HNF1A

- 850 cancer cell lines screened in Broad Institute’s PRISM lab - - Rencofilstat active on 220 cancer cell lines spanning 86% of cancer types – EDISON, N.J., Sept. 21, 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 results from a study with in which the anti-cancer activity of Hepion’s lead drug candidate, rencofilstat, was tested in a high through-put screen on 850 cancer cell lines spanning 28 types of cancer at the PRISM lab at the Broad Institute of MIT and Harvard. The Broad Institute is one of the few institutions in the world with such an expansive cancer cell line screening program. By utilizing advanced technologies and global collaborations, the Broad Institute has become a global leader in understanding cancer and other human diseases and helping to develop effective therapeutics. Rencofilstat was administered at eight concentrations to each cancer cell line in culture for 5 days, followed by measurement of surviving cells to determine how effectively the drug candidate killed or suppressed proliferation of the cancer cells. Defining “anti-cancer responsiveness” as 50% or greater reduction in viability following treatment, 26% of all tested cancer cell lines (220/850) spanning 86% of cancer cell types (24/28) were responsive to rencofilstat. Some of the rencofilstat-sensitive cell lines were HCC cells, which further supports Hepion’s plans for a clinical trial in this indication. Furthermore, the reductions in viability in responsive cells occurred at drug concentrations similar to those observed in individuals participating in Hepion’s NASH clinical trials. Thus, administration of rencofilstat to cancer patients with the standard regimen of once-daily oral dosing may be efficacious for those with responsive types of cancer. The screening study also integrated additional information collected by the Broad Institute about the cancer cell lines, such as gene mutations, gene expression, and protein and metabolic profiles, to provide insights into rencofilstat’s mechanisms of action and identify biomarkers associated with its anti-cancer activity. Some of the markers uncovered by these analyses were related to familiar rencofilstat mechanisms, whereas others pointed to new processes. Genes known to be mutated in HCC or other types of cancer, including ATM, PTPRB, HNF1A, NOTCH1, ALK, TP63, IDH2 and MAP3K, were among the many genes identified to possibly influence the sensitivity of cells to rencofilstat. “The results from this high-throughput screen provide valuable insights into how rencofilstat directly arrests cancer cells and adds to the discoveries being made from our in-house research. These direct effects on cancer cell lines may be an important part of rencofilstat’s anti-cancer activity,” remarked Daren Ure, Hepion’s Chief Scientific Officer. “We have already observed that rencofilstat fights cancer through other indirect mechanisms, and in particular by changing the tissue environment in which the tumor grows. For example, we previously found that rencofilstat altered the immune cell composition of liver tumors in mice, suggesting an enhanced immune attack on the tumors. Directly targeting cancer cells while simultaneously modulating their microenvironment provides additional weapons for attacking cancer. Our ongoing research aims to further define the characteristics of liver cancer and other types of cancer that make them most susceptible to rencofilstat, and to thereby help identify who may benefit most from treatment.” About Hepion Pharmaceuticals The Company's lead drug candidate, rencofilstat, is a potent inhibitor of cyclophilins, which are involved in many disease processes. Rencofilstat has been shown to reduce liver fibrosis and hepatocellular carcinoma tumor burden in experimental disease models and is currently in Phase 2 clinical development for the treatment of NASH. In November 2021, the U.S. Food and Drug Administration (“FDA”) granted Fast Track designation for rencofilstat for the treatment of NASH. That was followed in June 2022 by the FDA’s granting of Orphan Drug designation to rencofilstat for the treatment of HCC. Hepion has created a proprietary Artificial Intelligence deep machine learning (“AI/ML”) platform designed to better understand disease processes and identify patients that are rencofilstat responders. This AI/ML has the potential to shorten development timelines and increase the observable differences between placebo and treatment groups. In addition, Hepion’s AI/ML can be used to drive its ongoing NASH and HCC clinical development programs and identify other potential therapeutic indications for cyclophilin inhibition with rencofilstat. Forward-Looking Statements Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimated,” and “intend,” among others. These forward-looking statements are based on Hepion Pharmaceuticals’ current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, substantial competition; our ability to continue as a going concern; our need for additional financing; uncertainties of patent protection and litigation; risks associated with delays, increased costs and funding shortages caused by the COVID-19 pandemic; uncertainties with respect to lengthy and expensive clinical trials, that results of earlier studies and trials may not be predictive of future trial results; uncertainties of government or third party payer reimbursement; limited sales and marketing efforts and dependence upon third parties; and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. As with any drug candidates under development, there are significant risks in the development, regulatory approval, and commercialization of new products. There are no guarantees that future clinical trials discussed in this press release will be completed or successful, or that any product will receive regulatory approval for any indication or prove to be commercially successful. Hepion Pharmaceuticals does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in Hepion Pharmaceuticals’ Form 10-K for the year ended December 31, 2022, and other periodic reports filed with the Securities and Exchange Commission. For further information, please contact: Stephen KilmerHepion Pharmaceuticals Investor RelationsDirect: (646) 274-3580skilmer@hepionpharma.com

The constant evolution of new COVID-19 variants makes it critical for clinicians to have multiple therapies in their arsenal for treating drug-resistant infections. Researchers have now discovered that a new class of oral drugs that acts directly on human cells can inhibit a diverse range of pathogenic SARS-CoV-2 strains. The constant evolution of new COVID-19 variants makes it critical for clinicians to have multiple therapies in their arsenal for treating drug-resistant infections. Researchers have now discovered that a new class of oral drugs that acts directly on human cells can inhibit a diverse range of pathogenic SARS-CoV-2 strains. In their newly published study, the team found a novel mechanism through which the gene that expresses angiotensin converting enzyme-2 (ACE-2) -- the cellular receptor to which SARS-CoV-2 binds so that it can enter and infect the cell -- is turned on. They also found that a class of oral drugs currently in human clinical trials can block this pathway and potentially be a therapeutic for all SARS-CoV-2 variants, as well as any newly emerging SARS-like viruses. The team published its findings in Nature Genetics on March 8.. "Because of drug-resistant variants, we're down to only one drug, Paxlovid, as far as our oral options," says Craig Wilen, MD, PhD, associate professor of laboratory medicine and of immunobiology, and a member of Yale Cancer Center. "Targeting these master regulatory complexes complements existing approaches and fills a need for a new drug class that can be exploited to help combat drug resistance and infection." Wilen and Cigall Kadoch, PhD, of Dana-Farber Cancer Institute, were co-senior authors of the study. Researchers Identify mSWI/SNF Complexes and as Potential Anti-Viral Targets In a previous study published in 2021, Wilen's team at Yale performed genetic screening to identify host factors that are essential for SARS-CoV-2 infection. One of the key players was the mammalian switch/sucrose non-fermentable (mSWI/SNF, also called BAF) chromatin remodeling complex, a group of over a dozen very conserved proteins that allow certain genes to turn on. "At that point, I'd never heard of it in the setting of virus infection, and we couldn't understand why it was important for coronaviruses," says Wilen. Thus, the group teamed up with experts on this complex, the Kadoch Lab at the Dana-Farber Cancer Institute and Harvard Medical School to find out how the protein complex acts to make cells susceptible to infection and if newly emerging drugs against these complexes could stunt viral infection. At the time they embarked on their collaborative work, the U.S. Food and Drug Administration had authorized six monoclonal antibody treatments for emergency use, yet none of these treatments work against the newest Omicron variants. This leaves clinicians with remdesivir, which can only be administered through an IV, limiting its use; molnupiravir, an oral drug that works similarly to remdesivir but only has 30 percent efficacy; and Paxlovid, an oral antiviral that works through inhibiting the viral protease. Paxlovid, Wilen says, is the mainstay of current treatment. "It's a great drug that works well, but there has been some emerging drug resistance to it," he says. "And currently, that is the only drug in our toolbox that we can give as an oral form." The dwindling of effective treatments further highlights the critical need for a new class of drugs to add to the toolbox, and ideally, ones that are less susceptible to quick-acting resistance mechanisms. Blocking mSWI/SNF Protects Cells Against SARS-CoV-2 First, the team discovered that disrupting mSWI/SNF complexes prevented viral entry into human cells. Because mSWI/SNF is known to regulate genes turning on and off, they then hypothesized that it might also play a role in activating the ACE-2 receptor. Next, they uncovered its mechanism: mSWI/SNF binds to another protein called HNF1A, a transcription factor, which directs it to the gene that encodes ACE-2. Upon disrupting mSWI/SNF complexes, the cell could no longer make ACE-2 and became resistant to infection by any virus that uses that receptor. This includes many coronaviruses. Small molecule inhibitors that target mSWI/SNF have already been developed by Kadoch-founded Foghorn Therapeutics and are in phase I clinical trials as a therapeutic for several cancers. Wilen and Kadoch found that this class of drugs was effective against multiple variants of SARS-CoV-2 -- including a remdesivir-resistant strain isolated from a Yale patient -- without any adverse effects on the cell. "This is proof of principle that this can be a really important first- or second-line tool to combat drug resistance," says Wilen. "Further, this speaks to the wide, multi-disease potential for pharmacologic modulation of chromatin remodeling complexes," says Kadoch. "These molecular machines sit at the top of the pyramid in governing gene expression programs that go awry in many different human diseases -- we are just at the tip of the iceberg in identifying and exploring their utility." Wilen believes the drugs in these clinical trials can potentially be repurposed to inhibit both current and future coronaviruses. Furthermore, Wilen and Kadoch hope the work can provide insight into why certain people and specific cell types may be more susceptible to coronavirus than others. "Future work is needed to look at the underlying biology of why some people are asymptomatic while others experience severe infection and death," Wilen says. COVID-19 will not be the last severe viral outbreak. Wilen's lab studies coronaviruses circulating in wild bats, which he believes pose the highest risk for infecting humans and causing the next pandemic. Many of these viruses use ACE-2 as a receptor, which means that this new study may hold the key to slowing or stopping the next outbreak. "We're going to have another pandemic, whether it's in a few years or a decade. And we're underprepared for it," he says. "The best way to prepare is to have as many vaccines and drugs as possible ready to go so that we can combat the outbreak early with maximum effectiveness."

An international team of researchers have discovered a new genetic variant that is responsible for close to 7% of all cases of diabetes in Greenland. People with this form of diabetes, caused by the high-impact genetic variant, may require special treatment, which will be possible through improved genetic screening of patients. Not all diabetes is the same, and it goes well beyond the two main classifications, type 1 and type 2. Monogenic diabetes refers to forms of diabetes caused by single genetic variations. Maturity-onset diabetes of the young (MODY) is the most common clinical subdivision of monogenic diabetes, with diabetes typically arising in young adulthood. Now, an international team of researchers have discovered a new variant of the HNF1A gene, which can cause MODY that accounts for almost seven percent of all cases of diabetes in Greenland and is found nowhere else in the world. "We were excited to make this discovery of a new genetic variant that is responsible for close to seven percent all cases of diabetes in Greenland. Discoveries like these, which was made possible thanks to a generous collaboration with the Greenlandic people, help us better understand the complexity of diabetes" says Professor Torben Hansen from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen. He led the research together with Professors Anders Albrechtsen and Ida Moltke from the Department of Biology at the University of Copenhagen. Potential for precision medicine People with HNF1A-MODY are often misdiagnosed with either type 1 or type 2 diabetes and given medication that is not effective. Instead, HNF1A-MODY is most effectively treated with tablet therapy with sulphonylurea, which is rarely used today in the treatment of type 2 diabetes. Therefore, researchers are hopeful that this discovery will pave the way for precision treatment in Greenland. As monogenic diabetes is inherited, genetic tests can reveal if other family members also have the same type of diabetes. "This discovery is good news for the treatment of diabetes in Greenland, because most people with MODY can be treated with a simple and cheap tablet treatment and avoid insulin and other more complex forms of diabetes treatment. Therefore, we now offer genetic testing for MODY to all our patients with diabetes, and when we find people with HNF1A-MODY, we systematically offer that family members are also tested," says senior physician and professor Marit Eika Jørgensen at the Steno Diabetes Center Greenland. Marit Eika Jørgensen coordinated the research in Greenland, which involved more than 4,000 Greenlanders. Monogenic diabetes more common in Greenland than in Western populations Together with a previously described high-impact variant TBC1D4 variant, close to 1 in 5 Greenlanders with diabetes are carriers of common high-impact variants. Monogenic diabetes is, therefore, far more frequent in Greenland than in Western populations, where monogenic diabetes is estimated to account for only around 1 in 50 cases of diabetes. "This discovery clearly demonstrates how common diseases are much more complex than we previously thought. Thanks to the breakthroughs in genetic research and data science capabilities, many people around the world may benefit from new personalized medicine approaches that take ancestral, genetic, and environmental backgrounds into account," says PhD Student Anne Cathrine Baun Thuesen from CBMR, who was co-first author together with Frederik Filip Stæger from the Department of Biology at the University of Copenhagen. This research is a collaboration between researchers at the University of Copenhagen, University of Greenland, Steno Diabetes Center Greenland, Steno Diabetes Center Copenhagen, the University of Bergen, Haukeland University Hospital Bergen, Max Planck Institute for Metabolism Research, Helmholtz Zentrum München, University of Southern Denmark, TUM School of Medicine Münich, and the Western Norway University of Applied Sciences.