New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans
Bibliographic record
Abstract
BMS-986120 is a novel first-in-class oral protease-activated receptor 4 (PAR4) antagonist exhibiting robust antithrombotic activity that has shown low bleeding risk in monkeys. We sought to assess pharmacokinetics, pharmacodynamics, and tolerability of BMS-986120 in healthy participants and platelet responses to BMS-986120 in participants carrying PAR4 A120T variants. Phase I, randomized, double-blind, placebo-controlled single-ascending-dose (SAD; N = 56) and multiple-ascending-dose (MAD; N = 32) studies were conducted. Exposure was approximately dose-proportional: maximum concentrations 27.3 and 1536 ng/mL, areas under the curve (AUC) to infinity of 164 and 15,603 h*ng/mL, and half-lives of 44.7 and 84.1 hours for 3.0 and 180 mg, respectively. The accumulation index suggested an ~2-fold AUC increase at steady state. Single doses of 75 and 180 mg BMS-986120 produced ≥80% inhibition of 12.5 μM PAR4 agonist peptide (AP)-induced platelet aggregation through at least 24 hours postdose, and doses ≥10 mg for ~7 days inhibited aggregation completely through 24 hours. No differences in PAR4-mediated platelet response were seen between AA120 versus TT120 PAR4 variants. In cells expressing A120 or T120 PAR4 proteins, no differences in half-maximal effective concentration in receptor activation by PAR4-AP were observed. BMS-986120 was well tolerated with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range.ClinicalTrials.gov ID: NCT02208882.
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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 | 0.000 | 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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".