xanthine oxidase/XO

Tigulixostat (LC350189) is a novel non-purine selective inhibitor of XO under development for the treatment of gout and hyperuricemia. In an in vitro assay, LC350189 inhibited XO enzyme activity at a level that was comparable to febuxostat [1].

in an in vivo study, Tigulixostat (LC350189) sufficiently reduced SUA (data on file at LG Life Sciences). Furthermore, no significant toxicity was found in the preclinical studies up to 12.5 mg/kg and 200 mg/kg in the rat and dog, respectively, rendering the clinical development of LC350189 worthwhile. [1]

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Sixty-seven and 58 subjects were enrolled in the SAD and MAD studies, respectively. The mean Cmax and AUClast values increased with increasing doses, and exposure to Tigulixostat (LC350189) was dose proportional. The 24-hour mean serum uric acid (Cmean,24) decreased by 8.7%-31.7% (day 1) and 53.5%-91.2% (day 7) from baseline in the SAD and MAD studies, respectively, and the percentage decrease in Cmean,24 increased with higher doses. Conclusion: LC350189 was well tolerated in the dose range of 10-800 mg. It lowered the serum and urine uric acid levels substantially in this dose range; the extent of the decrease in the serum uric acid level in the 200 mg dose group was similar or higher compared to that of febuxostat 80 mg group in the MAD study. It is expected that LC350189 could be safely administered once daily to patients with hyperuricemia or gout, leading to a sufficient decrease in uric acid levels.[1]

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Tigulixostat (LC350189) is a novel selective xanthine oxidase inhibitor. It was well-tolerated in the dose range of 10–800 mg in healthy subjects and showed substantial efficacy for ULT. It is expected that LC350189 could be safe and efficacious in patients with hyperuricemia. [2]

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A total of 143 patients were randomized to receive tigulixostat 50 mg (n = 34), 100 mg (n = 38), or 200 mg (n = 37), or placebo (n = 34). A significantly greater proportion of patients in the tigulixostat groups achieved the target serum urate level <5.0 mg/dl at week 12 (47.1% in the 50 mg group, 44.7% in the 100 mg group, and 62.2% in the 200 mg group) compared to the placebo group (2.9%) (P < 0.0001). The mean percentage change in serum urate level from baseline was also significantly greater in the tigulixostat groups (-38.8% to -61.8%) than in the placebo group at all time points (P < 0.0001). The rate of gout flares requiring rescue treatment ranged from 9.4% to 13.2% in the tigulixostat and placebo groups. The incidence of adverse events was 50.0% to 56.8% across all groups, and their severity was mild or moderate. Conclusion: Tigulixostat significantly lowered serum urate compared to placebo at all doses studied with an acceptable safety profile[3].

This study was conducted using a randomized (in each dose group), double-blind, active and placebo-controlled, dose-escalation design after a single dose (part I) and multiple doses (part II). In part I, study participants randomly received a single oral dose of Tigulixostat (LC350189) or placebo in the fasted state after an overnight fast at a ratio of 6:2 (10 mg and 25 mg) or 8:2 (50 mg, 100 mg, 200 mg, 400 mg, and 600 mg). Furthermore, those assigned to 200 mg repeated the study in the fed state after a 7-day washout to assess the effect of a high-fat diet on the PK profile of LC350189. In part II, study participants randomly received multiple oral doses of LC350189, febuxostat at 80 mg, or placebo once daily for 7 days in the fasted state after an overnight fast at a ratio of 8:2:2 (100 mg, 200 mg, 400 mg, and 600 mg) or 6:2 (LC350189: placebo, 800 mg). Subjects were admitted to the Clinical Trials Center on 3 days before drug administration and discharged after finishing scheduled procedures. Each subject was administered placebo to evaluate baseline PD characteristics (day −1). During the confinement period, the subjects were provided with standardized meals (except for the high-fat diet on day 8 for the 200 mg dose group) to minimize the effect of food on PK/PD evaluations.[1]

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Researchers conducted a multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding trial. After screening, gout patients with hyperuricemia were randomly assigned, after appropriate washout, to receive daily oral administration of 50 mg, 100 mg, or 200 mg of Tigulixostat (LC350189), or placebo for 12 weeks. Colchicine gout flare prophylaxis was administered to all patients. The primary end point was the proportion of patients with a serum urate level <5.0 mg/dl at week 12[3].

LC350189 was rapidly absorbed after both a single and multiple oral administrations, reaching the peak plasma concentration approximately 3 hours post dose (Figure 5 and Table 4). Cmax and AUClast were judged to have increased in a dose-proportional manner based on the finding that the 95% CIs of the slope of the log-transformed Cmax and AUClast included 1.0 (Cmax 0.97–1.08, AUClast 0.99–1.11). Approximately, 20%–30% of LC350189 was excreted in the urine. Food delayed the absorption of LC350189 (~2 hours), and it also decreased Cmax by 38% (Figure 6); the geometric men ratio (90% CI) of Cmax (fed vs fasting status) was 0.624 (0.485–0.802). However, the overall exposure to LC350189 was comparable between the fasted and fed states, ie, the geometric mean ratio (90% CI) of AUClast with and without food was 0.973 (0.837–1.131). Steady state was reached within 2–3 days after multiple administrations of LC350189 (Figure 6 and Table 5). The 95% CI of the slope of the log-transformed Cmax and AUCtau,ss was 0.64–0.89 and 0.78–1.06, respectively, meaning that exposure to LC350189 was dose proportional. The fraction of the drug excreted unchanged in urine was similar to that in the SAD study. [1]

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The mean Ctrough, ss values of tigulixostat ranged from 159 to 590 ng/ml in the low-dose groups of 50 mg and 100 mg, and from 822 to 1,140 ng/ml in the 200 mg group after repeated oral administration of tigulixostat for 12 weeks (Supplementary Table 8, https://onlinelibrary.wiley.com/doi/10.1002/art.42447). The mean Ctrough, ss values of serum urate across all visits were comparable for the tigulixostat 50 mg and 100 mg doses, with values ranging from 4.91 to 5.41 mg/dl, decreasing for the 200 mg dose to a range of 3.62 to 4.09 mg/dl. The trough levels of serum urate in the tigulixostat 200 mg group were noticeably lower when compared to the placebo group, in which values ranged from 8.51 to 9.02 mg/dl (Supplementary Table 9).[3]

During the clinical study, the incidence of treatment-emergent adverse events (TEAEs) was similar among the tigulixostat dose groups and placebo group, ranging from 50.0% to 56.8% (Table 2). The most frequently reported TEAE was gout flare, with an incidence of 26.5% in the tigulixostat 50 mg group, 15.8% in the 100 mg group, 27.0% in the 200 mg group, and 17.6% in the placebo group. Gout flare TEAEs were investigator-reported and were recorded regardless of whether the gout flares required rescue treatment, whether the flares met the study definition for gout flare, or whether the flares were collected through patient diaries. The severity of gout flare was mostly mild or moderate, and the 2 reported severe cases (1 each in the tigulixostat 50 mg and 100 mg groups) were not related to the study drug administration. [3]

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A total of 11 cases of low-grade increase in creatine kinase (CK) were reported in all treatment groups, and the number of cases of increased CK tended to increase as the dose of tigulixostat increased (Table 2). Among these cases, 6 patients (1 in the tigulixostat 100 mg group, 4 in the tigulixostat 200 mg group, and 1 in the placebo group) had CK elevation from baseline before administration of the study drug. Of the 11 cases of CK increase, 8 cases were determined by the investigator to be unrelated to the study drug administration based on the patient's underlying information (medical history, concomitant medications, baseline value of CK, etc.), and 3 cases that occurred in the tigulixostat 200 mg group were reported to be related to the study drug administration. None of these 3 patients had full resolution of increased CK by the end of the study, but their CK increase was <3 times the upper limit of normal and did not require further treatment. Five cases of transaminase increase related to study drug administration were reported in the tigulixostat dose groups (Table 2). Two patients in the tigulixostat 200 mg group showed grade 2 alanine aminotransferase (ALT) elevation, and 1 of these patients as well as another patient with grade 1 ALT elevation had accompanied CK elevation simultaneously. One patient had grade 2 ALT and CK elevation and grade 1 aspartate aminotransferase (AST) elevation with normal gamma glutamyl transferase, alkaline phosphatase, and bilirubin levels, suggestive of hepatic injury. This patient was severely obese, with fatty liver disease at baseline. Hence, this abnormal laboratory finding could also be related to aggravation by the underlying condition. The other patient had CK elevation (<3 times the upper limit of normal) with no change in kidney function, followed by AST elevation (<2 times the upper limit of normal), suggesting possible muscle damage rather than liver injury, which might be related to tigulixostat treatment. None of the patients showed any clinical symptoms or other laboratory changes, and no additional treatment was required. Two patients (1 each in the tigulixostat 100 mg and 200 mg groups) discontinued study drug administration due to increased transaminase levels but did not require further treatment. Two other patients in the tigulixostat 100 mg group discontinued study drug administration due to TEAEs (gout flare and headache). These TEAEs were mild or moderate, and headache was reported to be related to the study drug administration. All 4 patients who discontinued the study drug due to TEAEs recovered after treatment discontinuation. No serious TEAEs or deaths were reported. Except for serum urate levels and those reported as TEAEs, no clinically significant changes or differences were found in laboratory tests, vital signs, or electrocardiography results across groups. [3]

[1]. Pharmacokinetics, pharmacodynamics, and tolerability of LC350189, a novel xanthine oxidase inhibitor, in healthy subjects. Drug Des Devel Ther. 2015 Aug 31;9:5033-49.

[2]. Pharmacological urate-lowering approaches in chronic kidney disease. Eur J Med Chem. 2019 Mar 15;166:186-196.

[3]. Serum Urate-Lowering Efficacy and Safety of Tigulixostat in Gout Patients With Hyperuricemia: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Trial. Arthritis Rheumatol. 2023 Jul;75(7):1275-1284.

Drug Indication
Treatment of hyperuricemia

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In this study, LC350189 was well tolerated after a single oral administration and multiple oral administrations in the dose range of 10–800 mg. LC350189 decreased SUA concentrations and reduced the amount of uric acid excreted in the urine. Particularly, the decrease in SUA concentration after multiple oral doses of LC350189 200 mg was comparable to that of febuxostat at 80 mg. Once-daily LC350189 can be developed as an effective treatment option for patients with hyperuricemia or gout. [1]

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Tigulixostat was generally well tolerated at all 3 doses investigated. No significant differences were identified between the tigulixostat and placebo groups with respect to TEAEs. In the tigulixostat 200 mg group, investigators reported 3 cases of increased CK and 3 cases of increased transaminases that might be related to study drug administration. These cases were asymptomatic, did not require any treatment, and did not result in any observed changes in renal function. The investigators assessed these cases of increased CK and transaminases as mild or moderate (grade 1–2), and the increased transaminase levels resolved after treatment discontinuation. Various factors may contribute to the elevation of CK and transaminase levels, and the relationship between increased transaminase and colchicine administration cannot be excluded. In this clinical trial, the number of patients with CK elevation tended to increase as the dose of tigulixostat increased. Considering the short treatment period and the small number of patients, additional follow-up is needed to better assess for elevated levels of CK and transaminase. No cardiac disorders, rash, or hypersensitivity reactions related to tigulixostat administration occurred. Short-term treatment with tigulixostat appeared to be well tolerated in gout patients with hyperuricemia. The safety of tigulixostat needs to be examined closely through additional monitoring in future long-term studies. The limitations of this study are that no active comparator xanthine oxidase inhibitor was used, and the xanthine oxidase inhibitor treatment period was relatively short. Therefore, efficacy and safety results should be interpreted with caution. In summary, tigulixostat treatment at all 3 doses studied significantly lowered serum urate level in gout patients with hyperuricemia compared to placebo. Tigulixostat was generally well tolerated at all 3 doses without clinically noticeable safety issues. The efficacy and safety of tigulixostat in patients with chronic gouty arthritis warrant long-term clinical studies. [3]

C16H14N4O2

294.3080

294.111

C, 65.30; H, 4.79; N, 19.04; O, 10.87

1287766-55-5

51039100

White to light yellow solid powder

1.9

1

4

3

22

486

0

O([H])C(C1C([H])=NN(C=1[H])C1C([H])=C([H])C2=C(C=1[H])C(C#N)=C([H])N2C([H])(C([H])([H])[H])C([H])([H])[H])=O

JLQQRYOWGCIMMZ-UHFFFAOYSA-N

InChI=1S/C16H14N4O2/c1-10(2)19-8-11(6-17)14-5-13(3-4-15(14)19)20-9-12(7-18-20)16(21)22/h3-5,7-10H,1-2H3,(H,21,22)

1-(3-cyano-1-propan-2-ylindol-5-yl)pyrazole-4-carboxylic acid

Tigulixostat; 1287766-55-5; Tigulixostat [INN]; WZ0PYQ6VLU; LC350189; LC-350189; UNII-WZ0PYQ6VLU; 1-(3-cyano-1-propan-2-ylindol-5-yl)pyrazole-4-carboxylic acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (339.78 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.49 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)