HS135, a Novel Investigational Activin Inhibitor for the Treatment of Pulmonary Hypertension (PH): Results From a Healthy Volunteer Phase 1 Trial Demonstrated Favourable Safety Profile and Pharmacodynamic Responses, Including Improved Body Composition and Cardiac Biomarkers
Bibliographic record
Abstract
Abstract Rationale: HS135 is an Fc fusion protein comprising a precision engineered Activin receptor ectodomain in development for PH, designed to trap Activins and Growth Differentiation Factors (GDFs) with high potency. Overactive Activin and GDF signalling is a driver of PH pathology and Activin signalling inhibition has been validated as an effective pharmacological strategy in Pulmonary Arterial Hypertension (PAH). Levels of follicle-stimulating hormone (FSH) are responsive to Activin and GDF inhibition. Accordingly, FSH represents a target engagement biomarker for Activin inhibitors which can help support selection of efficacious dose ranges. This first-in-human study was designed to explore HS135's potential for differentiated PH efficacy by evaluating its initial safety profile and its dose-responsive effect on FSH and other biomarkers of interest, as well as assessing changes in body composition. Methods: This Phase 1, double-blind, placebo-controlled, single ascending dose trial was designed to evaluate the safety, pharmacokinetics (PK) and pharmacodynamic (PD) responses of sub-cutaneous HS135 in healthy postmenopausal women. Pre-specified analyses included levels of FSH, body composition by DEXA and circulating proteins indicative of pathway modulation and efficacy potential. Results: 34 subjects were enrolled with a median age of 60 y (45-67) and BMI of 25.7 kg/m2(21.2-30.9). Treatment arms were placebo (n = 8), 0.5, 1, 1.5 (n=6 each), or 3 mg/kg (n=8) of HS135. HS135 was generally well tolerated with no treatment-related SAEs reported. HS135 PK was dose-proportional and in line with modeling. Statistically significant, dose-dependent and durable (>30 days) reductions in FSH were observed starting at the lowest dose level tested and reached saturation at the 3 mg/kg dose. PK/PD modeling enabled the prediction of efficacious dose ranges and supports Q2W to Q4W dosing in the chronic setting. Increases in lean mass of up to >2 kg were detected 2 weeks following single doses of ≥1 mg/kg and maintained for 8 weeks. Quantitatively similar reductions in fat mass, including trunk fat, were observed. Unbiased deep plasma proteome profiling by SomaScan revealed that HS135 treatment modulated circulating markers associated with metabolism, inflammation, heart failure (HF) and PAH. At baseline, several prognostic biomarkers, including natriuretic peptides, were elevated above the healthy reference median. HS135 treatment led to decreases in 87% of treated subjects, including normalization. Conclusion: HS135 was generally well tolerated and led to high levels of target engagement. The observed improvement in body composition as well as prognostic markers for PAH and HF support HS135's ongoing development in these patient populations.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".