GPVI

In a comparative study, researchers describe how two notable pathogens -- Escherichia coli and Acinetobacter baumannii -- employ distinctly different tools to fend off antibiotic attack by two different drugs. Antimicrobial resistance is a story of constantly moving parts and players. With every new or tweaked antibiotic or antimicrobial drug, the targeted pathogens begin the evolutionary dance of acquiring resistance, prompting researchers to constantly develop workarounds or entirely new classes of medicine. Understanding the underlying mechanisms of acquired antimicrobial resistance is critical to the fight, a case of knowing one's enemy. In a new paper published March 2, 2024 in npj Antimicrobials and Resistance, part of the Nature Portfolio, researchers at Sanford Burnham Prebys, working with Roche Pharma Research and Early Development, describe how two notable pathogens -- Escherichia coli and Acinetobacter baumannii -- employ distinctly different tools to fend off antibiotic attack. "This work was conceived as a comparative study of the mechanisms and dynamics of resistance acquisition for two drugs and two bugs," said senior author Andrei L. Osterman, Ph.D., at Sanford Burnham Prebys. "Comparing mutational landscapes triggered by the same drug in two distinct bugs allows us to deduce both shared and unique evolutionary trajectories toward resistance. A comparison of two drugs in the same bug reveals shared and unique mechanistic features of fundamental and translational importance, from drug discovery to rational optimization of treatment regimens." Both pathogens studied are gram-negative bacteria with shared characteristics, but also notable differences. For the most part, E. coli is a bacterium routinely found in the guts of humans and animals, where it resides with no ill effect. Some strains, however, do cause harm, everything from mild gastroenterological distress to urinary tract infections, respiratory illness and pneumonia. Acinetobacter baumannii is more problematic, particularly in clinical settings where it can cause severe infections, some life-threatening. Both bacteria have developed resistance to most current antibiotic treatments. In their paper, Osterman and colleagues combined experimental evolution in a continuous culturing device (morbidostat) with whole genome sequencing of evolving cultures to track how E. coli and A. baumannii acquired drug resistance against a pair of antibiotics that inhibit DNA gyrase, an essential enzyme in bacteria. Inhibiting the enzyme disrupts DNA synthesis and, subsequently, causes the bacteria to die. One antibiotic -- ciprofloxacin -- has been in active clinical use since 1987; the other -- GP6 -- is experimental. The researchers found that pathogenic bacteria with acquired resistance to ciprofloxacin remained susceptible to effective antimicrobial treatment by GP6 drug. However, the opposite was not true: evolution of resistance to GP6 also triggered resistance to ciprofloxacin. These findings underscored that E. coli and A. baumannii employ shared and unique mechanisms to acquire resistance to these two types of drugs. "Bacteria acquire resistance as a result of random mutational events that happen in the DNA replication as uncorrected 'typos'," said Osterman. "These spontaneously emerge in a handful of drug-resistant variants/strains out of godzillions of neutral mutations) under selective pressure." (A godzillion is a descriptive term, not a precise unit of measurement. It refers to a number of enormous size. In this case a number ranging between 108 to 109 neutral mutations.) These harmful mutations may underlie several types of resistance mechanisms, including modifying the protein targets of a given drug, the ability of bacterial cells to expel compounds (drugs) before they cause harm (efflux) and special bacterial enzymes that inactivate active drug compounds. Osterman said the work advances progress toward developing "resistibility profiles" of established and novel antimicrobial drugs, which would help set forth "boundaries for possible combinational treatment, including clinically relevant multidrug resistant strains. Our acquired knowledge provides crucial guidelines for all these translational activities." The findings are not limited to E. coli and A. baumannii. They have potential to at least partially predict resistance drivers across other closely related species posing significant health risks, including Pseudomonas, Salmonella and Klebsiella spp. all difficult-to-treat bacterial pathogens linked to serious and sometimes deadly infections. Additional authors on the study include Semen A. Leyn, James E. Kent, Jaime E. Zlamal and Marinela L. Elane, all at Sanford Burnham Prebys; and Maarten Vercruysse, Rocha Pharma. The study was supported by F. Hoffmann-La Roche Ltd and the National Institute of Allergy and Infectious Diseases (grant 5R01AI167977). The study's DOI is 10.1038/s44259-024-00021-y

PARIS--(BUSINESS WIRE)-- September 7th, 2023, the University of Birmingham and Acticor Biotech (Paris:ALACT) announce the full regulatory approval of LIBERATE clinical study. In 2021, the University of Birmingham and Acticor Biotech signed a partnership agreement to evaluate glenzocimab efficacy in myocardial infarction in a new clinical trial called LIBERATE. The University has received full regulatory approvals to initiate the study. This new clinical trial is based on a long-standing collaboration between Acticor Biotech and the University of Birmingham. The publication in August of a scientific paper from Dr Mark Thomas entitled: “Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy “ (link to the publication) in the Journal of Thrombosis and Haemostasis, reinforced the mode of action of glenzocimab and its major role as an antithrombotic drug. The randomised, double-blind Phase 2b LIBERATE study will recruit more than 200 patients suffering from a ST-elevation myocardial infarction (STEMI) and planned for a percutaneous coronary intervention. The study aims to assess the safety and the efficacy of glenzocimab 1000 mg versus placebo to reduce the myocardial infarct size at Day 90 post-treatment. The trial will be conducted in two acute care hospitals in the UK: the Queen Elizabeth Hospital, Birmingham and the Northern General Hospital, Sheffield. Patient recruitment is expected to start by the end of 2023. Doctor Mark Thomas, Associate Professor of Cardiology at the University of Birmingham and Honorary Consultant Cardiologist, who designed the trial and led its development, said: “Our recent studies of glenzocimab at the University of Birmingham have just been published – these explain the cellular mechanisms for why it is highly effective at reducing “blood stickiness”, particularly when combined with existing medications. We are very pleased to receive regulatory approval to launch the LIBERATE clinical trial to investigate whether glenzocimab can reduce the type of blood clotting that causes heart damage during heart attacks. This exciting collaboration with Acticor has the potential to benefit our patients in Birmingham and Sheffield, and across the world.” Professor Jon Townend, Consultant Cardiologist at University Hospitals Birmingham, Honorary Professor of Cardiology in the Institute of Cardiovascular Sciences at the University of Birmingham, and Chief Investigator of the trial said: “This new drug looks extremely promising and we are excited to be within sight of beginning recruitment for this important trial” Yannick Pletan, Chief Medical Officer, and General Manager of Acticor Biotech declared: “Glenzocimab has already delivered very promising results in the treatment of acute ischemic stroke and we hope to confirm its therapeutics potential in other cardiovascular emergency indications. LIBERATE phase 2b study extends glenzocimab development programme to myocardial infarction. We are delighted to collaborate with all the teams involved, the University of Birmingham particularly, sponsor of this study, to extend the therapeutic field of glenzocimab.” ENDS Notes to editor: The University of Birmingham is ranked amongst the world’s top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 6,500 international students from over 150 countries. The University of Birmingham is a member of Birmingham Health Partners (BHP), a strategic alliance which transcends organisational boundaries to rapidly translate healthcare research findings into new diagnostics, drugs and devices for patients. Birmingham Health Partners is a strategic alliance between five organisations who collaborate to bring healthcare innovations through to clinical application: University of Birmingham University Hospitals Birmingham NHS Foundation Trust Birmingham Women's and Children's Hospitals NHS Foundation Trust Sandwell and West Birmingham Hospitals NHS Trust West Midlands Academic Health Science Network About ACTICOR BIOTECH Acticor Biotech is a clinical stage biopharmaceutical company, a spin-off from INSERM (the French National Institute of Health and Medical Research), which is aiming to develop an innovative treatment for cardiovascular emergencies, including ischemic stroke. Acticor Biotech is developing glenzocimab (ACT017), a humanized monoclonal antibody (mAb) fragment directed against a novel target of major interest, platelet glycoprotein VI (GPVI). Glenzocimab inhibits platelet binding to the thrombus without affecting physiological hemostasis, thereby limiting the bleeding risk, particularly in the brain. The positive results from its Phase 1b/2a study, ACTIMIS, confirmed the safety pro showed a reduction in mortality and intracerebral hemorrhage in the glenzocimab-treated group in patients with stroke. The efficacy of glenzocimab is now being evaluated in ACTISAVE, an international Phase 2/3 study. In July 2022, Acticor Biotech was granted "PRIME" status by the European Medicines Agency (EMA) for glenzocimab in the treatment of stroke. This designation will allow the company to strengthen its interactions and obtain early dialogues with regulatory authorities. Acticor Biotech is supported by a panel of European and international investors (Karista, Go Capital, Newton Biocapital, CMS Medical Venture Investment (HK) Limited, A&B (HK) Limited, Mirae Asset Capital, Anaxago, Primer Capital, Mediolanum farmaceutici and the Armesa foundation). Acticor Biotech is listed on Euronext Growth Paris since November 2021 (ISIN: FR0014005OJ5 – ALACT). For more information, visit: Disclaimer This press release contains certain forward-looking statements concerning Acticor Biotech and its business. Such forward-looking statements are based on assumptions that Acticor Biotech considers to be reasonable. However, there can be no assurance that such forward-looking statements will be verified, which statements are subject to numerous risks, including the risks set forth in the Document de référence registration document as approved by the Autorité des marchés financiers under number R. 22-011 on 26 April 2022 and to the development of economic conditions, financial markets and the markets in which Acticor Biotech operates. The forward-looking statements contained in this press release are also subject to risks not yet known to Acticor Biotech or not currently considered material by Acticor Biotech. The occurrence of all or part of such risks could cause actual results, financial conditions, performance or achievements of Acticor Biotech to be materially different from such forward-looking statements.

Enrollment of the 200th patient in the ACTISAVE study Initiation of patient enrollment in the GREEN Phase 2/3 study in stroke Update on the clinical evaluation of glenzocimab in stroke and myocardial infarction PARIS--(BUSINESS WIRE)-- Acticor Biotech (ISIN: FR0014005OJ5 - ALACT), a clinical-stage biotechnology company focused on the development of innovative drugs for the treatment of cardiovascular emergencies, in particular stroke, today provides an update on the progress of its clinical programs with glenzocimab, its lead drug candidate. Gilles AVENARD, Chief Executive Officer and co-founder of Acticor Biotech, said: "The beginning of this year is an opportunity to review the progress of our clinical program portfolio, which has reached crucial milestones since our IPO a little over a year ago. Our clinical and regulatory development teams have done a remarkable job, particularly in discussions with the European regulatory authorities (EMA) for our Phase 2/3 study ACTISAVE, in order to advance the preparation of a marketing authorization application for glenzocimab in stroke. We have fully met our patient enrollment goals in 2022 and are involving new countries and hospitals in 2023. We are proud that the enrollment of patients in the Phase 2/3 GREEN study, promoted by the AP-HP in the framework of the RHU BOOSTER, has started. We look forward to continuing the clinical development of glenzocimab in the treatment of myocardial infarction in partnership with the University of Birmingham (UK). We will keep up our efforts to provide a therapeutic solution to this unmet medical need in cardiovascular emergencies.” 1) ACTISAVE: Phase 2/3 clinical study in stroke Study design and regulatory discussions ACTISAVE (NCT05070260) is a multinational, adaptive, multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2/3 study evaluating the safety and efficacy of a single dose of glenzocimab used in combination with standard of care (thrombolysis +/- thrombectomy) for acute ischemic stroke. The study is being conducted in 7 European countries, UK, Israel, and the USA. The European Medicines Agency (EMA) approved the adaptive design strategy and validated the choice of a dual primary endpoint: an ordinal endpoint of the difference between the Modified Rankin Scale (mRS)1 and a binary endpoint of the percentage of patients with severe disability or death, i.e. an mRS score of 4-6. The recognition of this pivotal study design supports a future application for marketing authorization for glenzocimab in stroke in Europe. In the context of the "PRIME" status received in July 2022, a program aimed at optimizing the development plan to speed up patient access to the drug candidate, the company is continuing its interactions with the EMA. In the United States, discussions are underway with the American regulatory agency (FDA) to set up a Type C meeting to validate the design and statistical analysis of the study in support of a future Biologic License Application (BLA) in the United States. An amendment to the study protocol allowing the use of the two recognized thrombolytic agents in stroke management, tenecteplase (TNK) and alteplase, was submitted to the FDA in November 2022, and is awaiting approval by the Ethics Review Board (IRB). Two patients have been enrolled to date. This amendment should accelerate enrollment, given the massive use of TNK in U.S. hospitals. Number of patients recruited to date: 203 patients. Next clinical step: an initial futility analysis is planned when 100 patients will be enrolled with thrombolysis + thrombectomy, treated and followed for 90 days to confirm the safety of the study and ensure that the preliminary results are consistent with the original trial assumptions. Results of this futility study are expected in the 3rd quarter 2023. 2) GREEN: Phase 2/3 clinical trial in stroke Study design GREEN (NCT05559398) is a randomized, double-blind, multicenter, placebo-controlled Phase 2/3 study of the efficacy and safety of glenzocimab as an adjunct to mechanical thrombectomy in acute ischemic stroke. The GREEN study is conducted under the auspices of the Paris Public Hospitals (Assistance Publique – Hôpitaux de Paris), and is part of the RHU BOOSTER, receiving financial support from the French National Research Agency (Agence Nationale de la Recherche) and the Government’s ‘Investments for the Future’ program (Programme Investissements d’Avenir). The primary objective of this study is to evaluate the efficacy of glenzocimab in combination with endovascular thrombectomy (EVT) versus EVT alone on 90-day functional outcome (mRS). Secondary objectives are to evaluate the impact of glenzocimab on overall survival, reperfusion, clinical improvement at 24 hours, symptomatic and asymptomatic intracerebral hemorrhage, serious adverse events (SAEs), serious unexpected adverse events (SUSARs) and quality of life. This study will include nearly 260 patients eligible for mechanical thrombectomy in 11 French neurovascular units and institutions of excellence. Number of patients recruited to date: 1 patient. Next clinical step: an interim analysis will be performed after the first 78 patients are included and is expected end of 2023. 3) LIBERATE: Phase 2b clinical trial in the treatment of myocardial infarction Study design LIBERATE (IRAS -1005400) is a randomized, double-blind, Phase 2b study that will include more than 200 patients in the acute phase of myocardial infarction to test the safety and efficacy of glenzocimab 1000 mg versus placebo in reducing cardiac damage remote from the infarction. This study is being conducted in partnership with the University of Birmingham (UK), with expert clinicians from the Institute of Cardiovascular Sciences and University Hospitals Birmingham NHS Foundation Trust. Current status of the study: submitted to the UK regulatory authorities. Next clinical step: Inclusion of the first patient planned for the second quarter of 2023. 4) Other indications for cardiovascular emergencies At this stage of development, Acticor Biotech has decided to focus its efforts on the development of glenzocimab in stroke and myocardial infarction with three ongoing studies (ACTISAVE, GREEN and LIBERATE) and to postpone the launch of its Phase 2 study, BREATHE in pulmonary embolism. About ACTICOR BIOTECH Acticor Biotech is a clinical stage biopharmaceutical company, a spin-off from INSERM (the French National Institute of Health and Medical Research), which is aiming to develop an innovative treatment for cardiovascular emergencies, including ischemic stroke. Acticor Biotech is developing glenzocimab (ACT017), a humanized monoclonal antibody (mAb) fragment directed against a novel target of major interest, platelet glycoprotein VI (GPVI). Glenzocimab inhibits platelet binding to the thrombus without affecting physiological hemostasis, thereby limiting the bleeding risk, particularly in the brain. In May 2022, Acticor Biotech presented positive results from its Phase 1b/2a study, ACTIMIS, at the ESOC, confirming the safety pro showing a reduction in mortality and intracerebral hemorrhage in the glenzocimab-treated group in patients with stroke. The efficacy of glenzocimab is now being evaluated in an international Phase 2/3 study, ACTISAVE, which will include 1,000 patients. In July 2022, Acticor Biotech was granted "PRIME" status by the European Medicines Agency (EMA) for glenzocimab in the treatment of stroke. This designation will allow the company to strengthen its interactions and obtain early dialogues with regulatory authorities. Acticor Biotech is supported by a panel of European and international investors (Karista, Go Capital, Newton Biocapital, CMS Medical Venture Investment (HK) Limited, A&B (HK) Limited, Mirae Asset Capital, Anaxago, Primer Capital, Mediolanum Farmaceutici and the Armesa foundation). Acticor Biotech is listed on Euronext Growth Paris since November 2021 (ISIN: FR0014005OJ5 – ALACT). For more information, visit: Disclaimer This press release contains certain forward-looking statements concerning Acticor Biotech and its business. Such forward-looking statements are based on assumptions that Acticor Biotech considers to be reasonable. However, there can be no assurance that such forward-looking statements will be verified, which statements are subject to numerous risks, including the risks set forth in the Document de référence registration document as approved by the Autorité des marchés financiers under number R. 22-011 on 26 April 2022 and to the development of economic conditions, financial markets and the markets in which Acticor Biotech operates. The forward-looking statements contained in this press release are also subject to risks not yet known to Acticor Biotech or not currently considered material by Acticor Biotech. The occurrence of all or part of such risks could cause actual results, financial conditions, performance or achievements of Acticor Biotech to be materially different from such forward-looking statements. 17-point ordinal scale (categories 0 to 6) to measure the degree of disability of a person who has had a stroke