Apabetalone, an Inhibitor of BET Proteins, Downregulates Alkaline Phosphatase and Improves Cardiovascular Risk
Bibliographic record
Abstract
Background: Elevated serum alkaline phosphatase (ALP) predicts major adverse cardiac events (MACE). ALP is associated with vascular calcification (VC), inflammation & endothelial dysfunction in patients with cardiovascular disease (CVD) /or chronic kidney disease (CKD). Apabetalone is an inhibitor of BET proteins - epigenetic readers modulating gene expression in pathological VC & inflammation. We studied apabetalone’s impact on tissue non-specific ALP (TNALP) expression in cell culture, then analyzed serum ALP in phase 2 trials. Methods: Expression of TNALP (gene symbol ALPL) was measured in primary hepatocytes, HepaRG, HepG2, primary mesangial cells (MC), vascular smooth muscle cells (VSMC) & vascular endothelial cells by q-PCR. TNALP was assessed by immunoblot & flow cytometry, ALP activity by enzymatic assays. Serum ALP was measured in CVD patients in phase 2 trials (ASSERT, SUSTAIN & ASSURE). Subpopulations had CKD (eGFR<60). Results: Apabetalone downregulated ALPL expression in liver cells by 60-80%. HepG2s had lower TNALP protein >55%, enzyme activity >40% & TNALP positive cells 15-30%; renal MCs had >90% decreases in ALPL expression & TNALP enzyme activity (p<0.001). ALPL was suppressed 50-70% in 3 vascular endothelial cell types with apabetalone. In VSMCs, apabetalone lowered ALPL expression, TNALP protein, enzyme activity & extracellular calcium deposition. In ASSERT, apabetalone dose dependently reduced serum ALP (p<0.001). In combined phase 2 analysis, apabetalone lowered ALP (p<0.001), including patients in the CKD subgroup (p=0.008). Notably, the apabetalonemediated decreases in serum ALP in phase 2 correlated with reduced MACE at 12-14 weeks (HR 0.64 per 1-SD in ALP, 95% CI 0.46-0.90 p=0.009 1-SD=13U/L); similar associations were observed at 24-26 weeks (HR 0.66 per 1-SD ALP 95% CI 0.43-0.99 p=0.045; 1-SD=14U/L). Conclusions: Apabetalone lowers serum ALP, consistent with reduced hepatic, renal & vascular TNALP production. Modulation of ALP by apabetalone may affect pathogenetic processes to lower cardiovascular risk. This study provides insight to MACE reductions in phase 2 clinical trials. Funding: Commercial Support - Resverlogix
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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 | 0.001 |
| 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 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".