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.

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] AUCtau 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).