Hepion’s Phase II NASH Study Hits Primary and Secondary Endpoints
By Mark Terry
May 23, 2024
Non-alcoholic steatohepatitis (NASH) has been a very tough nut to crack, with numerous companies’ compounds failing to hit the mark in late-stage trials. Edison, NJ-based Hepion Pharmaceuticals has reason to be optimistic, with the announcement that its Phase II ALTITUDE-NASH trial of rencofilstat hit both primary and secondary endpoints.
NASH is a form of non-alcoholic fatty liver disease (NAFLD) that includes liver inflammation, liver damage, such as fibrosis (scarring), and fatty liver. It can lead to cirrhosis but is typically unrelated to alcohol use. According to the American Liver Foundation, NASH affects about 5% of U.S. adults.
Rencofilstat specifically binds cyclophilin isomerase enzymes while inhibiting cyclophilin function. In the ALTITUDE-NASH trial, the drug hit the primary endpoint, demonstrating improved physiologic liver function. It also hit additional secondary endpoints, including reductions in the liver injury biomarkers, alanine and aspartate transaminases, multiple fibrosis-associated biomarkers, including ProC3, PIIINP, TIMP1, hyaluronic acid and enhanced liver fibrosis scores.
Todd Hobbs, Hepion’s Chief Medical Officer, said in a conference call that the study met “several goals” including “primarily confirming the Phase IIa AMBITION trial, which was 28 days.” He added that they “really wanted to build on that with a longer study. In addition, we are very much impressed with the HepQuant SHUNT Test.”
The HepQuant SHUNT Test was used in the trial under an FDA-issued Investigational Device Exemption (IDE). It is a minimally invasive test that follows changes in the degree of liver function. In the trial, it was used to track four key measures: HepQuant DSI (Disease Severity Index) score, mostly a reflection of hepatocyte function; SHUNT, which marks micro-architectural changes, for example, the effect of fibrosis on blood flow through the liver; HepQuant HR (Hepatic Reserve); and RISK ACE, which tabulates the annual risk of the patient developing an adverse clinical outcome.
Hobbs added that they were able to “look at hepatic function and how to apply it to the Phase IIb ASCEND-NASH biopsy study, which is currently recruiting.” He also said the trial “did confirm safety and tolerability in an advanced population.”
The study, Hobbs indicated, was able to identify two very strong key areas of responders, in particular with the 225 mg dose, which demonstrated the most benefit to liver function as well as multiple NASH-associated biomarkers. “More than half of the advanced group of subjects really responded,” Hobbs said.
Gregory Everson, Founder and Chief Scientific Researcher for HepQuant, the company that created The HepQuant SHUNT Test, said that the test “recently completed a pivotal study and is under substantive review by the FDA.”
Within the ALTITUDE-NASH trial, Everson said, “After four months of treatment, we saw improvement in the SHUNT test and improvement in the advanced population. It also proved to be useful in identifying patients for the study and for tracking improvement.”
During the conference call, Patrick Mayo, Hepion’s Senior Vice President, Clinical Pharmacology & Analytics, noted, “We are dealing with a population with very advanced disease and extensive liver damage. As patients become more and more advanced, you can actually see a reduction in the dose-response in biomarkers. The drug works best in patients with active disease which is really exciting data.”
NAFLD is viewed as an emerging global epidemic and is the most common cause of chronic liver disease in the Western world. No drugs have been approved by the FDA for treating biopsy-proven NASH.
On May 19, the FDA’s Gastrointestinal Drugs Advisory Committee (GIDAC) met to review Intercept Pharmaceuticals (Morristown, NJ)’ New Drug Application (NDA) for obeticholic acid (OCA) for pre-cirrhotic fibrosis due to NASH. Of the 16 voting-eligible advisors, 12 voted no on the question, “Given the available efficacy and safety data, do the benefits of OCA 25 mg outweigh the risks in NASH patients with stage 2 or 3 fibrosis?” Two abstained. To the question, should the agency “defer approval until clinical outcome data from trial 747-303 are submitted and reviewed, at which time the traditional approval pathway could be considered,” 15 of 16 voted yes. The drug’s target action date is June 22, 2023.
Panel member James Floyd, an associate professor at the University of Washington, said, “If you’re talking about millions of people with NASH who could go on this drug, 1-in-1000 could get severe DILI (drug-induced liver injury), you’re talking about a new epidemic of liver disease as an adverse effect of a drug.”
The presenters for Hepion’s conference call all mentioned the safety and tolerability of rencofilstat, with Stephen Harrison, Chairman and Co-Founder of Summit Clinical Research and Chair of Hepion’s Scientific Advisory Board specifically mentioning the Intercept NDA advisory committee vote.
Hepion’s executives appeared especially pleased with the safety and tolerability data as well as the ability of the HepQuant SHUNT Test as well as AGILE 3+ screening, a score for diagnosis advanced fibrosis and for predicting liver-related events in NAFLD, for tracking liver function and identifying appropriate patients for the trial. No deaths or hepatic decompensation events were observed in the study. There were a total of five serious adverse events (SAEs) with four unrelated to the study drug (COVID-19, headache, fibula francture, COPD), and a single SAE (biliary acute pancreatitis) classified as possibly related to the drug in a patient diagnosed with a pancreatic stone as the probable cause of the pancreatitis. Other safety signals, such as EKGs and physical exams showed no safety signals or concerns.
Harrison said, “You don’t think about one particular testing to tell the story, but the collective changes we’re seeing across the board are setting us up nicely for the ASCENT biopsy study.”
Robert Foster Foster, Chief Executive Officer of Hepion, added, “We’re in a really good position to move this company forward.”
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
