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The novel Ceragenin™ class of anti-infectives and the Barrier Repair technology are complementary technologies that derive from the Company’s expertise in, and in-depth understanding of the skin and human host-defense systems. These novel technologies capitalize on the latest medical/scientific insights into the critical roles and functions of the outer layers of the skin and have led Ceragenix to develop promising new products which address serious medical conditions addressable by innate immunity agents. In particular, the stratum cornuem (SC) plays critical functional roles in a number of important areas importantly including both maintenance of proper skin hydration via its barrier function to minimize trans-epidermal water loss as well as providing the first line of defense against pathogens via anti-microbial peptide related mechanisms.
These technology platforms represent significant advances over current approaches. The BRT technology has been validated in vivo and in a clinical study and the first skin Barrier Repair Technology product, EpiCeram® was recently cleared by the FDA. Products based on the Ceragenin™ technology have demonstrated significant activity in vitro against most of the important human pathogens, including highly resistant and potentially lethal strains, and are currently entering preclinical testing.
Skin / Barrier Repair Scientific Background
The process by which healthy skin renews itself depends on the presence of a healthy stratum corneum (SC), in which cells are produced and shed in a steady state. The SC is the outermost layer of skin and is critical to maintaining the epidermal barrier function of the skin. Researchers have discovered that the disruption of this barrier function plays a critical role in the pathogenesis and maintenance of a wide variety of skin disorders from winter xerosis to severe conditions such as psoriasis and atopic dermatitis (AD or eczema). The latest medical research has demonstrated that the presence of adequate amounts of 3 classes of lipids in the extracellular matrix of the skin is critical to proper SC function, namely, ceramides, cholesterols, and free fatty acids. Skin barrier function is abnormal or a contributing factor in many skin dermatoses, and genetic or acquired dysfunction can trigger and sustain these diseases.
Paradigm for skin disease / skin barrier relationship
Peter Elias, M.D., Ceragenix’s Chief Scientific Officer and renowned research dermatologist has extensively studied the molecular, biochemical, and structural properties of the skin, with a focus on the effects of disease on SC and how an altered SC impacts disease, particularly dermatoses. AD in particular is characterized by abnormal extracellular lipids and a global decrease in lipids with a specific and pronounced deficiency of ceramides. This deficiency leads to a biochemical response involving the cytokine cascade which recruits T-cells which in turn create an inflammatory response. In the course of his research, Dr. Elias discovered a very specific combination of physiologic lipids — ceramides, cholesterol and fatty acids — that restore the function of these membranes, and when applied topically, forms a human-identical skin barrier. This restoration and normalization of the skin’s barrier has been shown to hold great promise in addressing a number of chronic dermatological conditions.
Data & Initial Studies
EpiCeram® has been successfully tested in highly reliable animal models of skin barrier repair as well as inflammation and is currently entering human clinical trials where it will be compared head to head with the leading classes of prescription drugs currently used to treat AD. The preclinical studies indicated that EpiCeram® has a dramatic and rapid positive impact on skin barrier repair as well as an effect on inflammation similar to that seen with steroids.
Intellectual Property
Ceragenix’s Barrier Repair Technology was licensed from the University of California where it was invented in the laboratory of Peter Elias, M.D. The license grants exclusive U.S. and international rights to issued patent 5,643,899 “Lipids for epidermal moisturization and repair of barrier function” for use in prescription products. The patent covers the combination and specific molar ratio of physiologic lipids, (including ceramides, cholesterol and fatty acids), which help to restore proper skin barrier function and is in effect until 2014.
Ceragenins — Scientific Background
Ceragenins™ are a new class of broad-spectrum antimicrobial agents designed to capture the properties of naturally occurring host defense peptides. The skin actively contributes to host defense by mounting an innate immune response that includes the production of antimicrobial peptides, and it is estimated that 99%+ of all pathogens reaching the body (that are able to break through the skin’s barrier) are eliminated by these peptides. This widely studied class of compound is found extensively in nature and is produced by most species. Antimicrobial peptides possess direct bactericidal properties and provide rapid, broad-spectrum defense against infection. In addition to their natural antibiotic activity, cationic peptides play a key role in the innate immune response, and recent evidence suggests that host defense peptides are effective adjuvants, are synergistic with other immune effectors, and support wound healing.
The peptides’ antimicrobial activity is due in part to their unique physiochemical properties and their cationic charge in particular, which allows these compounds to attach to and insert into the surface of pathogens and form pores which effectively disintegrate bacterial, fungal or viral membranes. Conventional antibiotics generally kill microbes by inhibiting internal targets, which are active during their growth and which can evolve to resist or evade the drug targeting them. Thus microbes can evolve different mechanisms by which they resist current antibiotics. In contrast, host defense peptides have bacteria killing activity at any stage of growth and disintegrate the microbial membrane, a target that is much less subject to change than internal targets, and without which organisms are generally unable to survive. Thus, pathogens are much less likely to develop resistance against this unique mechanism of action.
In collaboration with Ceragenix, Dr. Savage has designed and synthesized the first series of this novel class of small molecule compounds based on cationic aminosterols steroids which led to their initial description as “cationic steroid antibiotics”. This class of compounds is now referred to as Ceragenins.™
Two lead compounds were selected from the series; these compounds are polyfunctional and have activity not only against bacteria, but also against certain fungi (Candida) and viruses (orthopox family) and against biofilms. CSA-13 is currently the lead development candidate and CSA-54 was selected for further study as an antiviral agent.
Data & Initial Studies
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Bacterial Strain
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MIC Value (μ/ml)
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Pseudomonas aeruginosa
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1 to 3
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E. coli
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2 to 4
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Methicillin-resistant staph aureus (MRSA)
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0.5
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Vancomycin-resistant staph aureus (VRSA)
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0.16
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Vancomycin-resistant enterococci (VRE) faecium
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0.125 to 0.5
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Vancomycin-resistant enterococci (VRE) faecalis
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0.5 to 4
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