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Brilacidin, Host Defence Peptide Mimetic, One of a New Class of Immunomodulatory Agents That Can Target Multiple Disease Indications

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Brilacidin, Host Defence Peptide Mimetic, One of a New Class of Immunomodulatory Agents That Can Target Multiple Disease Indications EV0201 2015 ECCMID Copenhagen, Denmark Brilacidin, Host Defence Peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications Richard W Scott1, Stephen T Sonis2, Bozena Korczak3, Katie B Freeman1, William F DeGrado4, Ashok Kumar5, David P Brennan5, Sylvia A Holden5, Karima Chafai-Fadela5, Siya Ram5, Krishna Menon5 1Fox Chase Chemical Diversity Center, Doylestown PA, USA. 2BioModels LLC, Watertown MA, USA. 3NewMed, Wayne PA, USA. 4University of California, San Francisco CA, USA. 5Cellceutix Corporation, Beverly MA, USA Oral mucositis Acute radiation hamster oral mucositis Immunomodulatory activity of brilacidin Brilacidin has broad spectrum in vitro Oral ulcerative mucositis (OM) is a common, study HDPs are a key component of the innate immune antimicrobial activity painful, dose-limiting toxicity of drug and In vivo efficacy of brilacidin was assessed system and have multiple modes of action: MIC for antimicrobial activity was assessed for radiation therapy for cancer characterized by using the radiation-induced oral mucositis immunomodulatory, anti-inflammatory, and rapid brilacidin. Brilacidin has potent Gram positive breakdown of the oral mucosa that results in model in hamsters. The buccal cheek pouch microbial killing. activity, Gram negative coverage, but low the formation of ulcerative lesions (Scully was exposed to radiation followed by brilacidin Radiation and/or chemotherapy results in cytotoxicity against mammalian cells. 2006). In granulocytopenic patients, the at various doses and schedules. Mucositis was oxidative stress and an inflammatory response in ulcerations that accompany mucositis are scored on a scale of 0 to 5 using an oral mucosa which leads to activation of Brilacidin frequent portals of entry for indigenous oral Mammalian established blinded method. Hamsters transcription factors and signal transduction Gram - MIC range (µg/ml) Gram + MIC90s (µg/ml) cytotoxicity bacteria often leading to sepsis or bacteremia 2 – 3 clinical isolates received a single 40Gy radiation dose. pathways, including NF-κB and p53. mRNA levels (EC , µM) (Donnelly 2003). 50 Brilacidin was applied topically 3 times daily at of TNF-α and IL-1β in oral mucosal tissue Entero K. RB Hep Mucositis occurs in more than one third of MSSA MRSA CoNS E. coli pneum bacter 3T3 1, 3 or 10 mg/ml over 28 days. correlates with severity of mucosal injury. NF-kB Cs G2 . spp. patients receiving chemotherapy and in Brilacidin significantly reduced mucositis activation induces inflammatory cytokines, e.g., >50 1,03 virtually all patients who receive radiation 1 1 0.5 - 1 1 - 2 1 - 4 0.5 - 4 430 scores at 1, 3 and 10 mg/ml in a dose IL-6, IL-1β, TNF-α, that affect mucosal integrity. 0 1 therapy for tumors of the head and neck dependent manner (Scott 2012). These pro-inflammatory cytokines initiate an (Sonis 2004, Sonis 2007). inflammatory cascade leading to activation of Host defense proteins (HDPs) form part of the matrix metalloproteinases (MMPs) and Monocyte Brilacidin has rapid bactericidal activity against E. innate immune system, and serve as the first Chemoattractant Protein-1 (MCP-1) that further coli D32 (0.5hr, 4μg/mL) or S. aureus 27660 (2hr, line of defense against microbial infection in damages tissue. Ulceration develops and creates 20μg/mL) and potent, rapid activity against many species. HDPs can also perform many portals for bacterial entry and colonization. stationary phase cultures of MSSA and MRSA. activities related to innate immunity including Importantly, brilacidin has a low risk for resistance chemotaxis, modulation of cytokine production Brilacidin inhibited TNF-α development: FSR was <10-11 at 3X MIC against and inhibition of pro-inflammatory responses MRSA 33591. of host cells to bacterial components. Brilacidin (PMX30063), is a synthetic mimic of Host Defence Protein (HDP), with both Phase 2 clinical trial of brilacidin for Oral antimicrobial and immunomodulatory Fractionated radiation hamster oral Mucositis properties. mucositis study While we believe the efficacy in the pre-clinical Based on these studies, brilacidin is being assessed The objective of this study was to demonstrate for the prevention of oral mucositis induced by OM model is primarily the result of brilacidin’s efficacy of brilacidin on OM induced by immunomodulatory activities, its antimicrobial chemoradiation regimens used for the treatment of fractionated radiation that reflects radiation cancers of the head and neck in the US. function can also play a role in treating the regimens used clinically. Hamsters received lesions. 7.5Gy radiation 8X over 10 days. Brilacidin was Brilacidin inhibited MMP-9 The Phase 2 study is a randomized, double-blind, Brilacidin completed a successful Phase 2 applied topically at 3 mg/mL, 3X daily: Days 0- clinical trial as an anti-staphylococcal agent for placebo-controlled, 2-arm trial to be conducted in 35; 0-3,6-9; 0-12; or -1,4,5,10. patients receiving chemoradiation for the treatment of treatment of Acute Bacteria Skin and Skin Brilacidin significantly reduced mucositis scores Structure Infections (ABSSSI) [ECCMD-2969]. squamous cell carcinoma of the mouth and/or when administered daily for 35 days. Less oropharynx. Subjects will receive either oral rinse The activity of brilacidin for chemoradiation frequent dosing was ineffective (Scott 2012). therapy induced OM is being tested in Phase with placebo or oral rinse with 3 mg/mL brilacidin 2 trial. given 3 times daily for approximately 7 weeks during chemoradiation. REFERENCES Scully C, Sonis S, Diz PD. Oral Dis. 2006;12:229-41 Donnelly JP, Bellm LA, Epstein JB, et al. Lancet Infect Dis. 2003; 3:405-12. Brilacidin reduced the levels of TNF-α and MMP-9 Please contact Cellceutix Corporation Sonis ST, Elting LS, Keefe D, et al. Cancer. 2004;100:1995-2025. at 978-236-8717 Sonis ST. Nat Rev Cancer. 2004;4:277-84. in LPS-induced rat macrophages as assayed by [email protected] Sonis ST. J Support Oncol. 2007;5:3-11. ELISA. Brilacidin also reduced levels of IL-6, More information on this and related projects can be obtained at Scott RW, Korczak B, Watkins B, Sonis S. J Clin Oncol 30. 2012 IL-1β, MCP-1, and MIP2- α (data not shown). www.cellceutix.com (suppl abstract 9119). Copyright © 2015 Krishna Menon.
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