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].

Following both single and multiple oral administrations, LC350189 was rapidly absorbed, reaching peak plasma concentrations approximately 3 hours post-administration (Figure 5 and Table 4). Based on the 95% confidence intervals (Cmax 0.97–1.08, AUClast 0.99–1.11) of the logarithmically transformed slopes, Cmax and AUClast were determined to increase dose-proportionately. Approximately 20%–30% of LC350189 was excreted in the urine. Food delayed LC350189 absorption (approximately 2 hours) and reduced Cmax by 38% (Figure 6); the geometric mean (90% confidence interval) of Cmax in the fed and fasting states was 0.624 (0.485–0.802). However, the overall exposure to LC350189 was comparable between fasting and eating states, with a geometric mean ratio (90% CI) of 0.973 (0.837–1.131) between fasting and eating states. Steady state was reached within 2–3 days after multiple doses of LC350189 (Figure 6 and Table 5). The 95% CIs for the logarithmically transformed Cmax and AUCτ,ss slopes were 0.64–0.89 and 0.78–1.06, respectively, indicating that LC350189 exposure was dose-dependent. The proportion of unchanged drug excreted in urine was similar to that found in single-dose (SAD) studies. [1]

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After 12 weeks of continuous oral administration of ticolistat, the mean trough concentration (ss) in the low-dose groups (50 mg and 100 mg) ranged from 159 to 590 ng/ml, and the mean trough concentration in the 200 mg group ranged from 822 to 1,140 ng/ml (Supplementary Table 8, https://onlinelibrary.wiley.com/doi/10.1002/art.42447). The mean trough concentration (ss) of serum uric acid was comparable in the 50 mg and 100 mg ticolistat groups at all visits, ranging from 4.91 to 5.41 mg/dl, while the mean trough concentration (ss) of serum uric acid decreased to 3.62 to 4.09 mg/dl in the 200 mg group. Compared with the placebo group, the serum trough urate level was significantly lower in the teglipizide 200 mg group, which ranged from 8.51 to 9.02 mg/dl in the placebo group (Supplementary Table 9). [3]

During the clinical study, the incidence of treatment-induced adverse events (TEAEs) was similar in all ticoullistat dose groups and the placebo group, ranging from 50.0% to 56.8% (Table 2). The most frequently reported TEAE was gout attack, with an incidence of 26.5% in the ticoullistat 50 mg group, 15.8% in the 100 mg group, 27.0% in the 200 mg group, and 17.6% in the placebo group. TEAEs of gout attacks were reported by the investigator and recorded regardless of whether the gout attack required resuscitation, met the definition of gout attack in the study, or was collected through patient diaries. The severity of gout attacks was mostly mild or moderate, and the two reported severe cases (one in the ticoullistat 50 mg group and one in the 100 mg group) were unrelated to administration of the study drug. [3]

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A total of 11 cases of mild creatine kinase (CK) elevation were reported in all treatment groups, and the number of cases of CK elevation increased with increasing ticoullistat dose (Table 2). Of the 11 patients (1 in the ticoullixim 100 mg group, 4 in the ticoullixim 200 mg group, and 1 in the placebo group), CK levels were already elevated from baseline before administration. Of the 11 cases of elevated creatine kinase (CK), researchers determined that 8 cases were unrelated to the study drug based on patient information (medical history, concomitant medications, baseline CK levels, etc.), while 3 cases occurred in the ticoullixim 200 mg group and were reported to be related to the study drug. In these 3 patients, CK levels did not fully return to normal at the end of the study, but their CK elevations were all less than 3 times the upper limit of normal, requiring no further treatment. A total of 5 cases of transaminase elevations related to the study drug were reported across all ticoullixim dose groups (Table 2). Two patients in the ticoullixim 200 mg group had grade 2 alanine aminotransferase (ALT) elevations, one of whom, along with another patient with grade 1 ALT elevation, also had elevated CK. One patient presented with grade 2 elevated ALT and CK, and grade 1 elevated aspartate aminotransferase (AST), but normal levels of gamma-glutamyl transferase, alkaline phosphatase, and bilirubin, suggesting liver damage. This patient was severely obese and had fatty liver disease at baseline. Therefore, this abnormal laboratory result may also be related to the exacerbation of the pre-existing condition. Another patient presented with elevated CK (less than 3 times the upper limit of normal), with no change in renal function, followed by elevated AST (less than 2 times the upper limit of normal), suggesting possible muscle damage rather than liver damage, which may be related to ticolidustat treatment. None of the patients developed any clinical symptoms or other abnormal laboratory findings and required no additional treatment. Two patients (one each in the ticolidustat 100 mg and 200 mg groups) discontinued the study drug due to elevated transaminase levels, but no further treatment was required. Two other patients in the ticolidustat 100 mg group discontinued the study drug due to adverse events (gout attack and headache) that occurred during treatment. These adverse events were mild to moderate, with headache reportedly related to the use of the study drug. All four patients who discontinued the study drug due to adverse events recovered after discontinuation. No serious adverse events or deaths were reported. Apart from serum uric acid levels and reported adverse events, no clinically significant changes or differences were found in laboratory tests, vital signs, or electrocardiogram results between the 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 In this study, LC350189 was well tolerated after single and multiple oral doses (dose range 10–800 mg). LC350189 reduces serum uric acid concentration and decreases uric acid excretion in urine. In particular, the reduction in serum uric acid concentration after multiple oral doses of 200 mg LC350189 was comparable to that of 80 mg febuxostat. Once-daily LC350189 shows promise as an effective treatment option for patients with hyperuricemia or gout. [1] Tigurilstat was generally well tolerated at all three study doses. No significant difference was found in the number of treatment-exclusive adverse events (TEAEs) between the tigurilstat and placebo groups. In the tigurilstat 200 mg group, investigators reported 3 cases of elevated creatine kinase (CK) and 3 cases of elevated transaminases, possibly related to administration of the study drug. These cases were asymptomatic, required no treatment, and no changes in renal function were observed. Researchers assessed these cases of elevated CK and transaminase levels as mild to moderate (grade 1-2), with transaminase levels returning to normal upon discontinuation of the drug. Multiple factors can contribute to elevated CK and transaminase levels, and a relationship between elevated transaminase levels and colchicine administration cannot be ruled out. In this clinical trial, the number of patients with elevated CK increased with increasing ticolidus dose. Given the short treatment duration and small patient number, additional follow-up is needed to better assess elevated CK and transaminase levels. No cardiac events, rashes, or hypersensitivity reactions related to ticolidus administration occurred. Short-term use of ticolidus appears to be well-tolerated in patients with gout and hyperuricemia. The safety of ticolidus needs to be closely assessed with additional monitoring in future long-term studies. A limitation of this study is the lack of an active control xanthine oxidase inhibitor and the relatively short treatment duration of xanthine oxidase inhibitors. Therefore, efficacy and safety results should be interpreted with caution. In summary, compared with placebo, all three study doses of ticolidustat significantly reduced serum uric acid levels in patients with gout and hyperuricemia. All three doses of ticolidustat were generally well tolerated, with no clinically significant safety issues observed. The efficacy and safety of ticolidustat in patients with chronic gouty arthritis warrant long-term clinical investigation. [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.)