Growth Factor Biology
Why target growth factor pathways for fibrotic indications?
Fibrosis represents an aberrant response of a tissue to injury, leading to progressive tissue scarring that may be triggered by trauma, inflammation, infection, cell injury or cancer, amongst others. As a result, fibrosis can lead to organ dysfunction and failure.
The body’s normal response to injury involves the activation of cells that produce collagen and other components of the extracellular matrix, or ECM, that are part of the healing process for the tissue. Under normal physiological circumstances, scarring is self-limited and the resulting scar resolves itself, leaving behind a tissue architecture similar to what was present before the injury.
However, in certain chronic disease states, this process of healing becomes both prolonged and excessive, resulting in fibrotic remodeling which interferes with organ function. Fibrosis can occur in many organ systems throughout the body including the lungs, liver, kidneys, gastrointestinal tract, skin and muscles. While the exact pathologies for diseases in these organs differ, fibrosis involves many of the same cell types and signaling pathways across different organs and tissue.
The body’s normal response to injury involves the activation of cells that produce collagen and other components of the extracellular matrix, or ECM, that are part of the healing process for the tissue. Under normal physiological circumstances, scarring is self-limited and the resulting scar resolves itself, leaving behind a tissue architecture similar to what was present before the injury.
However, in certain chronic disease states, this process of healing becomes both prolonged and excessive, resulting in fibrotic remodeling which interferes with organ function. Fibrosis can occur in many organ systems throughout the body including the lungs, liver, kidneys, gastrointestinal tract, skin and muscles. While the exact pathologies for diseases in these organs differ, fibrosis involves many of the same cell types and signaling pathways across different organs and tissue.
Why are we targeting the TGFẞ pathway?
Signaling by TGFβ has been shown to play a central role in the pathophysiology of fibrosis.
The well understood role of the TGFβ pathway, including through the ALK5 receptor, in driving multiple aspects of fibrosis, has made it an attractive target for antifibrotic drug development. In healthy tissue, TGFβ’s physiological role is to initiate healing after injury.
In fibrotic diseases, however, TGFβ signaling remains continuously activated in response to prolonged insults such as inflammation, leading the surrounding tissue to deposit excess ECM, which eventually leads to tissue fibrosis. There is strong preclinical evidence and encouraging preliminary clinical evidence that TGFβ inhibition could be effective in multiple indications; however, development of previous ALK5 inhibitors has been limited due to safety concerns as systemic inhibition of TGFβ causes toxicity in the heart and large vessels.
We believe our programs have the potential to overcome these systemic toxicity challenges by acting locally within tissue of interest and avoiding systemic exposure while allowing us to leverage the well-described role of TGFβ in fibrosis.
The well understood role of the TGFβ pathway, including through the ALK5 receptor, in driving multiple aspects of fibrosis, has made it an attractive target for antifibrotic drug development. In healthy tissue, TGFβ’s physiological role is to initiate healing after injury.
In fibrotic diseases, however, TGFβ signaling remains continuously activated in response to prolonged insults such as inflammation, leading the surrounding tissue to deposit excess ECM, which eventually leads to tissue fibrosis. There is strong preclinical evidence and encouraging preliminary clinical evidence that TGFβ inhibition could be effective in multiple indications; however, development of previous ALK5 inhibitors has been limited due to safety concerns as systemic inhibition of TGFβ causes toxicity in the heart and large vessels.
We believe our programs have the potential to overcome these systemic toxicity challenges by acting locally within tissue of interest and avoiding systemic exposure while allowing us to leverage the well-described role of TGFβ in fibrosis.
Why are we targeting the HGF/MET pathway?
The HGF pathway, like TGFβ, has also been established to be a key modulator of fibrosis and represents a promising target for progressive liver cirrhosis, as well as gastrointestinal, pulmonary, and renal disorders.
In contrast to TGFβ, however, the HGF pathway possesses anti-fibrotic activity. The HGF pathway is a critical modulator of the proliferation, survival, motility, and differentiation of epithelial cells and has a strong regenerative effect.
We have an HGF-mimetic monoclonal antibody in our development pipeline that we believe has the potential to act as an agonist of the MET receptor in a robust, stable, specific, and convenient fashion, something which has not been possible with putative small molecule agonists or native HGF.
In contrast to TGFβ, however, the HGF pathway possesses anti-fibrotic activity. The HGF pathway is a critical modulator of the proliferation, survival, motility, and differentiation of epithelial cells and has a strong regenerative effect.
We have an HGF-mimetic monoclonal antibody in our development pipeline that we believe has the potential to act as an agonist of the MET receptor in a robust, stable, specific, and convenient fashion, something which has not been possible with putative small molecule agonists or native HGF.
