MILESTONE ACHIEVED IN PHASE I CLINICAL TRIAL FOR HUTRUKIN™ STROKE DRUG
Dosing Cohort 2 Completed in Phase I Hutrukin Study
August 21, 2023
Cohort 2 of XBiotech’s Phase I study for Hutrukin have now completed dosing and safety evaluation. Hutrukin was well tolerated and the study will now begin enrolling subjects into Cohort 3.
Hutrukin is a novel candidate treatment for reducing brain injury after stroke. If a blood clot occurs in an artery supplying blood to the brain, the blocked artery results in loss of blood supply which starves the brain of oxygen (ischemia). The loss of oxygen to the brain as a result of a blot clot is known as an ischemic stroke. Clot-busting drugs and or devices such as catheters have been developed to re-open clogged arteries after a stroke. Surprisingly, however, opening a clogged artery may not reduce the harm from the stroke. In fact, after opening the clot, the return of blood supply to ischemic brain (reperfusion) can result in aggravation of ischemic injury, with a rapid expansion of brain damage.
Hutrukin is being developed as a drug that is given immediately prior to clot-busting procedures, where it is intended to reduce injury associated with reperfusion. There is currently no drug available to treat reperfusion injury. Hutrukin, has the potential to be a novel, breakthrough therapy in the management of ischemic stroke, the second most common cause of death or disability worldwide.
XBiotech is conducting a Phase I study to evaluate safety and pharmacokinetics of Hutrukin in healthy volunteers. The study involves sequential dose escalation, using three groups (or cohorts) of subjects, receiving a single intravenous infusion of either placebo or Hutrukin at 1,000 mg (Cohort 1), 3,000 mg (Cohort 2), or 5,000 mg (Cohort 3) dose levels, respectively. Dose escalation will utilize a 6+2 design with sentinel dosing and doses will be explored with 8 subjects in each cohort (6 subjects are dosed with Hutrukin and 2 subjects with placebo).
Milestone Achieved in Phase I Clinical trial for Hutrukin™ Stroke Drug
Dosing Cohort 1 Completed with no Safety Concerns in Phase I Hutrukin Healthy Volunteer Study
May 17, 2023
XBiotech is conducting a Phase I study to evaluate safety and pharmacokinetics of its candidate stroke therapy Hutrukin in healthy volunteers. The study uses sequential dose escalation involving three groups (or cohorts) of subjects to prove Hutrukin tolerability. Participants receive a single intravenous infusion of either placebo or active drug Hutrukin at either 1,000 mg (Cohort 1), 3,000 mg (Cohort 2), or 5,000 mg (Cohort 3) dose levels. Dose escalation will utilize a 6+2 design with sentinel dosing and doses will be explored with 8 subjects in each cohort (6 subjects are dosed with Hutrukin and 2 subjects with placebo).
Subjects in Cohort 1 have now completed dosing and safety evaluation. Hutrukin was well tolerated in all subjects. The study will now begin enrolling subjects into Cohort 2.
Hutrukin is a novel treatment to reduce brain injury as part of urgent therapy for stroke victims. If a blood clot occurs in an artery that supplies blood to the brain, the loss of blood supply starves a portion of the brain of oxygen (ischemia). This is known as an ischemic stroke. Clot-busting drugs and/or catheters can be used to re-open the clog artery. However, surprisingly, after opening of the clogged artery, return of blood supply to ischemic brain can result in aggravation of ischemic injury, often with a rapid expansion of brain damage.
Hutrukin is intended to be given immediately prior to clot-busting procedures. Hutrukin is intended to reduce reperfusion injury associated with the resumption of blood supply to the hypoxic brain tissue. There is currently no drug available to treat reperfusion injury. Hutrukin, therefore, has the potential to be a novel, breakthrough therapy in the management of ischemic stroke. Stroke is the second most common cause of death or disability worldwide.
XBiotech Submits New Non-clinical Safety and Pharmacodynamic Data to the FDA in Support of Natrunix Therapy
New Non-Clinical Toxicology and Ex-vivo Clinical Pharmacodynamic Studies Support Safety and Guide Optimal Dosing Frequency in Rheumatoid Arthritis (RA) Patients
April 26, 2023
XBiotech submitted a complete safety and pharmacokinetic-pharmacodynamic package to the FDA in support of its proposed Phase II Clinical Study of Natrunix in rheumatoid arthritis patients. Natrunix works to block the activity of interleukin-1a (IL-1a), a substance naturally produced by the body in response to injury. IL-1a stimulates inflammation, heightens sensitivity to pain, breakdowns connective tissue scaffolding that provides support to body tissues, induces new blood vessel formation and acts as a messenger notifying the brain of injury. Under disease conditions, IL-1a activity may cause undesired inflammation, destruction of healthy tissue, pain and malaise. In arthritis, IL-1a may play a crucial role in joint inflammation, destruction of synovial tissue and joint pain.
Natrunix was derived from—and is indistinguishable from—a naturally occurring antibody present in a healthy human. The use of Natrunix in arthritis is expected to be extremely safe, and XBiotech believes that the drug represents a breakthrough treatment for the disease, which affects 54 million people in the US, and is the leading cause of disability (American Arthritis Foundation).
After discovery, testing and development of Natrunix, XBiotech planned to compare Natrunix head-to-head in clinical trials to methotrexate—which is the current treatment standard for arthritis. Methotrexate is a cytotoxic and immunosuppressive drug with well-known and extensive list of serious toxicities and side effects. XBiotech has blocked IL-1a in multiple prior human clinical trials with no known toxicity. However, in response to XBiotech’s investigational new drug application, in 2022 the FDA recommended that additional studies be performed in animals to further examine the safety of Natrunix before human clinical trials could begin.
Since Natrunix is a human antibody, it is highly specific to human IL-1a, and does not effectively block the activity of IL-1a in animals. A so called “surrogate antibody” to block IL-1a in animals was therefore needed. XBiotech used a mouse derived antibody that blocks mouse related IL-1a.
In the recently completed study, mice were given twelve weekly doses of the surrogate antibody—at up to 50-fold excess over the intended human clinical dose—and monitored for toxicity. The study evaluated a standard battery of safety endpoints including clinical signs, clinical pathology (hematology, and clinical chemistry), macroscopic and microscopic evaluation of an exhaustive list of tissues, ophthalmologic and toxicokinetic analysis. No study drug related changes of any kind were observed in any animal.
The FDA also requested additional dose justification and mechanism of action data for Natrunix to support its use in treating arthritis. XBiotech developed these data using an innovative ex vivo pharmacodynamic model generated by researchers at XBiotech (see news release ‘XBiotech Shows How Natrunix Stops Inflammation in Synovial Cells Taken from Rheumatoid Arthritis Patients’ published online on 14 March 2023). These data confirmed the ability of Natrunix to stop production of inflammation causing substances and tissue degrading enzymes from synoviocytes isolated from joints of arthritis patients.
All these findings have now been provided to the FDA as part of an extensive package of requested additional information. The human study for Natrunix in arthritis is on clinical hold until the FDA reviews the current data and determines whether they believe Natrunix is safe enough to begin clinical studies. The timing for feedback or approval from the FDA is unknown at the present time.
XBiotech Submits Clinical Safety Report to the FDA for its Subcutaneous Formulation of Natrunix
Study results show subcutaneous formulation of Natrunix is very well tolerated in healthy human volunteers. Formulation is ready to be evaluated in Rheumatoid Arthritis (RA) patients.
March 19, 2023
XBiotech has submitted the Clinical Safety Report to the FDA relating to the use of Natrunix in healthy human volunteers. The Nartunix formulation was developed to be highly concentrated to minimize injection volume. The product is used in a syringe designed to be given by needle injected through the skin by Rheumatoid Arthritis patients. The Clinical Safety Report is based on data from a Phase I study that investigated the safety, uptake and distribution of the drug after injection in healthy human volunteers. Three dosages were tested in the study: group 1 received 100mg; group 2 received 200mg; and group 3 received 400mg of Natrunix. Participants were monitored for acute reactions, blood chemistry and hematology immediately after dosing and at multiple time points up to 28 days.
The results from this study showed that Natrunix was extremely well tolerated in all the subjects throughout the study. There were no significant adverse events; no toxicity; and no significant changes in vital signs, EKGs, physical exams, blood chemistries or blood laboratory values in the people given Natrunix injection.
Rheumatoid arthritis involves chronic joint inflammation, resulting in severe pain, stiffness and malaise. Interleukin-1 alpha (IL-1a) causes synovial cells to produce inflammation causing substances, that stimulate the influx of white blood cells, stops the production of normal synovial fluid, and causes the breakdown of surrounding tissue, including cartilage and bone. When the joint fills with inflammatory white blood cells and debris from the breakdown of cartilage and other tissue, this diseased synovial fluid functions poorly to enable joint rotation. Blood vessels and nerve fibers begin to grow into the eroding cartilage, bringing sensitivity and pain to joint movement. Natrunix binds and neutralizes the activity of IL-1a—potentially stopping a fundamental process for joint dysfunction, erosion and pain.
XBiotech Shows How Natrunix Stops Inflammation in Synovial Cells Taken from Rheumatoid Arthritis Patients
Synovial cells from RA patients help establish effect and Guide Dosing for Natrunix in RA Patients
March 14, 2023
At the request of the FDA, XBiotech developed a method to evaluate the ability of Natrunix to block inflammation causing substances in the diseased joint in Rheumatoid Arthritis (RA). These new findings provide XBiotech’s clinical development program guidance on dosing and monitoring of human subjects for response to treatment with Natrunix.
XBiotech scientists developed means to test Natrunix using cells taken from the synovial lining of joints of patients suffering from rheumatoid arthritis. The synovium is comprised of specialized cells, synoviocytes, that form a membrane around the joint. Joints, such as those of the hand, knee and shoulder are lined with a layer of synovial tissue. Synoviocytes produce fluid that contains substances such as hyaluronan and lubricin, keeping the joint healthy and operating smoothly.
Rheumatoid arthritis involves chronic joint inflammation, resulting in severe pain, stiffness and malaise. Interleukin-1 alpha (IL-1a) causes synovial cells to produce inflammation causing substances, that stimulate the influx of white blood cells, stops the production of normal synovial fluid, and causes the breakdown of surrounding tissue, including cartilage and bone. When the joint fills with inflammatory white blood cells and debris from the breakdown of cartilage and other tissue, this diseased synovial fluid functions poorly to enable joint rotation. Blood vessels and nerve fibers begin to grow into the eroding cartilage, bringing sensitivity and pain to joint movement. Natrunix binds and neutralizes the activity of IL-1a—potentially stopping a fundamental process for joint dysfunction, erosion and pain.
XBiotech research using synoviocytes from arthritis patients, the Company has established that these cells are very sensitive to IL-1a, which causes the cells to produce inflammatory cytokines and so-called metalloproteinases that are directly involved in joint inflammation and destruction. Since Natrunix targets and neutralizes human IL-1a, the Company has used this model to test the ability of Natrunix to stop synoviocytes from producing substances that cause inflammation and joint destruction—the hallmark of arthritis pathophysiology.
As part of our drug development program, XBiotech used cultured RA-derived synoviocytes to establish a full dose response curve for Natrunix. Using this system, the company was able to define the optimal dosing for testing Natrunix in its upcoming clinical trials for treating rheumatoid arthritis. These new data are now being used by XBiotech to design clinical studies in RA patients.
Completion of Level 3 (500mg dosing) in Phase I portion for Natrunix™, Trifluridine/Tipiracil (TASKIN) study
Level 3 XB2001 500mg + Trifluridine/Tipiracil completed
February 28, 2023
Subjects continue to be enrolled in the TASKIN study, where they are receiving the XBiotech’s True Human antibody Natrunix as part of their treatment for advanced colorectal cancer. Enrollment has now been completed for all patients receiving “Level 3” or 500mg dosing, as part of the Phase I portion of the study. In addition to Natrunix™, subjects also receive Trifluridine/Tipiracil as part of their treatment.
The Phase II Dose is being established based on the results from this Phase I portion. One additional cohort of up to 6 patients remain to be dosed in the Phase I portion after which the study will transition into Phase II. The Phase II portion will be a multicenter, randomized, double blind, placebo-controlled, non-comparative trial that will enroll 160 subjects.
The clinical portion of the study is funded by the French National Cancer Institute (INCA) and headed by Dr. Ghiringhelli and Dr. Come Lepage. Dr. Ghiringhelli, is a Professor in Medical Oncology and Director of the INSERM research team at the Georges-Francois Leclerc Cancer Centre, and Prof. Come Lepage, is a Professor in Gastroenterology and Digestive Oncology Department, University Hospital Dijon, Dijon, France.
