CRV431 Lowers Production of Collagen and Fibronectin in Several Cell Types
CRV431 is a small molecule being developed as an investigational treatment for non-alcoholic steatohepatitis (NASH) and viral hepatitis-induced liver disease. Both of these conditions are characterized by fibrosis (scarring) in the liver.
Fibrosis is the result of a pathological build-up of extracellular matrix (ECM), the network of proteins and other molecules that exist outside of cells that help physically maintain the structure of cells and tissues. In particular, the ECM proteins collagen and fibronectin are known to be overproduced during fibrosis in multiple organs, including the liver and lungs. These ECM proteins are primarily produced by cells called fibroblasts.
“Fibrotic scarring is a major pathological feature and driver of organ dysfunction in many diseases, including liver cirrhosis, IPF [idiopathic pulmonary fibrosis], chronic kidney disease, and several heart conditions. Yet, there are very few treatments available that attenuate the scarring,” Daren Ure, PhD, Hepion’s chief scientific officer, said in a press release.
Hepion investigated the treatment effects of CRV431 on ECM protein production in five different types of cells: lung fibroblasts from a person with IPF, cardiac (heart) fibroblasts, dermal (skin) fibroblasts, renal mesangial cells (which produce ECM in the kidneys), and the LX2 hepatic stellate cell line (a line of liver fibroblasts).
In all five types, CRV431 lowered the production of both collagen and fibronectin in a dose-dependent manner: That is, as more CRV431 was added, the less of these ECM proteins were produced.
At clinically relevant concentrations, ECM protein production was decreased by as much as 55%, with no detected toxic effects to the treated cells, the company said.
CRV431 is believed to reduce ECM proteins by inhibiting proteins called cyclophilins, namely cyclophilin B, which are involved in ECM production among other processes. Lowering cyclophilin B levels cut ECM protein production to a similar degree as with CRV431 treatment, supporting its mechanism of action.
In addition, CRV431 reduced collagen and fibronectin production to a similar degree in cells treated with transforming growth factor beta, a signaling molecule that drives fibrosis. That’s consistent with CRV431 acting on the production of fibrotic molecules themselves, rather than on other related signaling pathways.
“Most treatments attempt to reduce fibrosis by targeting the stimulation of fibroblastic cells, but these signaling events may vary by patient, type of fibrotic disease, or disease stage,” Ure said. “The advantage of CRV431, based on our findings, is that its effects appear to be independent of the type of stimulatory signal.”
The findings show that CRV431 could have applications in a wide range of fibrotic diseases, not just those affecting the liver.
“Liver fibrosis arising from NASH and other chronic insults continues to be Hepion’s primary focus, but the results of these recent studies raise the intriguing possibility that CRV431 could be evaluated for a host of other disorders,” said Robert Foster, PhD, CEO of Hepion. “IPF is one such example of an aggressive fibrotic disease in tremendous need of new treatments.”
CRV431’s safety profile is currently being evaluated in healthy volunteers and people with chronic hepatitis B infections in a Phase 1 clinical trial (NCT03596697).
“[O]ur Phase 1 study in healthy volunteers continues to demonstrate a very good safety profile for CRV431, further supporting its possible use for other indications,” Foster said.