Phase II year
2020
(last award dollars: 2021)
Phase II Amount
$1,996,642
The goal of this Phase II SBIR project is to advance a new treatment for interstitial cystitis/bladder pain syndrome (IC/BPS) to clinical trials. IC/BPS is a chronic disease characterized by lower pelvic pain, urinary urgency and frequency, and urge incontinence. Chronic pain results from a disruption of the protective glycosaminoglycan (GAG) layer of the bladder wall, causing permeability and urinary leakage. There are few therapeutic options and approved treatments have met with limited success. Hence, the 4-12 million Americans suffering with IC/BPS face a lifetime of chronic debilitating abdominal pain and other symptoms. One promising treatment option to restore bladder impermeability is GAG replenishment therapy. However, the single chain, low molecular weight (MW) GAGs that are currently used do not properly mimic the proteoglycan- bound GAG layer of the normal urothelium, and response rates are low. Proteoglycans display multiple sulfated GAG chains in clusters, creating zones of high anionic charge and bound water. Glycologix has developed a novel and innovative family of high MW, branched biopolymers known as SuperGAGs that mimic the structure of proteoglycans. SuperGAGs have been designed to improve adherence to the urothelium due to their greater size, dendritic structure, and affinity for the bladder surface. In the Phase I project, synthesis and preclinical evaluation of first-generation SuperGAGs successfully demonstrated proof of concept for the preparation of large SuperGAG biopolymers (MW > 1MDa), and the ability of these biopolymers to restore bladder impermeability and reduce visceral pain in a well-characterized rat model of bladder permeability. This result was confirmed in a second model in which bladder permeability was induced through an inflammatory process and bladder permeability was quantified using magnetic resonance imaging (MRI). In this Phase II project, Aim 1 is to synthesize and characterize a small number of SuperGAG derivatives bearing targeting ligands and other groups known to enhance binding to the bladder wall using methods validated in Phase I. Aim 2 is to compare the effectiveness of these biopolymers in a well-established mouse model of induced IC/BPS in which bladder permeability is induced by inflammation. Quantitative contrast- enhanced MRI will be used to measure restoration of bladder impermeability. The SuperGAG with the longest adherence time, tightest binding and most effectiveness will be selected for clinical development. Aim 3 will initiate development of the SuperGAG clinical candidate by executing required GLP safety studies and GMP synthesis in concert with input from the FDA. At the conclusion of the Phase II project, Glycologix intends to submit an Investigational Device Exemption with the FDA to gain approval for initiation of human clinical trials of SuperGAG Bladder Instillate as a new medical device treatment option for patients suffering with IC/BPS.
Public Health Relevance Statement: PROJECT NARRATIVE The goal of this project is to develop a novel treatment for interstitial cystitis/bladder pain syndrome (IC/BPS), a highly prevalent chronic disease with few effective treatment options that is characterized by lower pelvic pain, urinary urgency and frequency, and urge incontinence. In a successful Phase I project, Glycologix LLC demonstrated that a novel class of SuperGAG biopolymers was effective in restoring bladder function and reducing abdominal pain in animal models of IC/BPS. Successful completion of this Phase II project will result in an optimized SuperGAG therapeutic candidate that binds well to the target tissue, and collection of preclinical data that will be required by the FDA for initiation of human clinical trials.
Project Terms: Abdominal Pain; Adherence; Affinity; American; Animal Model; Binding; Biological Assay; biomaterial compatibility; Biopolymers; Bladder; Brain; CCL2 gene; Charge; Chelating Agents; Chemicals; Chemistry; Chondroitin Sulfates; Chronic; Chronic Disease; chronic pain; Clinical; clinical candidate; clinical development; clinical material; Clinical Trials; comorbidity; compare effectiveness; Consultations; contrast enhanced; Cyclic GMP; Data; design; Development; Devices; Disease; effective therapy; Effectiveness; Etiology; Extravasation; Face; Family; FDA approved; Filtration; Fluorescent Dyes; Future; Generations; Glycosaminoglycans; Goals; Heparin; Human; hyaluronate; Hydrophobicity; improved; Increased frequency of micturition; Inflammation; Inflammatory; innovation; Interstitial Cystitis; Intravesical Administration; Investigation; Irritable Bowel Syndrome; Label; Lead; Lectin; Ligands; Magnetic Resonance Imaging; Measures; Mediating; Medical; Medical Device; meetings; Methods; micturition urgency; Modality; Modeling; Molecular Weight; Morbidity - disease rate; mouse model; Normal Range; novel; novel therapeutics; Organ; Pain; Patients; Pelvic Pain; Performance; Permeability; Phase; polysulfated glycosaminoglycan; pre-clinical; preclinical development; preclinical evaluation; preclinical study; Preparation; Process; programs; Proteoglycan; Rattus; research clinical testing; Research Contracts; residence; response; restoration; Safety; safety study; scale up; Small Business Innovation Research Grant; solute; Spinal; Structure; success; Surface; Symptoms; System; Testing; Therapeutic; therapeutic candidate; Time; Tissue Banks; Tissues; Toxicology; Transgenic Mice; Treatment Efficacy; treatment strategy; United States; Urge Incontinence; urinary; Urothelium; Visceral pain; Wa
