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Foster talks to Pharm Exec about why liver disease is on the rise, and Hepion’s new therapy, rencofilstat, in development to treat it.
Robert Foster, PharmD, PhD, is a scientist, researcher, former professor, entrepreneur, and founder of four successful biopharma companies. Currently, he is the CEO of Hepion Pharmaceuticals, a publicly traded biopharmaceutical company focused on the development of targeted therapies for chronic liver diseases, with clinical programs moving ahead in both non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), liver cancer.
Foster first began working on cyclophilin drug development in 1988. Cyclophilins are a family of diverse enzymes that participate in many pathophysiological processes. Pharmacologic inhibition of cyclophilins has shown high potential for therapeutic effects in diseases such as chronic liver disease and cancer, as well as antiviral activity.
In 1993, he founded Isotechnika Pharma, where he was chairman and CEO for approximately 21 years. During his tenure there, Foster discovered voclosporin, an immunosuppressive drug to treat autoimmune diseases.
Later, he was founding CEO, and subsequently CSO, of Aurinia Pharmaafter it was acquired by Isotechnika in 2013. Voclosporin (Lupkynis™) was approved by FDA for the treatment of lupus nephritis in January 2021.
Prior to Hepion, Foster was CEO and founder of Ciclofilin Pharmaceuticals Inc., which merged with Hepion in 2016.
Pharmaceutical Executive caught up with Foster to talk about why liver disease is on the rise, and Hepion’s new therapy, rencofilstat, in development to treat it.
Pharm Exec: What inspired you to start a fourth biopharma company, after achieving such success with three other companies?
Foster: Hepion represents a natural progression of the research that our group has been conducting over the past approximately 25 years. Our initial foray into the field began with creating immunosuppressive drug molecules for the treatment of solid organ transplantation and the treatment of autoimmune diseases. This led us to the discovery of chemically related molecules that were developed by our team, where we removed immunosuppression and boosted other potentially beneficial activities. We brought these molecules to Hepion; and this latest venture represents the next chapter in our team’s evolving drug development journey.
Pharm Exec: The risk of dying from cancer in the US has decreased dramatically over the past few decades. Early detection, lifestyle changes, science, and new therapies to treat cancer are helping people live longer. Yet the incidence of liver cancer, specifically HCC, in both men and women is on the rise. Why do you think this is the case?
Foster: Yes, and there are many factors that are contributing to this statistic.For example, HCC may arise from viral infections or from metabolic diseases, such as obesity and its related fatty liver disease and NASH. In their earlier stages, many of these diseases are not readily apparent in people. As such, early diagnosis and effective treatments may be lacking.
The HCC incidence rate associated with nonalcoholic fatty liver disease (NAFLD) and NASH is also increasing; and the global burden of mortality from HCC is predicted to reach 1 million deaths annually by 2030. Patients who are diagnosed in the advanced stages are often ineligible for surgery, and to date, therapeutic options for advanced HCC patients are limited in availability and efficacy, which is why our team began working on and developing a new therapy to target multiple types and stages of liver disease and cancer.
Pharm Exec: Hepion’s lead molecule, rencofilstat, is in development to target multiple types and stages of liver disease and cancer.
Foster: Yes, rencofilstat is being developed to target liver disease that is caused by NAFLD, its more advanced form, NASH, and HCC. The Phase IIa results of our clinical trials in NASH patients taking rencofilstat show that there are positive effects on the liver, and in several animal studies we have seen a decrease in hepatocellular carcinoma. This has encouraged us to move into clinical studies in HCC patients this year alongside our advancement of the NASH trials.If our hypotheses are accurate, we believe rencofilstat will be the first—or one of the first—FDA-approved treatment for NASH, that at the same time plays a critical role in the overall progression of liver disease and cancer, including the triggering events all the way to the end-stage disease with its many complications. And FDA’s recent authorization for the IND is an important milestone that allows rencofilstat to go directly to Phase IIa for the treatment of HCC, liver cancer.
Pharm Exec: What is the therapy’s mechanism of action?
Foster: Rencofilstat is the first of a new class of medication called cyclophilin inhibitors. Its function is to bind to these proteins throughout the body and inhibit their function. The actions of rencofilstat, in diseases like NASH, are due to the fact that multiple cyclophilin forms exist in the body and participate in many disease processes. Cyclophilins assume especially prominent roles in disease processes such as cell death, fibrosis, and cancer cell growth and metastasis. Also, many viruses have evolved to recruit cyclophilins into their life cycles to assist in viral replication and evade the immune system. By blocking the participation of cyclophilins in these processes, Rencofilstat displays a variety of therapeutic activities.
Pharm Exec: So Hepion’s therapy is intended to target multiple molecular pathways?
Foster: That’s correct. Rencofilstat is intended to target multiple molecular pathways across the full spectrum of liver disease progression, from the triggering events that initiate disease to the pathological events that directly impair liver function and integrity.
Optimal treatment of chronic liver diseases—halting progression and stimulating repair—requires intervention at multiple steps in the disease process. The traditional approach is to combine several drugs with discrete mechanisms of action, which carries a risk of drug-to-drug interactions, cumulative drug side effects, and lengthy development times with multiple therapeutic agents. We believe that a safer and more efficient approach is to alleviate multiple disease pathways with single-drug compounds, resulting in multiple therapeutic actions.
Pharm Exec: When and how does NAFLD develop into NASH, and become more serious?
Foster: NAFLD may evolve into NASH when the fatty liver begins to advance into stages of cell injury, inflammation, and fibrosis. At least 4% to 5% of the global population is estimated to have NASH. In the US, it’s estimated one in four people have NAFLD, and most do not even know it because they are asymptomatic.
People who develop NASH may often be obese and may have predisposing conditions, such as diabetes and hypertension. But we don’t know the exact biochemical events that trigger and maintain the progression.
Pharm Exec: There are no blood tests to diagnose or track the progression of NASH; and there aren’t any approved therapies to specifically treat this advanced liver disease. Why is this?
Foster: The first line of treatment for NAFLD and NASH is lifestyle modification and weight loss. Dieting, exercising, and eating healthy can reduce fat and inflammation in the liver. However, the degree of weight loss required for lasting improvement ofNASH is hard to achieve and maintain.
In some cases, bariatric surgery is the only effective long-term weight-loss therapy and has also demonstrated gains in cardiovascular outcomes, the leading cause of premature mortality in patients with NAFLD.
For pharmaceutical companies, NASH has remained an attractive but elusive area for drug development over the past 40 years. No disease-specific approved therapies have made it to market. The NASH pipeline is littered with failures in late-stage trials.
Pharm Exec: Why do you believe that rencofilstat will prove to be effective, when there have been so many previous failures?
Foster: Our preclinical work has given us the confidence that rencofilstat will be effective across these multiple stages of liver disease, and this new agent will not only slow but reverse the progression toward long-term complications such as cirrhosis and liver cancer.
Hepion’s approach of chemically creating new drugs based on pre-existing known drug scaffolding, with long histories of clinical usage, significantly reduces the risk of unanticipated side effects and other problems throughout drug development. Maximizing the drug concentrations at its intended site of action minimizes the risk of side effects arising from off-target effects in other organs.
Pharm Exec: Does Hepion use artificial intelligence (AI), big data, or machine learning in drug development?
Foster: Hepion uses a platform known as AI-POWR™, which combines AI, big data, and machine learning to decode disease, develop targeted therapies, and to select patients who will be more likely to respond to Hepion therapies. This system enables our team of scientists and researchers to facilitate a precision medicine-based approach to treating NASH through its ability to identify rencofilstat responders and inform the development of biomarkers.
AI-POWR™ is used to fine-tune patient selection for clinical trials or when designing clinical studies. Hepion can also identify and evaluate additional potential indications for rencofilstat to expand our clinical footprint in the cyclophilin inhibition therapeutic space and beyond.
We also believe that our AI will be useful in identifying future drug combinations that may be synergistic with rencofilstat. As we look forward to several future clinical updates, and even back at discovering and developing an FDA-approved drug for kidney disease, our team is reminded of what motivates us—and that is the patient.
Our lead therapy, rencofilstat, is showing measured promise as it advances through clinical trials. We remain optimistic and encouraged about the possibility of bringing an FDA-approved treatment to the millions of patients suffering from NASH, and to those patients who are in the more advanced stages of liver disease, with HCC.