Skin barrier impairment, a new paradigm in dermatology conditions and diseases.

The skin barrier is comprised of the uppermost layer of skin as shown in Figure 1. It is crucial for protection of the living layers of the skin from environmental agents such as sunlight, infectious agents, and environmental pollutants. The skin barrier must be continually renewed by activation of cells in the basal layer of skin to regenerate the stratum corneum layer that is the most important part of the skin barrier. Published research over the past 10 years has revealed that multiple dermatology conditions with different causes share a common feature, defective epidermal renewal of the skin barrier (differentiation). These conditions include skin photodamage, actinic keratosis (AK) lesions and squamous cell skin cancers, psoriasis, acne, rosacea, and atopic dermatitis. Additionally, dermatology drugs such as topical retinoids, topical steroids and cancer chemotherapy drugs cause skin barrier impairment leading to side effects of these drugs such as photosensitivity and skin rashes. Drugs that can restore epidermal differentiation to repair the skin barrier have great potential as new efficacious dermatology drugs.

Niadyne Pharma has discovered an unequaled approach for restoring skin barrier integrity.

Niacin (Vitamin B3) has long been known to be an important vitamin and a drug highly effective in controlling blood cholesterol. NPI research has pioneered the discovery of important vitamin and drug effects of niacin in skin. However, niacin itself cannot be used therapeutically for skin due to a side effect termed "skin flushing", which is harmless but severely limits compliance with therapy. NPI has developed patented derivatives of niacin that can deliver niacin to skin without side effects. Our lead drug candidate, Nia-114 is shown in Figure 2. Nia-114 is a "prodrug" of niacin that is generated by addition of a hydrophobic "tail" to the niacin molecule. This slows down the release of Nia-114 into the living layers of the epidermis. After release into the epidermis, Nia-114 is converted back to niacin, which exerts benefit to skin. The slow release of Nia-114 into skin solves the side effect problem of niacin as a therapeutic drug by preventing the skin flushing side effects associated with free niacin.

Nia-114 restores normal epidermal differentiation and skin barrier integrity in chronically sun-damaged skin, a precondition for the formation of AK lesions and skin cancer. An example from a published study (Jacobson et al., Experimental Dermatology, 16, 490-499, 2007) is shown in the left panel of Figure 3, which show typical features of long-term sun exposure (baseline), a thinning epidermal layer and stratum corneum that is the result of poor epidermal differentiation that in turn results in an impaired skin barrier. The top panel labeled 12 weeks shows that treatment with a placebo cream has no significant effect while the three lower panels show the results of treatment with a cream containing Nia-114. The increase in stratum corneum thickness, a key measure of skin barrier integrity is readily apparent. Analysis of the entire study group revealed that Nia-114 (myristyl nicotinate, abbreviated as MN) treatment resulted in an increase in stratum corneum thickness of nearly 70% as shown in the right panel of Figure 3.

The ability of Nia-114 to repair epidermal differentiation defects in photodamaged skin has also been demonstrated in a recently published paper by Niadyne scientists that examined effects of Nia-114 on two key markers of epidermal differentiation, caspase 14 and filaggrin as shown in Figure 4 (Bermadez et al., Public Library of Science Journal, in press, 2011). The left panel shows an example biopsy showing caspase 14 and filaggrin staining at base line and after 12 weeks treatment with a formulation of Nia-114. Quantitative analysis of the placebo and Nia-114 (myristyl nicotinate) groups are shown in the right panel. Nia-114 treatment resulted in increases of approximately 30% for caspase 14 and 20% for filaggrin, respectively, while the placebo formulations has no significant effect. The unequaled ability of Nia-114 to restore normal epidermal differentiation and skin barrier function creates multiple new drug development possibilities in dermatology.

Niadyne Pharma research has shown that niacin reduces skin cancer and normalizes immune function.

In addition to promoting epidermal differentiation, niacin also plays an important role in modulation of the immune system as initially revealed in studies that first reported prevention of skin cancer and immune suppression by sunlight (Gensler et al., Nutrition & Cancer 34, 34-41, 1999). In this study, niacin inhibited skin cancer formation by more than 70% and prevented 85% of the immune suppression caused by UV light exposure. Published studies provide clear evidence of the ability of niacin to reduce skin cancer and normalize immune function.

Nia-114 functions in skin by both nutrient and receptor mediated mechanisms.

Niacin delivered to skin by Nia-114 provides benefit by both nutrient and receptor mediated effects as shown in Figure 5 (Benevente et al., Current Pharmaceutical Design 15, 29-38, 2009). Nutrient effects involve conversion of niacin (NA) to its intracellular bioactive form, NAD, which plays a central role in cellular energy generation as well as a substrate for two classes of enzymes crucial to cell regulation and maintenance of genomic integrity, poly(ADP-ribose) polymerases (PARPs) and NAD-dependent protein deacetylases called sirtuins. Drug effects involve the interaction of niacin with a membrane G-protein coupled receptor that is present in epidermal cells that promotes epidermal differentiation by effects on epidermal keratinocytes and immune normalization by effects on epidermal Langerhans cells (Bermadez et al., Public Library of Science Journal, in press, 2011). The combined nutrient and drug effects of niacin in skin have revealed why delivery of niacin by Nia-114 has such high potential for dermatology drug development.