MO002APABETALONE (RVX-208) IMPACTS KEY BIOMARKERS AND PATHWAYS ASSOCIATED WITH CHRONIC KIDNEY DISEASE IN PATIENTS WITH SEVERE RENAL IMPAIRMENT
Bibliographic record
Abstract
INTRODUCTION AND AIMS: Chronic kidney disease (CKD) is associated with a progressive loss of renal function and a high risk of cardiovascular complications that lead to unfavorable outcomes in nearly half of patients. Apabetalone is a first-in-class orally active bromodomain and extraterminal domain inhibitor (BETi) associated with a reduction in major adverse cardiac events in phase 2 clinical trials in patients with cardiovascular disease (CVD). Here, apabetalone was studied in a phase 1, open-label, parallel group study to examine single dose pharmacokinetics (PK) and levels of CKD markers in patients with impaired renal function. METHODS: Eight subjects with stage 4 CKD not on dialysis (mean eGFR=20 ml/min/1.73m2) and eight age-, gender-, and BMI-matched subjects (mean eGFR=78.5 ml/min/1.73m2) received a single 100 mg oral dose of apabetalone. Plasma samples from participants were collected at multiple time points over a period of 48 hours for PK analysis and at 12 hours post dose for proteomic analysis using the SOMAscan® 1.3K platform. Proteomics data were analysed with Ingenuity® Pathway Analysis (IPA) software to identify the top pathways dysregulated in CKD patients compared to healthy subjects, and the effect of apabetalone treatment on those pathways. RESULTS: PK parameters, including mean Cmax, AUClast, and t½, were similar in healthy subjects and CKD patients, with median tmax at 4h in both groups. At baseline, plasma proteomics showed enrichment of markers known to correlate with disease progression in CKD patients, as compared to matched controls, including cystatin C and β2 microglobulin (3-fold and 5-fold enrichment, respectively, p<0.001). Accordingly, pathway analysis of CKD plasma proteome at baseline confirmed an upregulation of pathways known to be activated in CKD such as the inflammatory response, immune response, thrombosis, calcification and oxidative stress, compared to controls. These pathways were robustly and highly significantly downregulated in CKD patients by apabetalone at 12h post dose. Apabetalone treatment also downregulated the abundance of circulating CKD biomarkers involved in vascular inflammation, endothelial dysfunction, acute phase response, coagulation and vascular calcification, including IL-6, TNFα, IL-1, ICAM-1, VCAM-1, CRP, plasminogen activator inhibitor-1 and osteopontin (p<0.05). CONCLUSIONS: In stage 4 CKD patients, a single oral dose of apabetalone rapidly reduces circulating markers and molecular pathways linked to progression of renal disease and accompanying CVD complications. The potential long term impact of apabetalone on biomarkers, renal function and CVD outcomes in patients with impaired kidney function is currently being studied in a subpopulation of the phase 3 BETonMACE CVD outcomes trial.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".