Transforming Growth Factor-beta (TGF-beta) has long been a target for those in the biopharmaceutical industry seeking to develop therapies to treat fibrotic indications. TGF-beta plays a key role in initiating the cascade of events that culminates in the production of CTGF, which causes the formation of scar tissue. However, TGF-beta has normal functions in the body that make chronic administration of any inhibitor that indiscriminately blocks TGF-beta activity problematic due to unwanted side effects. Thus, a major goal at FibroGen has been to make TGF-beta inhibitors that selectively block the fibrotic activity of TGF-beta, leaving all other functions intact.

FibroGen's TGF-beta research has focused on upstream events involving how TGF-beta signals, upregulates and activates CTGF, and on downstream events involving how CTGF signaling causes matrix protein production and initiates conversion of various healthy cell types into fibrotic myofibroblasts.These two parallel programs have relied on assays and technology developed at FibroGen, adapted to high throughput modes, and then used to screen a diverse small molecule library containing over 200,000 compounds. This work has resulted in the identification of two distinct classes of compounds: 1) those that block very early events in TGF-beta signaling and thus broadly inhibit TGF-beta action; and, 2) those that affect downstream events in pathways that mediate TGF-beta action and thus have more restricted inhibitory profiles.

Although there are many companies that are sponsoring anti TGF-beta compounds in the clinic, to FibroGen's knowledge, all of those programs worldwide are using broad-spectrum TGF-beta inhibitors. FibroGen, by using its proprietary assays, has developed first in class selective TGF-beta antagonists.

Both classes of TGF-beta inhibitors have promise for applications in cancer and in fibrosis. In certain cancers, TGF-beta pathways are adapted to promote tumorigenesis and neoplastic disease progression. Broad inhibition of TGF-beta action by the class of inhibitors that act on early signaling events is expected to effectively block this essential aspect of the neoplastic process. In fibrosis, the class of inhibitors that affect downstream events, such as CTGF production in signaling pathways activated by TGF-beta is expected to selectively block connective tissue deposition and thus inhibit abnormal scarring. This class of compounds, which was chosen for more limited blockade of TGF-beta effects, will selectively spare the beneficial aspects of TGF-beta signaling that operate in normal physiology.

FibroGen's current objective is to further characterize and optimize the most promising molecules with the intent of selecting one for preclinical development by next year.