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

Abstract

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.

Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies

“…GLPG1690 showed superior results compared to pirfenidone and was similar to nintedanib, a tyrosine kinase inhibitor, in reducing the Ashcroft fibrotic score and collagen levels. 247 GLPG1690 was already tested in humans in order to test the safety, pharmacokinetics and pharmacodynamics of its doses, 248 and was well tolerated in a Phase 2a study (FLORA study) involving 23 patients with IPF. Treated patients had reduced plasma LPA C18:2 levels and showed improvement of disease control, such as stabilized FVC after 12 weeks of treatment.…”

Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target

“…Moreover, potent (IC50 2 nM), long term (3 weeks) pharmacological inhibition of ATX with PF-8380 (120 mg/Kg - 4 times the effective concentration; PO; bid) had no effects in survival or gross pathology of major organs ( 135 ), suggesting that ATX pharmaceutical targeting is safe and well tolerated in mice. In humans, GLPG1690 was reported to be well tolerated in a phase 1 randomized clinical trial (NCT02179502), safe and efficacious in a phase 2a randomized placebo-controlled clinical trial (NCT02738801), supporting ATX inhibition as a novel treatment for IPF ( 136 , 137 ). In addition, administration of BBT-877, another orally available small molecule inhibitor targeting ATX (IC50 ~6.7 nM), to healthy volunteers in a phase I clinical trial (NCT03830125), did not reveal severe adverse events ( 138 , 139 ).…”

Pharmacokinetics and Metabolism of Ziritaxestat (GLPG1690) in Healthy Male Volunteers Following Intravenous and Oral Administration

“…The pharmacokinetics (PK) of ziritaxestat have been reported separately. 18 Ziritaxestat is rapidly absorbed and eliminated, with exposure to parent increasing in a dose‐proportional manner. In vitro human recombinant cytochrome P450 (CYP) studies indicated that ziritaxestat was primarily metabolized by CYP3A4 with minor contributions (maximum of 2.1%) to metabolism from other phase 1 enzymes.…”