Rencofilstat Produces Positive Outcomes in Translational Study on Idiopathic Pulmonary Fibrosis

– Proteomics analysis showed that rencofilstat improved aberrant protein profiles in IPF tissues –

– Superior effects of rencofilstat alone and in combination with pirfenidone and nintedanib –

EDISON, N.J., Sept. 14, 2023 (GLOBE NEWSWIRE) -- Hepion Pharmaceuticals, Inc. (NASDAQ:HEPA), a clinical stage biopharmaceutical company focused on Artificial Intelligence (“AI”)-driven therapeutic drug development for the treatment of non-alcoholic steatohepatitis (“NASH”), fibrotic diseases, hepatocellular carcinoma (“HCC”), and other chronic diseases, today announced positive results from a translational research study in which Hepion’s lead drug candidate, rencofilstat, was administered to diseased human lung tissue from patients with idiopathic pulmonary fibrosis (“IPF”).

Proteomic quantitation of nearly 2,000 proteins showed that rencofilstat shifted protein profiles of IPF tissue towards normalized expression more robustly than the two standard-of-care drugs, nintedanib and pirfenidone, and with strong combinational effects especially when co-administered with nintedanib.

In this study, FibroFind Ltd. (Newcastle, UK) obtained diseased lung tissue from two individuals undergoing lung transplantation for end-stage IPF, a deadly fibrotic lung disease. Precision cut lung slices (PCLuS) were made and individually incubated in culture with rencofilstat, nintedanib, pirfenidone, or combinations of the compounds for four days. Proteomics analyses were conducted on lung tissues at the end of treatment by PhenoSwitch Bioscience (Sherbrooke, Canada) and identified 1,953 unique proteins in the samples. The changes in abundance of the proteins produced by the drug treatments relative to vehicle control were determined and compared to abnormal protein profiles in IPF lungs reported in multiple proteomics studies over the past 5 years.^1–3 These analyses demonstrated:

• Rencofilstat monotherapy altered levels of between 8 and 28% of the 1,953 proteins identified in PCLuS depending on dose and donor. This represented changes 2 - 4-times greater than nintedanib or pirfenidone in PCLuS from the first donor, and 2-fold greater than nintedanib in the second donor;
• Rencofilstat, in combination with nintedanib, altered levels of 16 - 42% of the 1,953 proteins depending on donor, which represented 2.7 - 7.8-fold more than nintedanib alone;
• Rencofilstat, in combination with pirfenidone, altered levels of 12 - 46% of the 1,953 proteins depending on donor, which represented 1.3 - 2.2-fold more proteins altered by pirfenidone alone;
• Among three studies reporting differentially expressed proteins in IPF lungs compared to normal controls,^1–3 up to 41% of the reported differential proteins were also found in the current PCLuS study to be altered by rencofilstat alone or in combination. Furthermore, the majority of rencofilstat’s effects on the overlapping proteins (increased or decreased abundance) were opposite to the disturbances reported in the large IPF studies, which is consistent with disease-normalizing actions of rencofilstat;
• The normalizing actions of rencofilstat monotherapy and combinations spanned many important classes of proteins, including multiple isoforms of collagens, laminins, integrins, keratins, and MHC antigens. Additional, notable proteins whose abundance was positively shifted by rencofilstat included TIMP3, nidogen, surfactant protein C, cathepsin B, myeloperoxidase, lysozyme, mimecan, and asporin; and
• Cyclophilin B protein, a primary target of rencofilstat, was reported to be elevated in IPF lung tissue,^1,2 suggesting a pathogenic role, and rencofilstat alone and in combination in PCLuS decreased tissue levels of cyclophilin B.

“The technological advances in recent years in proteomics and other “omics” methodologies have blown the doors wide open on the scope and complexity of molecular changes in diseases like IPF, helping us to understand why so many narrowly targeted drug candidates have failed to have therapeutic effects,” commented Dr. Daren Ure, Hepion’s Chief Scientific Officer. “Rencofilstat’s suppression of fibrotic collagen production through cyclophilin B inhibition is one well-established mechanism, but inhibition of additional cyclophilin isoforms likely helps to explain rencofilstat’s robust effects in the present study. Rencofilstat alone shifted protein profiles more extensively than nintedanib and pirfenidone in most instances, and rencofilstat combinations were superior to every monotherapy, which is very encouraging. The old dogma in drug development about narrowly targeted drugs needs to adapt to emerging insights on complex diseases, and rencofilstat is one such candidate that is advancing that new paradigm of systems-targeting drug.”