A198 PHARMACODYNAMIC EFFECTS OF THE ORAL, NON-STEROIDAL FARNESOID X RECEPTOR AGONIST GS-9674 IN HEALTHY VOLUNTEERS
Bibliographic record
Abstract
GS-9674 is a non-steroidal Farnesoid X Receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis (NASH) and cholestatic liver disorders. Oral GS-9674 increased plasma fibroblast growth factor 19 (FGF19), decreased 7-α-hydroxy-4-cholesten-3-one (C4), and improved liver histology in rodent and primate models of NASH. This first-in-human study evaluated the safety, pharmacokinetics (PK), and pharmacodynamic (PD) effects of GS-9674 in healthy volunteers. Data on PD markers (FGF19 and C4), PK/PD and PD/PD relationships, and the effects of GS-9674 on serum cholesterol are presented herein. In this randomized, double-blind, placebo-controlled study, subjects received single and multiple doses (QD, 14 days) of GS-9674 (10, 30, 100, or 300 mg while fasting [N=12/cohort]) or matching placebo (N=3/cohort) with a 6-day washout between the single and multiple dose periods. Plasma FGF19 (by ELISA) and serum C4 (by LC-MS/MS) were measured over 24 hours pre-dose (Day -1) and after single (Day 1) and multiple dose administration (Day 20). PD parameters for FGF19 and C4 (AUC2-8hr and Cmax or Cmin) were calculated and normalized to Day -1 values. Changes in serum cholesterol were also assessed. PD responses to GS-9674 observed on Day 1 and Day 20 were comparable. GS-9674 doses ≥30 mg significantly increased FGF19 and reduced C4 exposure compared to placebo (Table). Changes in FGF19 and C4 AUC2-8hr were inversely correlated (r= -0.335 p =0.02). While FGF19 exposure did not show dose-dependent changes, changes in C4 AUC2-8hr were inversely associated with GS-9674 AUCtau (r= -0.45 p <0.01). Effects of GS-9674 on serum cholesterol at Day 20 were mild and not significantly different from placebo. Oral GS-9674 administration results in increased levels of FGF19 and decreased C4 confirming its biological activity. These data support the evaluation of GS-9674 in patients with NASH and cholestatic liver disorders. Gilead Sciences, Inc.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".