Abstract 4366887: HS235, a Novel Activin Signaling Inhibitor, is Highly Efficacious in Preclinical Models of Pulmonary Hypertension and Heart Failure
Bibliographic record
Abstract
Background: HS235 is an activin receptor (ActR)-based ligand trap designed to potently neutralize Activins and growth differentiation factors (GDFs) while sparing homeostatic bone morphogenetic proteins (BMPs) including BMP-9 and BMP-10. Pulmonary Hypertension (PH), Heart Failure (HF), and metabolic syndrome are associated with dysregulated Activin and GDF signaling. In contrast, BMP-9 and -10 play important roles in vascular and lymphatic homeostasis and their neutralization should be avoided. HS235’s neutralization profile has the potential to achieve both improved safety and efficacy compared to first generation Activin signaling inhibitors. Methods: HS235’s efficacy in PH and HF was explored in a Group 2 PH mouse transverse aortic constriction (TAC) model. Briefly, mice underwent TAC surgery, recovered for 2 weeks, and were then treated with vehicle, HS235, or wild-type ActRIIA-Fc (a sotatercept surrogate) for 4 weeks. HS235’s efficacy in HF and obesity was confirmed in the High Fat Diet (HFD)/L-NAME model of obesogenic HFpEF. Briefly, mice were fed HFD and L-NAME for 10 weeks and then were treated with HS235 for 4 weeks. Results: In the TAC model, HS235 dose-dependently corrected left ventricular (LV) dysfunction, decreased TAC-induced pulmonary vessel muscularization and displayed greater efficacy than ActRIIA-Fc across readouts. Consistent with these results, HS235 more potently decreased levels of follicle-stimulating hormone (FSH, a circulating biomarker of Activin/GDF target engagement) relative to ActRIIA-Fc. In the HFD/L-NAME model, HS235 returned LV pressures to lean control levels and reduced fat while increasing lean mass. Importantly, these improvements resulted in a complete rescue of exercise tolerance. In both models, HS235 increased lean skeletal muscle mass, induced a more metabolically favourable muscle gene expression profile, and improved circulating NT-proBNP levels. Conclusion: HS235 improved PH, HF, body composition and exercise tolerance in in vivo models. These results demonstrate the differentiated therapeutic profile of HS235 and support its further development as a novel treatment of cardiopulmonary and cardiometabolic diseases.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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".