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.
Three healthy-participant studies found that oral tilpisertib fosmecarbil was rapidly converted to the TPL2 inhibitor GS-4875, produced sustained pathway biomarker inhibition, caused only grade 1 investigator-attributed adverse events, and increased creatinine through apparent renal transporter inhibition without measured GFR impairment.
Open original publication →What the AI sees
Three healthy-participant studies found that oral tilpisertib fosmecarbil was rapidly converted to the TPL2 inhibitor GS-4875, produced sustained pathway biomarker inhibition, caused only grade 1 investigator-attributed adverse events, and increased creatinine through apparent renal transporter inhibition without measured GFR impairment.
Research significance
The record demonstrates systemic exposure and pharmacodynamic inhibition of the TPL2 pathway in healthy participants; it can only be inferred—not concluded from these data—that TPL2 inhibition might have therapeutic value in a TPL2-dependent pediatric cancer, because no tumor models, patients with cancer, antitumor responses, or pediatric-specific outcomes were reported.
Source abstract
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).