5-HT2B BIOLOGY
5-HT<sub>2B</sub> BIOLOGY

5-HT2B RECEPTOR BIOLOGY

Serotonin or 5-hydroxytryptamine (5-HT) is well recognised as a stimulator of tissue fibrosis. Peripheral 5-HT is mainly produced by enterochromaffin cells and stored in platelets. Upon, for example, vascular damage, platelets become activated and release 5-HT resulting in increased local concentrations. Such dysregulated 5-HT activity has detrimental effect and leads to fibrosis.

Fibrosis is a serious process that occurs in several diseases where normal healthy tissue is replaced by fibrotic tissue, leading to organ dysfunction and contributing to morbidity and increased mortality of affected patients. Emerging research reveals a significant role of peripheral 5-HT2B receptors being upregulated in fibrotic tissue e.g. dermal fibroblasts isolated from patients with systemic sclerosis. Activation of the 5-HT2B receptor on e.g. resident fibroblasts results in increased myofibroblast differentiation and activation, excessive extracellular matrix synthesis and eventually fibrosis.

AnaMar’s first-in-class 5-HT2B receptor antagonists, including its candidate drug, AM1476, target the activated myofibroblast and interfere with TGF-β signalling pathways resulting in decreased matrix production and attenuated fibrosis. AnaMar’s approach has been validated in Proof of Principle studies using both human cells and disease models of fibrosis where it has been shown to halt the progression of fibrosis and even reverse the disease. The anti-fibrotic effects achieved by 5-HT2B receptor antagonism are valid in several fibrotic conditions such as dermal, lung, liver and heart fibrosis.

In addition, 5-HT and specifically the 5-HT2B receptor have a well-recognized involvement in diseases associated with inflammation, pain, vascular tonus and cell proliferation.

AnaMar has initially selected systemic sclerosis as the lead indication of AM1476, being an orphan indication with high medical need.