CRV431 Reduced Fibrosis Markers in IPF Lung Tissue, Hepion Reports

Hepion Pharmaceuticals‘ CRV431 has a similar, or even greater effect in reducing markers of idiopathic pulmonary fibrosis (IPF) in lung tissue, compared with standard-of-care IPF treatment, the company reported.

The therapy had positive results in lung tissue from an IPF patient, according to Hepion.

CRV431 is a molecule with potent blocking action against proteins called cyclophilins, which are important components of the extracellular matrix (ECM). The ECM is a network of several proteins and other molecules that exist outside of cells and help maintain the structure of cells and tissues.

Fibrosis, or scarring, is the result of ECM buildup, and is a major pathological or disease feature that affects many organs, such as the liver and lungs.

First developed to treat liver diseases, CRV431 has shown positive effects in treating non-alcoholic steatohepatitis (NASH), which is liver inflammation and damage caused by a buildup of fat in the liver. CRV431 was previously shown to reduce liver scarring and liver cancer burden in disease models.

Now, Hepion is studying its repurposing as a potential treatment for fibrotic diseases affecting other organs, including IPF.

“This study represented a rare opportunity to test CRV431 on diseased, IPF tissue. Several previous studies in animal models and human liver tissues demonstrated therapeutic effects of CRV431 in the liver, but this is the first study to show that CRV431 can attenuate disease markers in tissue from another organ,” Daren Ure, PhD, chief scientific officer of Hepion Pharmaceuticals, said in a press release.

In a previous preclinical study in several cell types, including lung fibroblasts — the cells that mainly produce ECM proteins — from a person with IPF, the company showed that CRV431 lowered the production of fibrosis-related proteins. Specifically, the therapy lessened production of collagen and fibronectin, in a dose-dependent manner, with no toxic effects to the cells.

Positive findings in lung tissue from an IPF patient are now being reported by the company.

The study, conducted by FibroFind, analyzed samples of lung tissue from a transplanted IPF patient that were treated with CRV431 at two concentrations (1 or 5 µM) on the final four days of a total of six days of culture in the lab.

Other lung samples were treated with Esbriet (pirfenidone) or Ofev (nintedanib), two approved standard-of-care therapies for IPF.

The researchers measured several markers of fibrosis, including collagen 1α1, TIMP1, MMP7, and hyaluronic acid, and inflammation, such as IL-6 and MCP-1. They also examined the activity of genes relevant to inflammation and fibrotic processes, specifically collagen 1α1, TIMP1, αSMA, TGFβ1, IL-6, and MCP-1.

The results showed that CRV431 treatment resulted in decreased gene activity and levels of every disease marker analyzed, in a dose-dependent manner.

At the highest tested dose (5 µM), CRV431 decreased gene activity by an average of 45%, similar to the effects of Esbriet at a 500-times higher concentration than CRV431 (46% reduction).

Regarding the secretion of disease markers, CRV431 induced a daily average decrease of 28%. Its potency in decreasing the levels of the fibrosis markers collagen 1α1 and TIMP1 was similar to that observed for Esbriet and Ofev, the company said.

The investigational therapy’s most potent effect was observed in the reduction of MMP7, an established IPF biomarker, by 61%. This effect was twice as potent as that observed with Ofev (31%) and similar to Esbriet (65% reduction).

“The results reinforce that CRV431 has direct-acting anti-fibrotic activity that may be applicable to a range of fibrotic diseases and disorders,” Ure said. “Having previously observed anti-fibrotic activities of CRV431 in isolated cells from an IPF lung, the current study extends those observations to intact, IPF tissue, which is significantly more relevant.”

The finding of this IPF lung study “suggest that CRV431 may work across many different tissues and organs,” according to Robert Foster, PhD, CEO of Hepion Pharmaceuticals.

“Depending on resources, we may choose to pursue one or more of these indications in addition to NASH-related fibrosis, but may also be open to collaboration,” Foster said

As for tests in humans, according to Hepion, so far a Phase 1 clinical trial (NCT03596697) showed that the therapy was well-tolerated and safe in healthy volunteers. CRV431 is now being tested in a multiple ascending dose study, the company said.