Carcinogenesis

Clinical and pre-clinical data generated from collaborations between the Tuebingen University Hospital, researchers from the Mayo Clinic in Rochester (USA) and HepaRegeniX HRX-215 proved to be safe and well tolerated in healthy volunteers, pre-clinical data showed increased regeneration of liver cells HRX-215 to be further developed to usher in a new era in oncological liver surgery and liver transplantation March 14, 2024 -- HepaRegeniX GmbH, a clinical stage company developing novel regenerative therapies for the treatment of acute and chronic liver diseases, today published clinical and preclinical results on its first-in-class MKK4 inhibitor HRX-215 in the prestigious journal Cell. The manuscript, available online here (DOI: 10.1016/j.cell.2024.02.023), describes strongly enhanced liver regeneration and prevention of liver failure by HRX-215 in preclinical model systems and a first-in-human trial showing safety and tolerability. HRX-215 is a small molecule inhibitor of Mitogen-Activated Protein (MAP) Kinase Kinase 4 (MKK4). “The positive results in terms of safety and tolerability confirm our intention to soon offer a drug that has the potential to revolutionize the treatment of severe liver diseases. The data pave the way for further Phase II studies evaluating the efficacy of HRX-215 in humans,” emphasizes Dr. Wolfgang Albrecht, COO of HepaRegeniX. In patients with liver metastases from colorectal cancer, which affect about 1 million people per year worldwide, or with primary liver tumors, complete resection of the liver tumors is the only curative therapeutic approach. However, when the remaining liver volume would be below a certain threshold, patients are at high risk of developing post-hepatectomy liver failure (PHLF), an often lethal complication limiting the surgical treatment of liver cancers. HRX-215 holds promise to make more extensive liver resections possible by safely preventing PHLF. “HRX-215 would not only be an urgently needed treatment option in the surgical removal of liver tumors, but would also be able to help overcome the major problem of organ shortage in the field of liver transplantation,” Prof. Lars Zender, Medical Director at the University Hospital Tuebingen points out the possible applications. Living donor transplants from the smaller left part of a healthy donor's liver would be a solution, as removal poses little health risk for healthy donors. However, this part of the liver is often too small to take over the function of the liver that was removed from the recipient. “Due to the rapid enhancement of liver regeneration mediated by HRX-215, we assume that HRX-215 treatment would enable the safe transplantation of small left liver lobes in normal size adults,” Prof. Zender continues. Before HRX-215 was tested in healthy volunteers in a Phase I study, it was thoroughly investigated in animal models. In particular, Tuebingen collaborated with Prof. Dr. Scott L. Nyberg at the Mayo Clinic in Rochester (USA), an internationally renowned expert in the field of transplantation and regenerative medicine. His team was able to show that treatment with HRX-215 can boost liver regeneration after partial liver removal (hepatectomy) while intact livers are not affected by the drug candidate. Further, HRX-215 was also able to protect hepatocytes from cell death in a model for acute liver injury. In the consecutive first in human trial, conducted by HepaRegeniX, HRX-215 was well tolerated at all doses with no drug-related adverse events being observed. “We are very excited about the results from this collaborative effort that have now resulted in a publication in Cell. I would like to congratulate the three teams for even making the cover of this leading scientific journal. MKK4 inhibition has proven to be an ideal mechanism of action for inducing liver regeneration because it depends on the activation of stress pathways and has an excellent safety profile even after long-term treatment without the risk of tumorigenesis. Our successfully completed Phase I trial further underlines the enormous potential this drug candidate has for treating acute and chronic liver damage in patients,” concludes Elias Papatheodorou, Chairman of HepaRegeniX’ Board of Directors. Since 2017, HepaRegeniX has successfully discovered and developed several drug candidates for the treatment of acute and chronic liver diseases based on a novel proprietary molecular target Mitogen-Activated Protein (MAP) Kinase Kinase 4 (MKK4). The first MKK4 inhibitor HRX-215 recently completed Phase 1 clinical testing. MKK4 is a key regulator of liver regeneration and suppression of MKK4 unlocks the regenerative capacity of hepatocytes even in severely diseased livers. This new and unique therapeutic concept was discovered by Prof. Lars Zender and his research group at the University Hospital Tuebingen, Germany. Investors in HepaRegeniX include the Boehringer Ingelheim Venture Fund (BIVF), Novo Holdings A/S, Coparion, High-Tech Gruenderfonds and Ascenion GmbH. The content above comes from the network. if any infringement, please contact us to modify.

GENT, Belgium & AMSTERDAM--( BUSINESS WIRE )--Fujirebio Europe and Self-screen B.V. today announced an expansion of their commercial collaboration with the distribution of the PreCursor-M AnoGYN methylation-specific molecular assay from Self-screen B.V. The test is intended for the detection of promoter hypermethylation of the genes ASCL1 and ZNF582 and is used to test the methylations status of anal specimens for research use only (RUO). It complements Fujirebio's HPV-associated molecular test portfolio. “The Human Papilloma Virus (HPV) test panel of Fujirebio Europe continues to grow with effective and accurate testing solutions, and we are pleased to add this new RUO methylation-based assay to our molecular testing toolbox,” says Christiaan De Wilde, CEO at Fujirebio Europe “With its unmatched accuracy and reliability, this innovative PreCursor-M AnoGYN assay represents a significant advancement for research studies in the field of anal cancer prevention. We wanted our customers to have access to this valuable research tool as soon as possible, ultimately catalyzing advancements in elimination of HPV-related diseases.” “ We are very happy with the continued partnership with Fujirebio in the distribution of Self-screen’s HPV tests and methylation tests, ” says Michelle Meijer, Chief Commercial Officer at Self-screen B.V. “ The PreCursor-M AnoGYN extends our offering of HPV products into the field of anal cancer. Also in this HPV-related cancer, methylation appears to be promising for future use as an accurate biomarker for objective risk stratification of anal lesions. The growing medical need for better and more supportive diagnostics tools for HPV related cancers such as anal cancer drove us to the development of the PreCursor-M AnoGYN RUO assay which is now available through Fujirebio.” About host cell DNA methylation and anal cancer Incidence of anal cancer is increasing worldwide. The majority of anal cancers are squamous cell carcinoma (SCC) and are, like cervical cancer, mainly caused by a persistent high-risk HPV infection and preceded by high-grade squamous intraepithelial lesion (HSIL). In analogy with cervical cancer screening, the screening and treatment of HSIL to prevent anal cancer in high-risk groups are under debate. Host cell DNA methylation is an epigenetic hallmark of HPV-induced carcinogenesis. The PreCursor-M AnoGYN assay is a robust and reliable tool to further investigate host cell DNA methylation in anal carcinogenesis and study its potential as a valuable biomarker for the detection of anal (pre-)cancer. 1-4 Please contact Fujirebio for further information about the local availability of the test. About Self-screen B.V. Self-screen B.V. is a company highly experienced in translational HPV related research, assay development and commercialization of In Vitro Diagnostics (IVD). Our dedication is towards the development and clinical application of molecular assays for the early detection of anogenital and head & neck (pre)cancers, to the benefit of patients and health care programs around the world. Our main focus is on cervical (pre)cancer screening and prevention. Self-screen markets two clinically validated CE-IVD assays. The HPV-Risk-Assay and the PreCursor-M+ Methylation Test, for screening and triage respectively, to support full molecular cervical screening and to assist the clinician in management of women with high-grade CIN. Recently PreCursor-M AnoGYN RUO is added. For more information, visit www.self-screen.nl . About Fujirebio Fujirebio is a global leader in the field of high-quality IVD testing. We have more than 50 years’ accumulated experience in the conception, development, production, and worldwide commercialization of robust IVD products. Fujirebio has a long-lasting tradition for developing high-quality routine and truly novel biomarkers. Our IVD product lines span the range from specialized manual and automated testing to fully automated routine clinical laboratory testing solutions covering a variety of disease states. Our global presence includes offices in the United States, Latin America, Europe and Asia as well as a vast international distribution network. For more information, visit www.fujirebio.com . References: van der Zee R.P. , et al. Host cell deoxyribonucleic acid methylation markers for the detection of high-grade anal intraepithelial neoplasia and anal cancer. Clin. Infect. Dis., 68 (7); 1110-1117, 2019 van der Zee R.P. , et al. Cancer risk stratification of anal intraepithelial neoplasia in human immunodeficiency virus-positive men by validated methylation markers associated with progression to cancer. Clin. Infect. Dis., 72 (12); 2154-2163, 2021 van der Zee R.P. , et al. DNA methylation markers have universal prognostic value for anal cancer risk in HIV-negative and HIV-positive individuals. Mol. Oncol., 15 (11); 3024-3036, 2021, 2021 Rozemeijer K, et al . Analytical validation and diagnostic performance of the ASCL1 / ZNF582 methylation test for detection of high-grade anal intraepithelial neoplasia and anal cancer. Tumour Virus Res. 30;17:200275, 2023

Researchers found that PD-1-enhanced DNA vaccination can induce sustained virus-specific CD8+ T cell immunity in an AIDS monkey model. The vaccinated monkeys remained free of AIDS for six years and achieved virologic control without the need for combination antiretroviral therapy (cART), a treatment used to suppress viral replication in individuals living with human immunodeficiency virus (HIV). The study also found that polyfunctional and broadly reactive effector-memory virus-specific T cells were maintained in the protected experimental macaques for over six years. The findings provide supporting evidence that the PD-1-enhanced DNA vaccine strategy holds promise as a third-generation DNA vaccine for AIDS prevention and immunotherapy. Researchers at the AIDS Institute, Department of Microbiology, School of Clinical Medicine, and the State Key Laboratory of Emerging Infectious Diseases, LKS Faculty of Medicine of the University of Hong Kong (HKUMed), in collaboration with HKU-Shenzhen Hospital, Foshan University and The Third People's Hospital of Shenzhen, found that PD-1-enhanced DNA vaccination can induce sustained virus-specific CD8+ T cell immunity in an AIDS monkey model. The vaccinated monkeys remained free of AIDS for six years and achieved virologic control without the need for combination antiretroviral therapy (cART), a treatment used to suppress viral replication in individuals living with human immunodeficiency virus (HIV). The study also found that polyfunctional and broadly reactive effector-memory virus-specific T cells were maintained in the protected experimental macaques for over six years. The findings provide supporting evidence that the PD-1-enhanced DNA vaccine strategy holds promise as a third-generation DNA vaccine for AIDS prevention and immunotherapy. The peer-reviewed study was published in the journal Microbiology Spectrum, by The American Society for Microbiology. Background Using cART for both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) contributes efficiently to reducing AIDS-related deaths and HIV-1 transmission cases. Despite the effectiveness of cART, HIV-1 can persist in latent reservoirs. This has made it challenging to achieve complete or sustained cART-free virologic control of HIV-1 infection for the past 40 years since the discovery of AIDS and its causative agent HIV-1 in the early 1980s. Moreover, the extensive HIV-1 genetic diversity facilitates the formation of mutational escape variants that resist cART drugs, resulting in the clinical failure of viral control. The huge number of viral variants also hampers AIDS vaccine development. Identifying novel vaccination strategies, including the induction of robust cross-reactive T cell responses, will enhance the arsenal against HIV/ AIDS epidemic. Research methods and findings The researchers developed a vaccine technology known as the programmed death-1 (PD-1)-enhanced DNA vaccine strategy, which involves using a DNA vector to encode specific antigens fused with the soluble domain of PD-1 protein. Our previous murine studies found that this strategy allows more efficient antigen delivery targeting to professional antigen-presenting cells, called dendritic cells. It results in the superiority of immunogenicity and the protective efficacy against both viral infection and tumorigenesis over conventional vaccines. Notably, PD-1-enhanced DNA vaccines elicit strong CD8+ T cell responses. In 2021, the researchers reported the findings of a rhesus monkey study, which evaluated the potential of a PD-1-enhanced DNA vaccine against the simian -- human immunodeficiency virus (SHIV). The rhesus monkeys were vaccinated with a DNA vaccine, pRhPD1-p27, designed based on the PD-1-enhanced DNA vaccine strategy. The vaccine resulted in sustained virological control against pathogenic SHIVSF162P3CN challenge, which was mediated by a strong polyfunctional vaccine-induced effector-memory CD8+ T cell response. In a group of four pRhPD1-p27-vaccinated macaques, an aviremic state (absence of detectable virus in the blood) was maintained for two years, indicating that potential cART-free virologic control could be achievable with the PD-1-enhanced DNA vaccine. The recent follow-up study demonstrated extended cART-free virologic control for over six years. Efficient strategies for HIV-1 cART-free virologic control are crucial for ending the AIDS epidemic. 'Our innovative PD-1-enhanced DNA vaccine was effective not only in inducing polyfunctional effector-memory CD8+ T cells for AIDS prevention in rhesus monkeys, but also in sustaining cART-free virologic control for over six years,' remarked Professor Chen Zhiwei, Director of the AIDS Institute and Chair Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, who led the study. 'The encouraging outcomes validate the continuation of ongoing clinical trials investigating the potential of the PD-1-enhanced DNA vaccine for achieving HIV-1 cART-free virologic control. Hopefully, the vaccine can be employed independently or in conjunction with other biomedical interventions for individuals living with the virus in the future.' If this efficacy can be replicated in humans, a therapeutic vaccine for cART-free HIV-1 control will be on the horizon. Currently, a Phase I clinical trial, in which the HKUMed team is collaborating with The Third People's Hospital of Shenzhen to test whether the non-human primate data can be replicated in humans, is underway. The report of the trial results is expected to be available in the second quarter this year.