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Promising results in uric acid-lowering in gout patients with a new xanthine oxidase inhibitor

Presented by
Prof. Robert Terkeltaub, University of California San Diego, CA, USA
ACR 2021
Phase 2
Demonstrating efficacious serum urate-lowering in gout patients with hyperuricemia, tigulixostat is now predestined for further development. No particular safety signals were reported and overall drug tolerance was good in new phase 2 results.

In the effective management of gout, keeping the level of serum uric acid below its limit of solubility is key, but a substantial part of patients does not reach this therapeutic goal [1,2]. “Tigulixostat is a novel selective xanthine oxidase inhibitor and, unlike allopurinol, it does not have a purine-like backbone structure,” Prof. Robert Terkeltaub (University of California San Diego, CA, USA) described the new agent.

A phase 2 study (NCT03934099) investigated tigulixostat for safety and efficacy in patients with gout and hyperuricemia [1]. The study population consisted of 156 patients with gout, who were randomised to receive either placebo or tigulixostat at dosages of 50 mg, 100 mg, or 200 mg daily over 12 weeks. After that, an additional 2-week safety follow-up was performed. Participants had to have a serum urate level of >6.0 mg/dL if on prior urate-lowering treatment and a value between 8.0 mg/dL and 12 mg/dL after a washout period, or if previously untreated. Colchicine 0.6 mg was given as gout flare prophylaxis. “The primary endpoint was the proportion of subjects achieving serum urates less than 5.0 mg/dL at week 12, as this target is recommended for severe disease including tophaceous gout,” stated Prof. Terkeltaub. The baseline characteristics of the study population included a mean age between 52.0 and 56.6 years, predominantly men, and a mean BMI little above 30 kg/m2. Prof. Terkeltaub also pointed out that about 20% had palpable tophi, and most pre-dosing serum urate levels were <9.8 mg/dL.

At week 12, 47.1% (50 mg), 44.7% (100 mg), and 62.2% (200 mg) of those on the study drug achieved a serum urate <5.0 mg/dL compared with 2.9% on placebo (P<0.0001 for all dosages; see Figure). The rate of patients reaching the secondary endpoint of serum urate <6.0 mg/dL was also significantly higher when on the study drug, with corresponding proportions of 58.8%, 63.2%, and 78.4% versus 2.9%, respectively. In a small active control group of 13 patients receiving febuxostat, 23% reached serum urate values <5.0 mg/dL.

Figure: Rates of study participants who reached the primary endpoint of a serum uric acid level (sUA) <5 mg/dL at week 12 [1]

*Difference in proportion (%) to placebo with P<0.0001; asymptotic limits of 95% CI and risk difference were determined by the Wald method.

As for safety, 50–56.8% on tigulixostat and 50% on placebo were affected by treatment-emergent adverse events, the majority of mild-to-moderate severity; 4 patients discontinued the study due to adverse events. Between 10.8% and 13.2% of tigulixostat patients and 9.4% of placebo patients experienced a gout flare that required rescue treatment.

“In conclusion, tigulixostat significantly lowered serum urate in gout patients, impressively achieved urate targets, and was well tolerated collectively. These results support its continued development for gout with uncontrolled hyperuricemia,” Prof. Terkeltaub summarised.

    1. Terkeltaub R. Phase 2 study results from a randomised, double-blind, placebo-controlled, dose-finding study to evaluate efficacy and safety of tigulixostat, a novel non-purine selective xanthine oxidase inhibitor in gout patients with hyperuricemia. Abstract L05, ACR Convergence 2021, 3–10 November.
    2. Mu Z, et al. Clin Rheumatol. 2019 Dec;38(12):3511-3519.


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