Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-<i>a</i>]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis

Desroy, Nicolas; Housseman, Christopher; Bock, Xavier; Joncour, Agnès; Bienvenu, Natacha; Cherel, Laëtitia; Labeguere, Virginie; Rondet, Emilie; Peixoto, Christophe; Grassot, Jean‐Marie; Picolet, Olivier; Annoot, Denis; Triballeau, Nicolas; Monjardet, Alain; Wakselman, Emanuelle; Roncoroni, Veronique; Tallec, Sandrine Le; Blanqué, R.; Cottereaux, C.; Vandervoort, Nele; Christophe, Thierry; Mollat, Patrick; Lamers, Marieke; Auberval, Marielle; Hrvačić, Boška; Ralić, Jovica; Oste, Line; Aar, Ellen van der; Brys, Reginald; Heckmann, Bertrand

doi:10.1021/acs.jmedchem.7b00032

Cited by 118 publications

(131 citation statements)

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“…Reduction in LPA C18:2 was also apparent in the pooled placebo group, only in the MAD part of the study; however, this was highly variable, and there was clear separation between placebo and GLPG1690 (even at the lowest dosage) in effects on LPA C18:2. These results indicate that GLPG1690 inhibited autotaxin effectively . After 14 days of GLPG1690 administration, plasma LPA C18:2 was reduced at predose by at least 70% for all doses; for GLPG1690 600 mg once daily and 1000 mg once daily, this finding indicates that GLPG1690 concentration remained at a level capable of inhibiting autotaxin for at least 24 hours postdose and that once‐daily dosing is sufficient.…”

Section: Discussionmentioning

confidence: 75%

“…GLPG1690 is a first‐in‐class autotaxin inhibitor currently being investigated as a novel therapy for IPF . This first‐in‐human study demonstrated that GLPG1690 was well tolerated after administration of single doses up to 1500 mg and multiple doses up to 1000 mg once daily for 14 days.…”

Section: Discussionmentioning

confidence: 83%

“…However, to establish a starting dose that was not expected to exceed the minimum anticipated biological effect level, the starting dose for the first-inhuman study was set at 20 mg, which was lower than the anticipated pharmacologically active dose based on available in vitro and in vivo pharmacology data. 20 Safety margins for the highest planned dose (1500 mg) were 6 (rat) and 11.5 (dog) based on predicted exposures corrected for plasma protein binding (>99% across all species 18 ).…”

Section: Study Designsmentioning

confidence: 99%

“…Because autotaxin is involved in the pathogenesis of lung fibrosis, autotaxin inhibition may confer clinical benefits in patients with IPF. GLPG1690 (2‐[[2‐ethyl‐6‐[4‐[2‐(3‐hydroxyazetidin‐1‐yl)‐2‐oxoethyl]piperazin‐1‐yl]‐8‐methylimidazo[1,2‐α]pyridin‐3‐yl]‐(methyl)amino]‐4‐(4‐fluorophenyl)thiazole‐5‐carbonitrile; compound code G451990; ) is a first‐in‐class inhibitor of autotaxin being investigated as a novel therapy for IPF . GLPG1690 selectively inhibits autotaxin, with ex vivo human plasma LPA release assays indicating a half maximal inhibitory concentration (IC 50 ) of approximately 100 nM .…”

mentioning

confidence: 99%

“…GLPG1690 (2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl] piperazin-1-yl]-8-methylimidazo [1,2-α]pyridin-3-yl]-(methyl)amino]-4-(4-fluorophenyl)thiazole-5-carbonitrile; compound code G451990; Supplemental Figure S1) is a first-in-class inhibitor of autotaxin being investigated as a novel therapy for IPF. 18 GLPG1690 selectively inhibits autotaxin, with ex vivo human plasma LPA release assays indicating a half maximal inhibitory concentration (IC 50 ) of approximately 100 nM. 19 In preclinical studies, GLPG1690 has demonstrated efficacy in a mouse bleomycin-induced pulmonary fibrosis model (therapeutic setting): GLPG1690 was superior to pirfenidone and similar to nintedanib in reducing the Ashcroft fibrotic score and collagen content.…”

mentioning

confidence: 99%

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Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials

Aar

Desrivot

Dupont

et al. 2019

The Journal of Clinical Pharma

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GLPG1690 is a novel autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis (IPF). We report phase 1 studies investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GLPG1690 in healthy subjects. We performed a first‐in‐human randomized, double‐blind, placebo‐controlled trial of single (20, 60, 150, 300, 600, 1000, 1500 mg) and multiple (14 days: 150 mg twice daily; 600 and 1000 mg once daily) ascending oral doses of GLPG1690 (NCT02179502), and a randomized, open‐label, crossover relative bioavailability study to compare the PK of tablet and capsule formulations of GLPG1690 600 mg and to assess the effect of food on PK of the tablet formulation (NCT03143712). Forty and 13 subjects were randomized in the first‐in‐human and relative bioavailability studies, respectively. GLPG1690 was well tolerated, with no dose‐limiting toxicity at all single and multiple doses. GLPG1690 was rapidly absorbed and eliminated, with a median tmax and mean t1/2 of approximately 2 and 5 hours, respectively. GLPG1690 exposure increased with increasing dose (mean Cmax, 0.09‐19.01 µg/mL; mean AUC0‐inf, 0.501‐168 µg·h/mL, following single doses of GLPG1690 20‐1500 mg). PD response, evidenced by rapid reduction in plasma lysophosphatidic acid (LPA) C18:2 levels, increased with increasing GLPG1690 plasma levels, plateauing at approximately 80% reduction in LPA C18:2 at around 0.6 µg/mL GLPG1690. Tablet and capsule formulations had similar PK profiles, and no clinically significant food effect was observed when comparing tablets taken in fed and fasted states. The safety, tolerability, and PK/PD profiles of GLPG1690 support continued clinical development for IPF.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 83%

Section: Study Designsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials

Aar

Desrivot

Dupont

et al. 2019

The Journal of Clinical Pharma

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Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis

Maher

Ford

Brown

et al. 2023

JAMA

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ImportanceThere is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).ObjectiveTo assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and ParticipantsThe 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.InterventionsPatients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.Main Outcomes and MeasuresThe primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).ResultsAt the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.Conclusions and RelevanceZiritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment.Trial RegistrationClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

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Prediction of Disease Progression and Clinical Response in Systemic Sclerosis: Experience From a Proof‐of‐Concept Trial

Neve,

Diderichsen,

Helmer

et al. 2024

ACR Open Rheumatology

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ObjectiveUsing the modified Rodnan skin score (mRSS) as a surrogate for disease activity, a phase 2a study in patients with systemic sclerosis (SSc) measured efficacy of the autotaxin inhibitor ziritaxestat. Mathematical modeling of mRSS was used to predict disease progression, examine candidate trial designs, and predict the probability of successfully discriminating treatment effect.MethodsPatients with SSc receiving 600 mg of ziritaxestat or placebo for 24 weeks were included, in addition to data up to week 52 of the open‐label extension (OLE). Longitudinal mRSS data were described using a disease progression model; drug effect was a binary variable. Parameters used to predict the OLE mRSS outcome were estimated using data from the 24‐week double‐blind phase and validated with observed data. Three trial designs were simulated to identify which had the highest probability of detecting a treatment effect. Power to detect a treatment effect was quantified using the simulations.ResultsMaximum decreases from baseline in mRSS were 50.4% (ziritaxestat) and 34.7% (placebo). Study designs based on 300 patients randomized 2:1 or 1:1 to 600 mg of ziritaxestat or placebo had similar probabilities of detecting a significant treatment effect. Power to detect a treatment effect was >80% for all simulations.ConclusionDisease progression and drug effect could be predicted beyond the range of observed data. This modeling and simulation approach may inform future trial design, including study duration, and predict the probability of success.

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Cited by 118 publications

References 42 publications

Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials

Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis

Prediction of Disease Progression and Clinical Response in Systemic Sclerosis: Experience From a Proof‐of‐Concept Trial

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