CHD1L

MARTINSRIED, Germany I September 16, 2024 I Eisbach Bio GmbH (“Eisbach” or the “Company”), a privately-held clinical-stage biotechnology company pioneering cancer medicines leveraging synthetic lethality, today announced that the first patient has been dosed in Module 1 of the ongoing Phase 1/2 MATCH clinical trial (NCT06525298) investigating the small molecule ALC1 inhibitor EIS-12656 in solid tumors. In this trial, Eisbach seeks to assess the safety, pharmacokinetics, pharmacodynamics and preliminary clinical activity of the allosteric ALC1 inhibitor in the monotherapy setting. The trial, which is being conducted at The University of Texas MD Anderson Cancer Center (MD Anderson), is co-funded with an investment from the Cancer Focus Fund, a unique investment fund established in collaboration with MD Anderson to provide funding and clinical expertise to advance promising cancer therapies. EIS-12656 is a first-in-class, selective, potent, oral and brain-penetrant small molecule inhibitor of the chromatin helicase ALC1 (CHD1L), a key molecular machine involved in DNA damage and genome repair mechanisms. EIS-12656 targets ALC1 through allosteric mechanisms, suppressing the cancer-relevant genome reorganization induced by DNA damage. Eisbach’s preclinical in vivo data with EIS-12656 showed rapid tumor growth inhibition, high bioavailability and excellent tolerability. “This milestone marks Eisbach’s entry into the cancer clinic with a transformative target and unique allosteric approach. ALC1 is a superior, orthogonal target in tumors with impaired DNA damage and repair. Its inhibitor EIS-12656 is the result of our ability to disrupt the function of the powerful machines that reorganize our genome in a very targeted manner,” said Adrian Schomburg, Ph.D., Founder and CEO of Eisbach. “This clinical study will assess the impact of EIS-12656’s ability to hit both genetic and molecular vulnerabilities in our cancer indications, potentially enabling its advancement as a drug that is both efficacious and well-tolerated.” About the Phase 1/2 Clinical Trial The open label study of EIS-12656 will evaluate its safety, tolerability and efficacy in patients with genetically-defined advanced solid tumors. Led by Principal Investigator Timothy A. Yap, M.B.B.S., Ph.D., Vice President, Head of Clinical Development in the Therapeutics Discovery Division and Professor of Investigational Cancer Therapeutics at MD Anderson, the trial includes dose escalation of EIS-12656 monotherapy, followed by dose expansion modules and evaluation in gynecological, pancreatic and prostate cancer patients progressing under PARP inhibitor treatment. Eisbach selected CTI Clinical Trial & Consulting, a global full-service Contract Research Organization, as a strong partner providing regulatory and clinical trial management service for this trial. About Eisbach Eisbach is at the forefront of precision oncology, developing allosteric drugs that selectively disrupt molecular machines vital for tumor genome reorganization. Combining genetic vulnerabilities with its proprietary ALLOS platform, which hits the molecular vulnerability of its cancer targets, Eisbach pioneers first-in-class therapies with fewer side effects. For more information, visit http://www.eisbach.bio and follow us on LinkedIn . SOURCE: Eisbach Bio

The FDA has cleared the investigational new drug (IND) application for EIS-12656, a first-in-class orally bioavailable and blood brain barrier-penetrant allosteric inhibitor of ALC1 (CHD1L), a key molecular machine in DNA repair. EIS-12656 targets homologous recombination repair deficient cancers. Its expected superior safety should facilitate novel combination therapies with and beyond PARP inhibitors in hard to treat cancers. Eisbach Bio expects to start enrolling patients in the second quarter of 2024. MARTINSRIED, Germany, May 6, 2024 /PRNewswire/ -- Eisbach Bio GmbH ("Eisbach" or the "Company"), a privately-held clinical-stage biotechnology company pioneering cancer medicines leveraging synthetic lethality, has announced United States Food and Drug Administration (FDA) clearance of its investigational new drug (IND) application for EIS-12656, a small molecule inhibiting the chromatin helicase ALC1 (CHD1L). EIS-12656 targets ALC1 through allosteric mechanisms, suppressing the cancer-relevant genome reorganization induced by DNA damage. This leads to ALC1 chromatin trapping and cancer cell killing. EIS-12656 impacts tumors deficient in DNA repair pathways. It demonstrated substantial tumor growth inhibition in preclinical models, including in combination with standard-of-care therapies. Its allosteric mechanism of action should afford selectivity compared to related synthetic lethal targets, contributing to the exceptional safety observed in all relevant preclinical models. "EIS-12656 selectively targets tumors with no apparent effects on normal tissues." said Adrian Schomburg, Ph.D., Founder and CEO of Eisbach. "Our clinical study will also explore combination therapies that were hindered by combinatorial toxicity in the past." The discovery of EIS-12656 builds on the pioneering research of Eisbach founder Prof. Andreas Ladurner, whose team discovered that PARP effects in cancer cells are reliant on chromatin remodeling by ALC1. Eisbach built upon this knowledge and designed a first-in-class, once-daily small molecule therapy, directly targeting cancer genome reorganization induced by DNA damage at its source – the PARP-activated helicase ALC1. About the Phase 1/2 Clinical Trial The open label study of EIS-12656 will evaluate its safety, tolerability and efficacy in patients with genetically-defined advanced solid tumors. Led by Principal Investigator Timothy A. Yap, M.B.B.S., Ph.D., Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, the trial includes dose escalation of EIS-12656 monotherapy, followed by dose expansion modules and evaluation in patients progressing under PARP inhibitor treatment. About Eisbach Eisbach is at the forefront of precision oncology, developing allosteric drugs that selectively disrupt molecular machines vital for tumor genome reorganization. Combining genetic vulnerabilities with its proprietary ALLOS platform, which hits the molecular vulnerability of its cancer targets, Eisbach pioneers first-in-class therapies with fewer side effects. For more information, visit and follow us on LinkedIn. Contacts: Eisbach Bio GmbH Adrian Schomburg, CEO +49 89 2153 7900 Jonathan Iorio +49 89 2153 79013 Logo - SOURCE Eisbach Bio

A study on almost four thousand people of African descent has identified a gene that acts as natural defense against HIV by limiting its replication in certain white blood cells. This research paves the way for new treatment strategies and underscores the importance of studying diverse ancestral populations to better address their specific medical needs and global health disparities. A study on almost 4000 people of African descent has identified a gene that acts as natural defense against HIV by limiting its replication in certain white blood cells. An international effort co-led by EPFL, Canada's National Microbiology Laboratory, and Imperial College London, it paves the way for new treatment strategies. "We searched for human genetic variation that associates with spontaneous control of HIV and identified a novel region in the genome that is only variable in populations of African ancestries," says Professor Jacques Fellay at EPFL's School of Life Sciences. "We used a combination of computational and experimental approaches to explore the biological mechanism behind the genetic association and provide evidence that the gene CHD1L acts to limit HIV replication in a subset of white blood cells." HIV is still a problem Despite significant advances in treatment and access to therapy, the human immunodeficiency virus remains a global health challenge with almost 40 million affected individuals, no vaccine and no cure. The virus attacks the person's immune cells (helper T cells, macrophages, and dendritic cells) damaging their ability to mount an immune response. Without treatment, the infected person grows more susceptible to opportunistic infections and cancer, and can develop acquired immunodeficiency syndrome, the well-known AIDS. Although annual HIV infections have been declining because of widespread antiretroviral therapies, the trend has slowed substantially since 2005, and there are now alarming increases in the number of newly infected adults in some regions. HIV and studies on the human genome The way to therapies involves fundamental research, including studies into the relationship between the human genome and the progression of HIV infection, which can reveal possible therapeutic targets. These Genome-Wide Association Studies, or GWAS, analyze the entire genome of a large number of individuals to identify genetic variants associated with a clinical outcome, such as the ability to naturally control viral replication. Measuring HIV replication control: not enough in African populations The degree of viral infection is measured by the virus' "setpoint viral load" (spVL), which refers to the relatively stable level of HIV replication in the body after the initial, acute phase of infection in untreated individuals. A critical determinant of HIV infection progression and transmissibility, spVL is expressed as the number of viral copies per milliliter of plasma. The spVL of HIV varies widely in the infected population, depending on the ability of every individual's immune system to control viral replication without antiretroviral drugs. Although there have been large studies of spVL control in populations of European descent, much less has been done in populations of African ancestries, which are still drastically underrepresented in human genomic studies. This is both a significant problem considering the disproportionate HIV burden in Africa and a missed opportunity given the high genome diversity among people of African descent, which fosters a high probability of genetic discoveries. A key gene for resistance to HIV replication in people of African ancestries To address this disparity, a large international collaboration of scientists and clinicians has now performed large-scale GWAS using data from diverse populations of African ancestries. In total, the scientists analyzed the genomes from 3,879 individuals living with HIV-1. Using computational analysis and fine-mapping techniques, they identified a novel region in the genome that shows a strong association with spVL control. The study was co-led by Jacques Fellay at EPFL, Paul McLaren at the Public Health Agency of Canada's National Microbiology Laboratory, and Manjinder Sandhu at Imperial College London. It is now published in Nature. This region corresponds to a gene known as CHD1L (for "Chromodomain Helicase DNA Binding Protein 1 Like"), which encodes a protein that helps DNA unwind after it has been damaged, allowing it to be repaired. But in this study, the CHD1L gene showed genetic variation specific to populations of African ancestries, and that was linked to the spontaneous control of the most common and virulent type of HIV, called HIV-1. Having identified CHD1L as a potential modulator of HIV-1 infection, the researchers explored the biological mechanism behind the genetic association and determined that CHD1L plays a role in limiting HIV replication in a subset of white blood cells. The discovery of CHD1L's role in limiting HIV replication could lead to improved treatment options for infected individuals. "Our findings provide insights into potential therapeutic targets, which are needed to continue the fight against HIV-1," says Fellay. "In addition, our results underscore the importance of performing genomic studies in diverse ancestral populations to better address their specific medical needs and global health inequities."