ING-006, A Novel Oral GPR40/GPR84 Fatty Acid Receptor Modulator: A Comparative Study With Nintedanib and Nerandomilast (BI-1015550) in Bleomycin-induced Lung Fibrosis and CAM-IPF Xenograft Models
Bibliographic record
Abstract
Abstract RATIONALE: GPR40 and GPR84 have been previously described to be involved in fibrosis of the lung, kidney, heart and liver. While GPR40 expression is reduced in IPF, GPR84 is significantly increased and is correlated with the %DLCO and the predicted FVC progression/severity of the disease. ING-006 is an oral GPR40 agonist/GPR84 antagonist with antifibrotic activity in lung and liver models. The main objective of this study was to compare the antifibrotic activity of ING-006 with that of nintedanib or nerandomilast in bleomycin-induced lung fibrosis and chorioallantoic membrane (CAM)-IPF xenograft lung fragment models.METHODS: Fibrosis was induced in 10-week-old female C57BL/6 mice by intratracheal instillation of bleomycin (0.010 mg/mouse) on day 0. Daily oral treatments with ING-006 (10 mg/kg), nintedanib (60 mg/kg) or nerandomilast (12.5 mg/kg) were started on day 7, and animals were euthanised on day 28. Flexivent analysis was performed on day 28. Lungs were harvested for histology and analysis of mRNA expression levels. In vivo antifibrotic activity was also evaluated in CAM-IPF treated with the antifibrotics from day 2 to day 7 post-implantation. Xenografts were harvested for histological analysis.RESULTS: Histological analysis showed that ING-006 significantly reduced collagen deposition (57%) compared to nintedanib (29%) and nerandomilast (27%) in bleomycin-instilled lungs. ING-006 decreased bleomycin-induced overexpression of the fibrogenic markers COLIA1, FN1, MMP2, TIMP1 and IL-6, while nerandomilast showed significant reduction in FN1 and IL6, and nintedanib had no significant effect. Only ING-006 induced a significant improvement in lung respiratory mechanics (compliance/elastic properties, inspiratory capacity) as demonstrated by an increase in PV-loop, FVC, FEV0.2, Cstat, IC and Crs close to those of the control group. In CAM-IPF, a single low dose of ING-006 (10ug) induced a significant reduction in collagen area, while no significant antifibrotic activity was observed with nintedanib or nerandomilast. In addition, ING-006 showed synergistic activity with low dose nerandomilast (10ug).CONCLUSIONS: Taken together, the data show that ING-006 reduces well-established lung fibrosis and improves the PV-loop, FVC, FEV0.2, Cstat and IC more efficiently than nintedanib or nerandomilast. These results suggest that ING-006 could be a promising candidate for the treatment of IPF based on its ability to preserve lung function and act in synergy in combination with other antifibrotic compounds.
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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) | 0.001 | 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) | 0.001 | 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".