1.Human genetics evidence linking the novel target X with heart failure

Analysis on a latest single cell RNA sequencing (scRNA-seq) dataset and a single nucleic RNA sequencing (snRNAseq) dataset (Nature 2024; 635:423- 433), including heart failure patients were afflicted with acute myocardial infarction, ischemic and nonischemic cardiomyopathies, shows:

The novel target X demonstrates a higher expression levelin fibroblasts from patients with AMI, NICM or ICM.
The expression levels of the novel target X is significantly increased in cardiomyocytes from patients with AMI, NICM or ICM.
The novel target X related pathways were upregulated in both fibroblasts and cardiomyocytes from patients of AMI, NICM or ICM.

2.Novel inhibitor design strategy

The novel target X activiation can increase the translocation of MRTF-A into the nucleus and the activation of SRF，which induces the expression of fbrosis-associated genes such as collagene1a2.

Asset can disrupt the nuclear translocation of MRTF-A and the colocalization with SRF by inhibiting the novel target X, which decreases the expression of Collagen and Fibronectin in cardiomyocytes to improve cardiac remodeling and fibrosis；

Asset functions as a molecular glue to promote the adhesion between the over-activated target X and its inactivated protein (GDIs), reduces the target X GTP/GDP exchange ratio, thereby inhibiting its over-activation.
Asset blocks G-actin to F-actin polymerization, inactivating MRTF-A and disrupting its interaction with SRF, reducing SRF and downstream fibrosis genes (COL1, COL3, FN1, VIM, MMP2), halting cardiac fibroblast-to-myofibroblast transformation and fibrosis.

3.Highligts

Efficacy studies in animal modelsof LAD ligation

Dosage Advantage

Asset achieves comparable efficacy on primary pharmacodynamic endpoints (e.g., ejection fraction [EF]) at substantially reduced dosages compared to Entresto.

Myocardial Structural Benefits

At 1/6 the therapeutic dosage of Entresto, asset demonstrates superior inhibition of pathological myocardial remodeling, including significant reductions in malignant fibrosis and hypertrophy.

Asset significantly improved renal pathological morphology and showed a trend toward enhancing renal function.

In the AngII-induced hypertensive model, asset reduced plasma creatinine and blood urea nitrogen (BUN) levels while increasing urinary creatinine excretion, indicative of improved renal filtration and reduced tubular injury.

The toxicological studies under GLP showed that asset has an excellent safety profile , no significant changes in ECG and blood pressure and safety margin