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
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».