Glycosaminoglycans to Treat and Prevent Radiation-Induced Oral Mucositis

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Project Summary/Abstract Oral mucositis is a devastatingly painful inflammatory disease that frequently develops during cancer therapy and affects half a million Americans. The accompanying pain is so severe that patients often require narcotic pain medicines. The clinical manifestations are ulcers in the mouth and gastrointestinal tract, which are exacerbated by opportunistic infections. Many patients also suffer from dry mouth causing difficulty in swallowing because of the decreased salivary gland function. As a result, these patients often need feeding tubes which interrupts their cancer treatment. The financial burden to the patient is staggeringly high, costing an additional $17,000 to $40,000 for each patient. Preventing oral mucositis will greatly enhance the cancer therapy as well as the wellness of the patients. GlycoMira's lead candidate, GM-1111, is a new class of anti- inflammatory drugs that modulate an overactive innate immune system when administered via once daily subcutaneous injection. The SBIR Phase I and II study results demonstrate its powerful efficacy in reducing the severity and the occurrence of the disease in radiation-induced oral mucositis models: GM-1111 reduced tissue ulceration and inflammation in the tongue. Histologically, oral tissues from the GM-1111 treated group showed markedly reduced damages in the epithelium with mild infiltration of leukocytes, thicker mucosal layers and prevention of mucous glandular alterations compared to the tissues from vehicle treated controls. Biochemical and gene expression analyses of the diseased tissues revealed increased expression of Toll-like receptors, NLRP3 inflammasome as well as their downstream pro-inflammatory cytokines all of which were reduced with GM-1111 treatment. Overall, the data suggest that GM-1111 has substantial potential to reduce oral mucositis in humans. GlycoMira also manufactured cGMP compliant GM-1111 and generated its manufacturing specifications. To further develop a commercially viable therapeutic for oral mucositis, we propose studies that will be used for the Investigative New Drug (IND) application to the FDA for clinical trials. The objectives are to (1) delineate the safety profiles of GM-1111 in nonclinical studies and (2) manufacture clinical trial ready sterile drug product (aseptic fill/finish and labeling/packaging) and test its stability. The results of the proposed research will lead the drug development to the clinical stage through IND application and propel the commercialization of the drug to the patients suffering from this devastating disease.