Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases
Why this work is in the frame
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Bibliographic record
Abstract
BACKGROUND & AIMS: Higher serum bile acid levels are associated with an increased risk of cirrhosis and liver-related morbidity and mortality. Herein, we report secondary analyses of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19, on the circulating bile acid profile in prospective, phase II studies in patients with metabolic or cholestatic liver disease. METHODS: One hundred and seventy-six patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis and elevated liver fat content (≥8% by magnetic resonance imaging-proton density fat fraction) received 0.3 mg (n = 23), 1 mg (n = 49), 3 mg (n = 49), 6 mg (n = 28) aldafermin or placebo (n = 27) for 12 weeks. Sixty-two patients with primary sclerosing cholangitis (PSC) and elevated alkaline phosphatase (>1.5× upper limit of normal) received 1 mg (n = 21), 3 mg (n = 21) aldafermin or placebo (n = 20) for 12 weeks. Serum samples were collected on day 1 and week 12 for determination of bile acid profile and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3), a direct measure of fibrogenesis. RESULTS: Treatment with aldafermin resulted in significant dose-dependent reductions in serum bile acids. In particular, bile acids with higher hydrophobicity indices, such as deoxycholic acid, lithocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, and glycocholic acid, were markedly lowered by aldafermin in both NASH and PSC populations. Moreover, aldafermin predominantly suppressed the glycine-conjugated bile acids, rather than the taurine-conjugated bile acids. Changes in levels of bile acids correlated with changes in the novel fibrogenesis marker Pro-C3, which detects a neo-epitope of the type III collagen during its formation, in the pooled NASH and PSC populations. CONCLUSIONS: Aldafermin markedly reduced major hydrophobic bile acids that have greater detergent activity and cytotoxicity. Our data provide evidence that bile acids may contribute to sustaining a pro-fibrogenic microenvironment in the liver across metabolic and cholestatic liver diseases. LAY SUMMARY: Aldafermin is an analogue of a gut hormone, which is in development as a treatment for patients with chronic liver disease. Herein, we show that aldafermin can potently and robustly suppress the toxic, hydrophobic bile acids irrespective of disease aetiology. The therapeutic strategy utilising aldafermin may be broadly applicable to other chronic gastrointestinal and liver disorders. CLINICAL TRIALS REGISTRATION: The study is registered at Clinicaltrials.govNCT02443116 and NCT02704364.
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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 | 0.000 |
| 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 it