Preclinical Research on FAP-Related Targets: AstraZeneca's Approach with AZD2389 | KBI Project Experience

Event Overview:

Recently, at the AASLD 2024 Liver Meeting, AstraZeneca presented preclinical data on their small molecule drug AZD2389, which targets fibroblast activation protein (FAP). The studies included in vitro experiments and investigations using a metabolic dysfunction-associated steatohepatitis (MASH) model in cynomolgus monkeys.

The data demonstrated significant biological effects of AZD2389 in MASH-affected cynomolgus monkeys, effectively inhibiting FAP activity while increasing levels of metabolically active α2-antiplasmin (Met-α2AP) and intact fibroblast growth factor 21 (FGF-21). Crucially, this compound has the potential to halt liver fibrosis progression, providing a promising new strategy and targeted therapeutic option for MASH treatment.

Mechanism of Action of AZD2389:

The severity of fibrosis is closely linked with disease progression and mortality among MASH patients. As an endopeptidase, FAP shows increased expression in plasma and pathogenic fibroblasts within fibrotic livers. Moreover, the expression levels of FAP in liver tissue correlate with disease severity.

FAP is believed to promote fibrosis by cleaving multiple proteins involved in extracellular matrix (ECM) turnover and metabolism, including collagen, α2AP, and FGF-21.

? FAP as a gelatinase: It degrades collagen, α2AP, and FGF-21.

? FAP-mediated α2AP cleavage: It converts N-terminal intact Met-α2AP into Asn-α2AP, thereby enhancing the inhibitory effect of α2AP on fibrin degradation by plasmin.

? FAP-mediated FGF-21 cleavage: It cleaves the C-terminal of FGF21, leading to its inactivation.

AZD2389, a potent and highly selective FAP inhibitor developed by AstraZeneca. It exhibits similarly effective inhibitory activity against FAP enzymes in humans, cynomolgus monkeys, and rodents. This consistency across species provides valuable insights into the potential therapeutic value of FAP inhibition in the treatment of liver fibrosis. ?

Thus, AstraZeneca had conducted a preclinical study at Kunming Biomed International (KBI) using male cynomolgus monkeys with diet-induced MASH and F1/F2 fibrosis to evaluate the relationship between FAP enzyme inhibition by AZD2389, and proof of mechanism biomarkers (cleavage of α2AP and FGF21) as well as pharmacodynamic effects on liver histology.

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Preclinical Study of AZD2389 in Non-Human Primates (NHPs)

Study Outcomes

AZD2389 treatment resulted in improved NAS and fibrosis scores compared to the control group.? Notably, 48% of the treatment group showed improvement in NAS scores, which was significantly higher than the 20% observed in the control group (p = 0.0008).

A statistically significant improvement in fibrosis scores was observed in 16% of animals treated with AZD2389, compared to 5% in the control group (p = 0.01).

These observed therapeutic effects of AZD2389 were independent of age and body weight changes.

The circulating biomarker for fibrosis, Pro-C3, decreased significantly after AZD2389 treatment, confirming the histological results while the liver enzymes (ALT and AST) and metabolic parameters such as fasting glucose, insulin, and triglycerides remained unchanged.

→For further experimental data and analysis, please refer to the poster presented by AstraZeneca at the AASLD 2024 Liver Meeting.

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Conclusion:

The preclinical research findings on AZD2389 by AstraZeneca hold significant scientific value. This study not only introduces new hope for MASH treatment but also paves the way for further drug development targeting FAP-related pathways. The notable improvements in NAS and fibrosis scores highlight AZD2389's potential as a promising therapeutic option for hepatic fibrosis treatment.

We look forward to AZD2389 progressing through subsequent research phases, ultimately advancing to clinical application to provide effective treatment solutions for MASH patients. Additionally, this study may inspire further research efforts in the development of MASH-targeted therapies, driving continuous innovation in hepatology.

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