An Oral, Inflammation-Targeting and Responsive Tacrolimus Formulation for the Treatment of Steroid-Refractory and Steroid-Dependent Inflammatory Bowel Disease
Abstract
Inflammatory bowel disease (IBD) is a chronic and debilitating disease of the gastrointestinal (GI) tract that affects over 1.6 million people in the US. Fortunately, patients with mild symptoms experience substantial relief with existing drugs, and some patients with more advanced symptoms get better with powerful drugs such as steroids. However, many patients experience worsening of their disease, where they either need to continually take these powerful steroids to control their symptoms (steroid-dependent; SD) or do not get better, despite taking their medication appropriately (steroid-refractory; SR). For these patients, few additional treatment options exist, and unfortunately a high number of patients must have their colons surgically removed to ease their symptoms. We propose a unique approach for treating SD/SR patients that works by delivering a potent drug precisely to the site of intestinal inflammation. This approach provides two important advantages over current therapies: (1) it improves the effectiveness of a drug by getting more of the drug to the diseased tissues, and (2) it improves the safety of the drug by limiting its exposure to healthy tissues. These benefits in drug delivery have been discovered using a form of vitamin C called ascorbyl palmitate (AP), a dietary supplement that the Food and Drug Administration (FDA) considers safe for oral consumption. Using AP, we form tiny structures that entrap and deliver potent drugs. In a breakthrough finding, pioneering scientists Professor Jeff Karp at the Brigham and Women’s Hospital (Harvard Medical School), Professor Robert Langer at MIT, and their colleagues demonstrated the capabilities of these tiny structures using animal models of IBD. Following their important proof-of-concept work, they founded Alivio Therapeutics to develop new drug products with this technology. As an extension of their initial work, we have demonstrated strong preclinical efficacy and safety in two rat IBD models using tacrolimus (tac) as the incorporated drug. This result has significant clinical implications because tacrolimus is a very effective drug but has had limited use because of its severe side effects. Therefore, we see potential for this therapy to benefit SD/SR IBD patients with advanced disease who otherwise have few treatment options. Building on our initial work, the main objective of our proposal is to advance our lead tac/AP formulation through the development phases and enable clinical testing in IBD patients. We have identified four specific aims to support this objective: • Aim #1: Complete testing in animal models of IBD. We propose to evaluate our lead capsule formulation in an acute model of IBD. • Aim #2: Develop a tac/AP-loaded capsule. Human sized capsules loaded with our lead tac/AP formulation will be developed by a subcontractor. • Aim #3: Develop a complete manufacturing process. Capabilities to manufacture tac/AP capsules that are sufficient for patient testing will be established at a subcontractor. • Aim #4: Determine the safe dosing range in healthy animals and complete a definitive animal safety study. Capsules will be tested in a short-term animal study to establish the maximum safe dose in preparation for larger safety studies. Clinically ready capsules will then be tested in a safety study that uses the same timing and duration as intended for patient use. At the completion of this project, we will have a clinically ready therapy for SD/SR IBD with demonstrated safety and efficacy that has multiple benefits for the military and civilian communities. For patients, it can provide a therapeutic option that defers or even prevents the need for colon removal, which can enable a faster return to active duty during flares or an overall longer duration of active service. By formulating in a standard drug capsules, the product can be easily issued at any medical facility and taken directly by the patient. In the lo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010645
Entities
People
- Gregory Zugates
Organizations
- United States Army