|
The novel Ceragenin™ class of anti-infectives and the Barrier Repair Technology (BRT) are complementary technologies that derive from the Company’s 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 with innate immunity agents. In particular, the stratum corneum (SC) plays critical functional roles in a number of important areas, including 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 two clinical studies. The first product, EpiCeram®, was launched by Promius Pharma in October 2008. Products based on Ceragenin™ technology have demonstrated significant activity against most important human pathogens, including highly resistant and potentially lethal strains, and are currently undergoing preclinical testing.
Skin Barrier Repair — Scientific Background
The process by which healthy skin renews itself depends on the presence of a healthy 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: ceramides, cholesterols, and free fatty acids. Abnormal skin barrier function is 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
Dr. Peter Elias, Chairman of Ceragenix’ Scientific Advisory Board 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 restores 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 and two human clinical trials. It was demonstrated to have comparable efficacy to a mid strength topical steroid and a commonly prescribed immunomodulator after 28 days of treatment.
Intellectual Property
Ceragenix’ 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.
Ceragenin™ Antimicrobial — Scientific Background
Ceragenins™ are synthetic non-peptides that mimic a key component of the human innate immune system.
Key Antimicrobial Attributes: highly effective at low concentrations, broad spectrum of activity, limited chance of resistance, prevents and eradicates biofilms.
Ceragenin™ CSA-13 may be incorporated directly into medical devices, coated as CeraSheild™ onto medical devices, or used in solution.
General Physical Characteristics of Ceragenins™:
- White, lyophilizable powder
- Relatively simple to prepare and purify
- Readily soluble in water (up to 5 percent)
- Heat stable (autoclavable)
- Can be stored for long periods without degradation
- Simplicity of structure allows Ceragenins™ to attach to polymers and surfaces
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.
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. Paul Savage of Brigham Young University has designed and synthesized the first series of this novel class of small molecule compounds based on cationic aminosterol 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 biofilms. CSA-13 is the primary development candidate.
Data & Initial Studies
|
Bacterial Strain
|
MIC Value (μ/ml)
|
|
Pseudomonas aeruginosa
|
1 to 3
|
|
E. coli
|
2 to 4
|
|
Methicillin-resistant staph aureus (MRSA)
|
0.5
|
|
Vancomycin-resistant staph aureus (VRSA)
|
0.16
|
|
Vancomycin-resistant enterococci (VRE) faecium
|
0.125 to 0.5
|
|
Vancomycin-resistant enterococci (VRE) faecalis
|
0.5 to 4
|
|
