First‐In‐Human Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Tilpisertib Fosmecarbil (GS‐5290), an Oral Prodrug of a Tumor Progression Locus 2 Inhibitor in Healthy Participants

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Tilpisertib fosmecarbil (TIP; GS‐5290) is an intestinally cleaved prodrug of GS‐4875, a potent tumor progression locus 2 (TPL2) inhibitor being investigated for ulcerative colitis (UC). The pharmacokinetics, pharmacodynamics, and safety of single or multiple (over 10 days) oral doses of TIP (N = 73; 75‐1500 mg) or GS‐4875 (N = 82; 15‐450 mg) were assessed in two randomized, placebo‐controlled studies in healthy participants. A third study (N = 32) assessed the renal effects of GS‐4875 (300 mg daily) due to observed serum creatinine increases. TIP was generally undetectable in plasma after administration, indicating rapid conversion to GS‐4875. GS‐4875 had a half‐life of 19‐29 h after TIP administration and exposure was greater than with mg‐equivalent doses of GS‐4875 (population mean [90% CI] AUC tau slope: 0.72 [0.59‐0.85] versus 0.57 [0.47‐0.67]). Inhibition of lipopolysaccharide‐stimulated phosphorylated extracellular signal‐regulated kinase (a TPL2 pathway pharmacodynamic biomarker) 24 h post last dose was greater with TIP versus GS‐4875 dosing (>90% [TIP 300‐900 mg] versus 75‐80% [GS‐4875 450 mg]). Investigator‐assessed, study drug‐related adverse events (AEs) occurred in 9.3% (5/54) of TIP recipients and 5.3% (1/19) of placebo recipients (all grade 1 severity). No serious AEs or deaths occurred. GS‐4875 and TIP reduced creatinine‐based estimated glomerular filtration rate (GFR; day 10 baseline‐adjusted geometric least‐squares means ratio [90% CI] for GS‐4875/placebo: 83.3% [79.2‐87.5%]); this was attributed to renal transporter inhibition rather than GFR impairment as cystatin C‐ and iohexol‐based GFR were unchanged. These data support further development of TIP in an ongoing phase 2 trial in UC (NCT06029972).