Multicentric Randomized Phase I/II Study to Evaluate Efficacy of Trifluridine/Tipiracil Plus XB2001 (Anti-IL-1α True Human Antibody) Versus Trifluridine/Tipiracil Plus Placebo in Metastatic Colorectal Cancer Patients After Failure of Oxaliplatin, Irinotecan, Fluoropyrimidine
Unresectable metastatic colorectal cancer (mCRC) remains an incurable disease. After failure of conventional treatments involving fluoropyrimidines, oxaliplatin and irinotecan in combination or not with biotherapies targeting EGFR and VEGF; regorafenib shows a modest improvement in overall survival. Recently, trifluridine/tipiracil has also shown efficacy in phase 3 with an overall survival of around 7 months. Trifluridine/tipiracil has become the standard of care for advanced mCRC in most western countries. However, the objective response rate remains very low and the survival gain remains moderate (+2 months). Therefore, new strategies are needed to ensure that mCRC patients who have received multiple lines of therapy can receive more effective treatments. Based on previous clinical trials on IL-1 inhibition and our preclinical data, IL-1 inhibition may increase the efficacy of trifluridine/tipiracil. The goal is to test whether the addition of XB2001 to trifluridine/tipiracil could be synergistic.
Acute respiratory distress syndrome (ARDS) in COVID-19 has been associated with catastrophic inflammation. We present measurements in humans and a new animal model implicating a role in danger-associated molecular patterns. Calprotectin (S100A8/A9) and high-mobility group box 1 (HMGB1) were measured in patients without/with ARDS, and admission calprotectin was associated with soluble urokinase plasminogen activator receptor (suPAR). An animal model was developed by intravenous injection of plasma from healthy or patients with COVID-19 ARDS into C57/BL6 mice once daily for 3 consecutive days. Mice were treated with one anti-S100A8/A9 antibody, the IL-1 receptor antagonist anakinra or vehicle, and Flo1-2a anti-murine anti-IL-1α monoclonal antibody or the specific antihuman IL-1α antibody XB2001 or isotype controls. Cytokines and myeloperoxidase (MPO) were measured in tissues. Calprotectin, but not HMGB1, was elevated in ARDS. Higher suPAR indicated higher calprotectin. Animal challenge with COVID-19 plasma led to inflammatory reactions in murine lung and intestines as evidenced by increased levels of TNFα, IL-6, IFNγ, and MPO. Lung inflammation was attenuated with anti-S100A8/A9 pre-treatment. Anakinra treatment restored these levels. Similar decrease was found in mice treated with Flo1-2a but not with XB2001. Circulating alarmins, specifically calprotectin, of critically ill COVID-19 patients induces tissue-specific inflammatory responses through an IL-1-mediated mechanism. This could be attenuated through inhibition of IL-1 receptor or of IL-1α.
XBiotech Inc. announced today completion of enrollment of the Phase II portion of its 1-BETTER study—a Phase I/II randomized, double-blind, placebo-controlled clinical study for Natrunix in combination with chemotherapy for treating pancreatic cancer.
Natrunix is indistinguishable from a naturally occurring antibody present in a healthy human. Natrunix binds and neutralizes a potent substance, a so called cytokine known as interleukin-1a (IL-1a), that causes connective tissue breakdown, growth of new blood vessels, and recruitment of white blood cells. Malignant tumors, like pancreatic cancer, stimulate the body’s production of IL-1a that induce tumor neovascularization, growth and spread. Additionally, IL-1a acts as an alarm signal when there is body injury (such as when tumors grow), enhancing pain perception, metabolism, appetite, fatigue, and anxiety. The insult from chemotherapy also induces IL-1a production. Adding Natrunix to your chemotherapy regimen may therefore provide numerous benefits, including anti-tumor activity, reduction in chemotherapy side effects, improvement in chemotherapy activity—including increasing the number of cycles of therapy that can be tolerated while improving quality of life.
Twenty-two leading cancer centers across the United States have been involved in the Phase I/II study. Pancreatic cancer is the 4th leading cause of cancer death in the United States and the incidence has been increasing steadily since 2000. In 2022, an estimated 50,000 people died from pancreatic cancer in the United States. The Natrunix antibody therapy represents a groundbreaking approach to therapy.
The Phase II portion enrolled 65 subjects using the maximum dose studied from the Phase I study that were randomized on a 1:1 basis to receive either Natrunix in combination with ONIVYDE+LV+5-FU (Arm 1), or placebo plus the chemotherapy combination. Key endpoints in the Phase II portion are safety and tolerability, progression-free survival, overall survival and time-to-treatment-failure.
Natrunix is a True Human™ antibody that was discovered, developed and manufactured by XBiotech. True Human™ antibodies are derived—without modification—from individuals who possess natural immunity to certain diseases. In many individuals, the body naturally produces antibodies to block pathological inflammation associated with interleukin-1, one of the most extensively studied inflammatory pathways in medicine. Other marketed biological drugs attempt to treat diseases by blocking interleukin-1, however none specifically and exclusively target interleukin-1 alpha (IL-1a). There is also no other marketed monoclonal antibody therapy derived unaltered from a natural human immune response.
XBiotech is a fully integrated global biosciences company dedicated to pioneering the discovery, development and commercialization of therapeutic antibodies based on its True Human™ proprietary technology. XBiotech is currently advancing a robust pipeline of antibody therapies to redefine the standards of care in oncology, inflammatory conditions, and infectious diseases. Headquartered in Austin, Texas, XBiotech is also leading the development of innovative biotech manufacturing technologies designed to more rapidly, cost-effectively and flexibly produce therapies urgently needed by patients worldwide. For more information, visit www.xbiotech.com.
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AUSTIN, Texas, Aug. 08, 2023 (GLOBE NEWSWIRE) -- xBiotech USA, Inc. (NASDAQ: XBIT) today began treating the first patient in a phase II, double-blind, placebo-controlled, randomized clinical study to evaluate Natrunix as a new treatment for Arthritis. Natrunix blocks a key cause of inflammation involved in pain and joint destruction in rheumatoid arthritis (RA).
The primary endpoint of the Phase II is the American College of Rheumatology (ACR) 20% Response (ACR 20) rate at 12 weeks. Secondary and exploratory endpoints include ACR 50, ACR 70, numerical rating scale (NRS) for pain score, inflamed and painful joint counts, Health Assessment Questionnaire Disability Index (HAQ-DI), Routine Assessment of Patient Index Data 3 (RAPID-3), Clinical Disease Activity Index (CDAI) and safety. These endpoints reflect the expectation that Natrunix may provide needed improvement with respect to pain, tenderness, mobility of joints and quality of life. Approximately 210 subjects will be enrolled into three different arms in the study. All subjects will receive methotrexate (MTX) and be randomized to receive either one of two doses of Natrunix or placebo.
Natrunix is a monoclonal antibody indistinguishable from a naturally occurring antibody from a human donor. Natrunix binds and neutralizes the action of one of the most potent inflammation-causing substances known—interleukin-1. For decades, interleukin-1 was seen as the key target for drugs to treat RA. However, to date, drugs that block interleukin-1 have not lived up to expectations as therapies for RA. XBiotech believes it has solved this puzzle.
Interleukin-1 actually describes two separate and distinct molecules—IL-1a and IL-1b—that are produced at different times and places in the body. XBiotech is the first to develop candidate therapies—like Natrunix—that directly and specifically neutralize IL-1a. In recent years, world-class research has shown that in many cases IL-1a may be the crucial target for blocking disease-causing activities of the interleukin-1 inflammatory pathway. Natrunix thus holds promise as a new generation anti-inflammatory therapy for arthritis. As a naturally derived human antibody, it is also by design expected to be among the safest and best tolerated medicines ever developed.
One in four adults, or over 50 million people in the United States are currently affected by Rheumatoid Arthritis, including 33% of those between the ages of 45-64 and 50% of person over 65 years of age. The number of persons affected by RA is expected to increase, with the CDC predicting that by the year 2040, 78.4 million adults, will suffer from RA in the United States. In addition, it is expected that 300,000 children will suffer from juvenile arthritis (Arthritis Foundation, 2023).
About True Human™ Therapeutic Antibodies
Natrunix was discovered by XBiotech researchers at the Company’s headquarters in Austin, Texas. XBiotech’s True Human™ antibodies are derived without modification from individuals who possess natural immunity to certain diseases. By harnessing the body’s natural immunity to cure disease, True Human™ antibodies have the potential to revolutionize medicine.
XBiotech is dedicated to pioneering the development of breakthrough therapies derived from natural human immunity. XBiotech discovered genetic engineering tools that enabled identification of rare antibodies present in human donor blood, and has built a pipeline of antibody therapies, including a candidate therapy that could revolutionize arthritis treatment. Headquartered in Austin, Texas, XBiotech has also lead innovation in biomanufacturing technology. For more information, visit .
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The library of libraries is a collection of synthesised antibody libraries. Credit: angellodeco / Shutterstock.com.
and Cancer Research UK’s innovation arm Cancer Research Horizons have signed an agreement to license a “library of libraries”.
Twist’s complete library of libraries will be licensed by Cancer Research Horizons for a five-year period.
Bromodomain Testis Specific Protein (Cancer/Testis Antigen 9 or RING3 Like Protein or BRDT) Drugs...
LOA and PTSR Model - Vilamakitug in Pancreatic Cancer
Twist Bioscience Corp
Cancer Research Horizons
Twist will obtain a library access fee and will be eligible for annual maintenance fees. It will also receive a portion of the revenue generated from any assets sold or transferred.
Cancer Research Horizons Therapeutic Innovation CEO Hamish Ryder stated: “We’re delighted to partner with Twist Bioscience, an exciting technology platform company that will enhance our antibody discovery capabilities with their highly diverse phage display libraries.
“We look forward to using this technology to accelerate the delivery of high-quality therapeutics and diagnostics to cancer patients, in collaboration with our academic and industrial partners.”
The library of libraries is a collection of synthesised antibody libraries, designed using naturally occurring sequences and incorporating innovative structural and developability features to encompass a range of antibody drug targets.
Twist Bioscience CEO and co-founder Emily Leproust stated: “Cancer Research Horizons acts as a conduit between academia and industry, with our collaboration enabling early-stage antibody identification through access to our “library of libraries.”
“With two mission-driven organisations aligning behind innovative technology solutions to improve health to make the world a better place, the opportunity to identify new biotherapeutics offers tremendous hope to those who need it most.”