113: Pharmacokinetics, Safety & Tolerability of GS-1427, a Pro-drug of a Potent & Selective Small-Molecule α4β7 Integrin Inhibitor, in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: GS-1427 is an oral prodrug of GS-1069518, a highly potent and selective small-molecule inhibitor of the α4β7 integrin. The efficacy and safety of α4β7 inhibition is clinically validated in Crohn’s disease and ulcerative colitis (UC). GS-1427 is being developed for treatment of UC.  Herein, we describe the pharmacokinetics (PK), safety and tolerability of GS-1427 from the first-in-human study.

Description of Methods & Materials: Single oral doses (20 -1000 mg) or multiple oral doses (20 -500 mg once-daily for 14 days) of GS-1427 were evaluated in healthy volunteers. GS-1427 was administered using a liquid-filled capsule formulation or a tablet formulation under fasting or non-fasting conditions. The relative bioavailability of tablets versus capsules, and the effect of food on GS-1069518 plasma exposure were also characterized. Overall, 148 healthy participants were enrolled in the study and 144 completed study drug administration.

Data & Results: GS-1427 quickly converted to its active metabolite, GS-1069518, during the absorption process leading to negligible plasma exposure of the prodrug. GS-1069518 steady-state plasma exposures were reached by Day 5 with limited accumulation upon repeated GS-1427 once-daily dosing. At steady state, the mean terminal half-life of GS-1069518 ranged from 6.9 to 23 hours, and the median time to maximum GS-1069518 plasma exposures was 1 to 3 hours. Steady-state exposures of GS-1069518 increased in a slightly greater-than-proportional manner within GS-1427 dose range of 20 -500 mg. With the Phase II tablet formulation, a high-fat/high-calorie meal reduced GS-1069518 exposure by 20% to 40% relative to the fasting condition. GS-1427 was safe and overall well-tolerated in this study. No deaths or serious adverse events were reported. All AEs were Grade 1 in severity. The most reported treatment-emergent adverse events in participants who received GS-1427 were nausea (7 out of 122 participants, 5.7%), headache (5 out of 122 participants, 4.1%), diarrhea (3 out of 122 participants, 2.4%). The occurrence of the corresponding TEAEs in participants who received placebo were 0 out of 26 participants for nausea, 1 out of 26 participants (3.8%) for headache, and 0 out 26 participants for diarrhea.

Interpretation, Conclusion or Significance: The pharmacokinetics, safety and tolerability results from this study supported further evaluation of GS-1427 in a Phase II trial in patients with UC.

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