June 2, 2022 PAO-06-022-CL-01
Robert Foster (RF): I grew up in a very entrepreneurial family. My dad was totally self-made and had his own businesses in heavy machinery, logging, and sawmills. Although I realized very quickly that I wasn’t interested in that kind of work, I enjoyed the business side of it. I went to university instead and took a shine to science, ultimately pharmaceutics. I started with a chemistry degree, followed by an undergraduate pharmacy degree and a post-baccalaureate Pharm.D. After completing my Pharm.D., I obtained a Ph.D. in pharmaceutical sciences. Following my graduate work, I spent 10 years in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta in Edmonton and became a tenured professor teaching pharmaceutics, therapeutics, pharmacokinetics, and other different subjects. Although I enjoyed the research, I never lost the desire to pursue something more entrepreneurial. In 1993, I resigned my faculty position and formed my own biotech company where I could apply my science and clinical background.
My idea at that point was to create an improved version of cyclosporine. Cyclosporine was a really transformative drug that made a big positive difference in the lives of a lot of people who had solid organ transplants. However, cyclosporine poses some clinical challenges. While cyclosporine can help avoid transplant rejection episodes, it can also induce nephrotoxicity. It also has an incredibly narrow therapeutic index: the window between the concentration of drug that elicits the desired pharmacologic response and the concentration that starts to create these toxicities is incredibly narrow
Cyclosporine is essentially a ring structure of 11 amino acids, each with specific geometry. My approach to improving cyclosporine was to make new versions of the molecule by using different amino acid isomers and adding on different functional groups with the aim of reducing side effects and making the drug more clinically viable.
During my 21 years at Aurinia Pharmaceuticals, the main focus was developing Voclosporin for solid organ transplant and autoimmune disease treatment. The drug ultimately received FDA approval in January 2021 for lupus nephritis.
RF: In 2007 at Aurinia, we established a research lab to work on derivatives of cyclosporine that were not immunosuppressant. We call them cyclophilin inhibitors, and they do not bind to the protein, calcineurin. We developed about 200 of these molecules and screened them for potential activity and relative potency. In 2014, I had suggested to the board of Aurinia that a subsidiary be spun out to pursue these molecules. The board only wanted to focus on getting Voclosporin commercialized, so I acquired the molecules and started a new company, bringing along several members of the research team.
Cyclophilin inhibitors are fairly potent antivirals in some instances, with activity against HIV-1, hepatitis C, hepatitis B, hepatitis D, and some SARS viruses. They also can be used to treat fibrotic disease or to treat things like reperfusion ischemia or ischemic events, including heart attack and stroke, and even to protect tissue injuries; for example, gunshot wounds or Duchenne’s muscular dystrophy. After our team presented data showing the activity of one of our drug candidates against hepatitis B and hepatitis C viruses, our new company was acquired by ContraVir in January 2016. However, by 2018, drugs had been approved that cured hepatitis C, and the world of hepatitis B was struggling. The search for an HBV cure poses a steep uphill climb.
At that point, we looked at the preclinical data foe our lead compound, which was called CRV431 and today has the generic name rencofilstat, and recognized the potential for rencofilstat as a potent antifibrotic effect. In preclinical studies performed in Japan and confirmed at the Scripps Research Institute in San Diego, the molecule exhibited a very consistent antifibrotic effect. We therefore decided to transition from antivirals to fibrosis treatments and changed the name of the company to Hepion Pharmaceuticals reflect our new focus.
RF: There are several types of fibrotic disease and inflammation, including NASH (non-alcoholic steatohepatitis), which involves liver fibrosis and inflammation as well as fat accumulation, and of course kidney fibrosis and lung fibrosis. Cyclosporine-related drugs are taken orally and largely end up in the liver, where they undergo extensive first-pass hepatic extraction. Since these drugs concentrate in the liver, focusing on liver fibrosis made perfect sense.
The promising results were observed not only in NASH mouse models but also in liver fibrosis induced by other mechanisms in additional models. No matter which approach we took to induce liver fibrosis, we observed quite a profound antifibrotic effect with rencofilstat/CRV431. We also did some toxicology work, and found the drug to be unbelievably clean, so we moved into the clinic.
We chose NASH as our focus because there is a huge unmet need there. NASH affects 20 million people in the United States alone and approximately 4–5% of the global population, in some geographic regions as high as 10–12%. Current treatment involves weight loss, the extent of which can be difficult for patients to achieve. Bariatric surgery is often the only effective weight-loss therapy. No drug has yet been approved for the treatment of NASH. Many drug candidates have stumbled or failed outright.
The scientific community is just now beginning to understand the pathophysiology underlying this common disease. Considering the serious outcomes linked to advancing NASH, the economic and social burden of the disease is enormous. If we are able to bring an effective treatment for NASH to market, we would be doing something that would really help and benefit patients.
RF: As a cyclophilin inhibitor, rencofilstat/CRV431 binds to multiple forms of cyclophilins in the body, which participate in many different biological processes, including cell death, fibrosis, and cancer cell growth and metastasis. Many viruses have also 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/CRV431 displays a variety of therapeutic activities.
For NASH, rencofilstat/CRV431 targets 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. This ability is important, because it is necessary to intervene at multiple steps in the disease process to halt progression and to stimulate repair. In addition, having multiple modes of action within one drug avoids the potential for drug–drug interactions when several different drugs operating by discrete mechanisms of action are used. It is a safer and more efficient approach to alleviate multiple disease pathways with single drug compounds having multiple therapeutic actions.
In addition, 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 development. Finally, maximizing the concentration of drug at its intended site of action maximizes drug efficacy and minimizes the risk of side effects arising from off-target effects in other organs.
RF: In a phase I trial, we tested the safety and tolerability of rencofilstat/CRV431 and again observed a very clean profile in humans — in fact, the placebo group experienced more adverse events than our treatment groups. Next, we conducted a 28-day phase IIa trial in NASH patients, because at the time we had toxicology data from 30-day studies, which limited the trial duration. We observed the same PK profile, and the safety and tolerability were once again incredibly good. It was also very encouraging that, when we looked at important NASH biomarkers, such as ALT, PRO-C3, and many others that provide an indication of liver health, the markers were moving in the right direction.
Taken together, the phase I and IIa results have shown us that safety should not be a concern, and we observed early signs of efficacy in terms antifibrotic activity, which also supports the preclinical work.
Additionally, a member of our research team who is an expert in artificial intelligence (AI) also looked at the impacts of rencofilstat/CRV431 on DNA/RNA, proteins, lipids, metabolites, and so on. He performed a multi-omic analysis looking to uncover signs of efficacy. For example, he investigated the collagen gene regulatory network and noticed certain genes being upregulated or downregulated. And, he noticed that these were often times important to restoring balance for these important collagen genes. We saw similar results when the analysis was repeated on frozen tissue samples from earlier preclinical studies. There was a very consistent, genomic signature that told us that the NASH or a fibrotic phenotype was being transformed back to a more balanced and normal phenotype.
RF: With the phase I and IIa data and the results of the multi-omics analysis, we were able to agree with the FDA on our plans for a larger phase IIb trial. This trial for rencofilstat/CRV431 in NASH will include 336 patients — mostly F3 types — and will begin in Q3 of 2022. It is a one-year trial with once-daily oral dosing. There will be a follow-up period of a month or so, and we hope to have a readout of data six months later. We will perform an initial evaluation once approximately one-third of the participants reach six months to get a sense of how the drug is working.
In addition to that trial, we are collaborating with HepQuant to evaluate its HepQuant SHUNT test, which is based on IV administration of cholate to assess liver function in a highly sensitive fashion, much earlier than is possible with needle biopsies, which are still considered the gold standard. The benefit of this collaboration is that we will get functional readouts in a much shorter timeframe compared with the biopsy study after the phase IIb trial is completed. These data will hopefully supplement the information we will be gathering in that larger phase IIb trial.
Hepion also has another program for rencofilstat/CRV431 in hepatocellular carcinoma (HCC), the most common form of liver cancer. A phase IIa study for rencofilstat/CRV431 in HCC will be initiated in the second half 2022, with a readout in approximately one year.
Unlike most other cancer types over the past decade, the number of HCC cases is increasing, likely because NASH is the biggest contributor to the development of HCC. The other major causes are hepatitis C and alcohol consumption. Globally, over 700,000 people die each year from liver cancer, which is second only to lung cancer among all cancer-related deaths. In most cases, HCC is preceded by significant, long-term damage to liver cells, inflammation, and fibrosis. The chronic injury to the liver leads to many genetic mutations and eventually to transformation of cells and formation of tumors. These various events underscore the importance of halting liver injury and scarring as early and effectively as possible to prevent cancer development.
We have some data suggesting that cyclophilin inhibitors like rencofilstat/CRV431 have an oncologic effect. For instance, we have treated mouse NASH models with well-established HCC liver tumors and observed a 50% reduction in the size and number of tumors. In other preclinical studies in the UK, we demonstrated a significant effect when animals with HCC tumors or fatty livers are given our drug alone or in combination with checkpoint inhibitors. Altogether, these data give us confidence that we will see a positive outcome in the phase II trial of subjects with HCC.
RF: Preclinical cell culture experiments have shown that rencofilstat/CRV431 decreases SARS-CoV-1 production of infectious virus. In addition, in a non-viral, acute lung injury model, rencofilstat/CRV431 attenuated lung inflammation and damage similar to or better than dexamethasone, including reductions in neutrophils and IL-6. These results suggest that, with this dual mode of action, rencofilstat/CRV431 could potentially treat both the viral infection and lung injury in COVID-19 patients, and it may also benefit patients suffering longer-term consequences of COVID-19 infections, including acute respiratory distress syndrome (ARDS).
RF: The AI platform we use is known as AI-POWR. It combines AI, Big Data, and machine learning to decode disease, to develop targeted therapies, and to select patients who will respond to Hepion’s therapies. We are using it to understand the disease in individual NASH patients, because NASH is a very heterogeneous disease. For a patient with well-established and mature fibrosis, for example, you want to promote catabolism to reverse that fibrosis, but other therapeutic approaches might be appropriate in other types of NASH patients.
We are using the AI-POWR platform to help determine when in the disease state it is best to use rencofilstat/CRV431 and what type of patient it is best suited to treat. The platform gives us the potential to facilitate a precision medicine approach to treating NASH through its ability to identify rencofilstat/CRV431 responders and inform the development of biomarkers. As a result, AI-POWR can also be used to fine-tune patient selection for clinical trials or to design clinical studies. We want patients that will respond well so that we have the opportunity to have the largest possible difference response rates between the placebo group and the drug. This may afford payers an opportunity to offer reimbursment for a drug that has the highest likelihood of success in this indication. As a result, we are also using AI as part of our commercial strategy.
Additionally, we are using the AI-POWR platform to identify and evaluate additional potential candidates beyond rencofilstat/CRV431, thus enabling Hepion to expand our footprint in the cyclophilin inhibition therapeutic space and beyond.
RF: There’s a lot more to reveal yet. I know classical pharmacology talks about the “lock and key,” like one molecule binding to a receptor to elicit a certain response, but the more I learn about drugs, the more I realize that that concept is outdated — this whole philosophy needs to be revisited. Even if you take the simple example of aspirin: we now know that aspirin does so many different things —antipyretic; anti-inflammatory; analgesic; it may have an effect on platelets; and people take 81 mg of aspirin per day to possibly protect against heart attacks.
Cyclophilin inhibitors are another example of a small molecule drug that can do many different things. Humans have 17 different types of cyclophilins. Cyclophilins are ubiquitous, found in the endoplasmic reticulum, the cytosol, nuclei, and mitochondria within cells. The pharmacokinetic profile of a drug candidate — whether it targets the liver, brain, or other tissue or organ — will dictate what indication(s) it can be used to treat. Cyclosporins don’t partition all that well into the brain, but they partition to other organs and have real potential to treat many types of diseases.
Given this knowledge, I believe that we have only scratched the surface in terms of what these molecules can do. Their ability to intervene in multiple molecular pathways is particularly attractive for indications that are currently addressed with a large number of different medicines. Cyclophilin inhibitors could help reduce drug–drug interactions and simplify patient treatment regimens, which could lead to higher compliance and better outcomes. Even though these molecules inhibit multiple cyclophilins, they are safe and well tolerated. For all of these reasons, I am still excited about these molecules, even after working with them for over 30 years. We are learning something new about them every day.
RF: I would like to emphasize that the core team involved in the discovery, testing, screening, and AI analysis that left Aurinia in 2014 is still with Hepion today — the entire collective memory of the drug discovery and development work remains within Hepion. This small group has a ton of experience, including the development of a drug — Voclosporin — that has reached the market. We have built on that core group and have a solid team. I think investors should look favorably at a team like the one at Hepion, as we’ve done this before and have extensive experience in this specific field of interest.
Robert Foster, Pharm.D., Ph.D.
Robert Foster, Pharm.D., Ph.D., is a scientist, researcher, former professor, entrepreneur, and founder of four successful biopharma companies. 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 began working on cyclophilin drug development in 1988. Cyclophilins are a family of diverse enzymes that participate in many pathophysiological processes.