EV0201 ePoster Viewing Antimicrobials: new antimicrobials Brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications

R.W. Scott1, S.T. Sonis1, B. Kroczak2, K.B. Freeman1, W.F. DeGrado3, S.A. Holden1, A. Kumar1, K. Chafai-Fadela1, S. Ram1, K. Menon1 1Fox Chase Chemical Diversity Center, Doylestown PA, USA 2NewMed, Wayne PA, USA 3University of California, San Francisco CA, USA

Objective Brilacidin, a synthetic mimic of Host Defence Proteins (HDP), is a promising immunomodulatory compound with both immunomodulatory and antimicrobial properties that possesses clinical potential beyond the treatment of antibiotic-resistant infections. Non-peptide HDP mimics were designed which maintain the structural and biological properties of HDPs and have improved pharmacological properties. HDPs are short cationic molecules produced by most multicellular organisms and serve as the first line of defence against microbial infection. HDPs have immunomodulatory functions, as well as antimicrobial activity, that can target both inflammatory diseases and multi- antibiotic-resistant infections. Cellceutix's leading HDP mimetic, brilacidin, is undergoing clinical evaluation as an immunomodulator (Phase 2 trial for Oral Mucositis) and as an anti-microbial agent (Phase 3 trial for Acute Bacterial Skin and Skin Structure Infection [ABSSSI]). Methods In vivo efficacy was assessed using acute and fractionated radiation-induced oral mucositis (OM) models in hamsters. Brilacidin was applied topically 3 times daily at 1, 3 or 10 mg/ml over 28 days, following a single 40 Gy radiation dose to the buccal cheek pouch. The brilacidin topical dose with fractionated radiation (7.5 Gy/day, 8 times over 10 days) was 3 mg/ml, 3 times daily over 35 days. OM was scored clinically. Anti-bacterial activity was assessed by the microbroth dilution assay, recommended by the Clinical and Laboratory Standards Institute, for determining in vitro antimicrobial activity. Results

In the acute OM model, brilacidin reduced the number of animal days with ulceration from 43% in vehicle-treated hamsters to <5% (χ2 test p<0.001). In the fractionated model, brilacidin significantly reduced the daily mucositis scores (Mann-Whitney Rank-Sum analysis, p<0.001) and reduced the number of animal-days with ulceration from 55% in vehicle-treated hamsters to 3.3% in brilacidin treated animals (χ2 test p<0.001). Brilacidin also demonstrated potent anti-bacterial activity against both Gram-positive and Gram-negative bacteria. Brilacidin was effective against Staphylococci (MIC90 1 μg/mL) and maintained a consistent activity profile against methicillin-resistant isolates relative to methicillin susceptible isolates. Among Gram-negative isolates, brilacidin was more potent against Enterobacter cloacae and Citrobacter spp. (MIC90 4 μg/mL) than Pseudomonas aeruginosa and Acinetobacter spp. (MIC90 16 μg/mL). Overall, brilacidin was potent against staphylococci and other gram-positive cocci including beta-hemolytic streptococci and Enterococcus faecium. Conclusion Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of cancer therapy with minimal treatment options. The well-tolerated and efficacious HDP mimetic, brilacidin, in the animal model supports its further development as a topical therapeutic for OM. While we believe the efficacy in the OM model is primarily the result of brilacidin’s immunomodulatory activities, its antimicrobial function can also play a role in treating the lesions. Based on these promising studies, a Phase 2 trial in radiation induced OM is ongoing.