. For instance, Hengrui Medicine’s SHR4640 is structurally derived from lesinurad. By 2019, its clinical trials for monotherapy in primary gout patients with hyperuricemia had reached Phase 3, though subsequent updates remain undisclosed. In 2022, Hengrui initiated a Phase 2 clinical trial combining SHR4640 with febuxostat, which analysts believe aims to mitigate safety concerns through combination therapy.
Similarly, Sinovio’s XNW3009 has drawn comparisons to dotinurad. Phase 2 clinical data revealed that a 0.5-mg dose of XNW3009 enabled over 72% of participants to achieve serum uric acid levels below 360 micromoles per liter, outperforming benzbromarone. Additionally, XNW3009 demonstrated excellent safety and tolerability, with adverse events primarily limited to mild Grade 1 or 2 reactions, and no significant liver or kidney toxicity observed.
Beyond URAT1 inhibitors, new avenues are being explored to treat gout and its complications. Targeting the interleukin-1 (IL-1) cytokine family has emerged as a promising strategy for managing gouty arthritis, as the inflammation associated with gout is driven by IL-1 alpha and IL-1 beta cytokine activity.
Companies like GeneScience Pharmaceuticals (GenSci) and Guojian Pharmaceutical are advancing IL-1-targeting therapies, many of which are already in Phase 3 clinical trials. These therapies aim to address the inflammatory component of gout, complementing the uric acid-lowering capabilities of traditional treatments.
The growing diversity of treatment options reflects a more dynamic and competitive market for gout therapies. As innovative approaches and improved safety profiles gain traction, these advancements may soon lead to a significant step forward in addressing the needs of gout patients.
KrASIA Connection features translated and adapted content that was originally published by 36Kr. This article was written by Hu Xiangyun for 36Kr.