Results of a non-clinical research study demonstrated that Hepion Pharmaceuticals’ (NASDAQ:HEPA) clinical phase drug candidate, rencofilstat (CRV431), synergistically decreased liver tumor growth and extended mouse survival when combined with an anti-PD1 antibody, an immune checkpoint inhibitor (ICI).
The effects were observed in fatty livers, which may be associated with lower anti-PD1 efficacy in hepatocellular carcinoma (HCC), suggesting that rencofilstat may increase the treatment potential of anti-PD1 treatment in human liver cancer.
The study was conducted by Fibrofind of Newcastle, UK in collaboration with Prof. Derek Mann, dean of research and innovation at Newcastle University.
In the study, mice were first fed a Western-type diet of high fat, cholesterol and sugar for three months to generate fatty livers, followed by surgical implantation of cancerous HCC cells (mouse hep53.4 cell line) into the livers. Drug treatments began on Day 14 after HCC cell implantation, when tumors were approximately 15% of their final, end-of-study size.
Mice received either once-daily, orally administered rencofilstat; twice-weekly, intraperitoneally administered anti-PD1 antibody; or a combination of both rencofilstat and anti-PD1.
In the first study arm, drugs were administered from Day 14 to Day 28 post-tumor cell implantation, followed by measurement of liver tumor size. In the second study arm, drugs were administered from Day 14 post-tumor cell implantation until ethical euthanasia or death of the mice resulting from tumor growth.
Neither rencofilstat nor anti-PD1 administered alone altered the size of tumors at Day 28, nor the survival of the mice, compared with vehicle treatment.
In contrast, combination treatment of rencofilstat plus anti-PD1 decreased tumor size by 69% at Day 28 (p=0.022) and increased median mouse survival time by 26% (vehicle 19.5 days; rencofilstat plus anti-PD1 24.5 days; p=0.0011), compared with vehicle treatment. A robust anti-tumor effect from the drug combination, but not from monotherapy treatments, is an indication of rencofilstat and anti-PD1 synergy.
In a statement, Daren Ure, Ph.D. and CSO of Hepion, said anti-PD1 therapies that stimulate immune cell attack on cancer cells are approved and effective in many types of cancer, but they have had limited success in HCC clinical trials. “Recent reports indicate that a fatty liver environment blocks the efficacy of anti-PD1 drugs, and perhaps other checkpoint inhibitors.”
In addition, he said that as successful treatments for viral hepatitis have been implemented, “NASH has been quickly becoming the leading cause of HCC.”
Citing the known limitation of these drugs, “our own studies found that treatment with either anti-PD1 or rencofilstat alone in the hep53.4 HCC model decreased tumor growth by 76% when tumorigenic cells were implanted into non-fatty livers but were not effective as monotherapies in fatty livers in the current study,” Dr. Ure said.
In addition, rencofilstat in combination with anti-PD1 not only decreased tumor growth, but also extended the survival of the mice in this very aggressive model of HCC. “We are continuing to study the mechanisms underlying the synergistic effect of rencofilstat and anti-PD1.”
Robert Foster, PharmD, Ph.D. and CEO of Hepion, said HCC is the most common type of liver cancer. It has a poor prognosis, compared with many other types of cancer, claiming approximately 800,000 lives annually across the globe. Although a few therapeutic compounds have been approved for non-resectable HCC, response rates are still low and there remains an urgent need for new, safe, and effective anti-HCC therapies, he added.
“We were excited to have received authorization from the FDA last month to move directly into a Phase 2a study of rencofilstat for the treatment of HCC and have already begun preparations to initiate the trial in parallel with our Phase 2b NASH clinical program in the second half of 2022,” Dr. Foster said.
“As far as we are aware, rencofilstat is the only drug in development that is being clinically evaluated in these two severe, and often comorbid liver indications,” he added.
