Inflammatory Skin Diseases
Inflammatory skin disorders are the results of immune system reactions that involve the skin. Psoriasis is a chronic inflammatory skin disease that affects approximately 7.5 million people in the US. The disease is characterized by an errant immune-system response that drives inflammation and thickening of the skin caused by rapid turnover of skin cells. Psoriasis and other inflammatory skin diseases such as atopic dermatitis can cause tremendous discomfort. The healthcare market has seen an increase in the introduction of systemic therapies, including biologics, to treat patients with moderate-to-severe psoriasis and atopic dermatitis. For the majority of affected patients with less severe disease burden, topical corticosteroids are the predominant therapies prescribed. None of the currently approved therapies are without side effects, and none are well-suited for chronic use.
According to a recent, peer-reviewed article in the British Journal of Dermatology, IL-17, a key inflammatory cytokine, is known to be or is likely to be related to the mechanism and severity of a number of inflammatory skin disorders. IL-17 activation leads to propagation of several pro-inflammatory signaling cascades. Binding of IL-17 to its cognate receptor signals keratinocytes and other cell types to generate and release pro-inflammatory cytokines IL-1ß and IL-6 resulting in enhanced inflammasome activation.
Nitric Oxide and NLRP3 Inflammasome
Nitric oxide has the potential to disrupt the propagation of IL-17 locally in the skin through its ability to disrupt the assembly and activity of the NLRP3 inflammasome. Nitric oxide has been previously shown to modify NLRP3 such that it is unable to associate with the adaptor protein ASC and caspase-1 to assemble the macromolecular NLRP3 inflammasome complex.
SB414, a topical cream-based product candidate, is being developed for the treatment of inflammatory skin diseases. Novan expects file an IND with the FDA for SB414 and initiate clinical development with two Phase 1b trials in patients with psoriasis and atopic dermatitis in the second half of 2017.
- In a psoriasis mouse model, SB414 significantly (p<0.05) reduced composite psoriasis scores and also inhibited the production of pro-inflammatory cytokines, including interleukin-17, or IL-17a and IL-17f.
- In two in vivo models that assess critical components of atopic dermatitis disease pathology, SB414 displayed potent anti-staphylococcal activity and dose-dependent inhibition of inflammation comparable to betamethasone, a mid-potency corticosteroid used to treat eczema patients.