A nitric oxide-releasing cream to treat psoriasis and atopic dermatitis is in development at Novan Inc.
The cream, currently called SB414, is a mixture of a hydrogel and Novan’s new chemical entity, the stable ointment containing NVN1000 which is also the active ingredient in three other nitric oxide-releasing drug products in development by Novan. The latter three are different gel formulations of the same product for different skin and nail conditions: SB204 for acne vulgaris, SB206 for external genital and perianal warts, and SB208 for tinea pedis and onychomycosis.
The cream differs from the gels in its release rate of nitric oxide, the concentration of the active ingredient and variances in pH, as well as cosmetic properties.
“What is so exciting about SB414 is that we have a stable drug product capable of delivering nitric oxide concentrations that can provide an anti-inflammatory pharmacological effect, with little or no toxicity,” says Stanley Hollenbach, senior vice president of research and development at Novan. He spoke on SB414 at the annual meeting of the Society for Investigative Dermatology held in April in Portland, Oregon.
The product’s design, a dual chamber pump, is as important as the active ingredients which are designed to work together. “When the ointment and hydrogel are dispensed together and mixed, a self-emulsifying cream formulation is created that immediately starts to release nitric oxide from the polysiloxane macromolecule that harnesses the nitric oxide,” he said.
Nitric oxide’s role
Nitric oxide works by suppressing cytokines IL-17a and IL-17f, which are known to play a role in the pathogenesis of psoriasis. It also directly inhibits NF-kB and suppresses other pro-inflammatory cytokines, such as IL-1β. And, it inhibits the NLRP3 inflammasome assembly via S-nitrosation of the NLRP3 protein components.
The antibacterial properties of nitric oxide are also of benefit in treating atopic dermatitis, Mr. Hollenbach said.
“All of our creams and gels have been able to demonstrate anti-microbial effects. SB204 and SB414 have demonstrated potent bactericidal effects against Staphylococcus aureus, which we believe plays a significant role in the initiation and severity of the disease. Typically, the affected sites of atopic dermatitis patients are populated with an inordinate amount of Staphylococcus aureus,” he said.
Mr. Hollenbach and his colleagues at Novan are encouraged by the pre-clinical data published recently by Gallo and co-workers at the University of California, San Diego, and the hypothesis that Staphylococcus aureus penetrates down below the epidermal layers and into the dermis and adipose tissue, as a clinically relevant stimulus of atopic dermatitis disease.
“Nitric oxide can penetrate through the epidermal layers. With SB414’s extraordinarily strong and powerful antibacterial effects, we expect that we will be able to eradicate the bacterial component of atopic dermatitis disease, as well as modulate the inflammatory components of the disease,” he said.
For atopic dermatitis, SB414 was evaluated in a mouse inflammation model of delayed hypersensitivity and in a mini pig model of partial thickness skin wounds infected with a methicillin-resistant Staphylococcus aureus strain isolated from a patient with atopic dermatitis.
“SB414 treatment demonstrated anti-inflammatory effects equivalent to a high potency corticosteroid in the mouse model and, with only five daily treatments, was able to essentially eradicate 99.9% of the Staph infection in the porcine infected wound model,” Mr. Hollenbach said.
Novan plans to initiate clinical development of SB414 this summer by filing an investigational new drug application, which will be followed by a phase 2 proof-of-concept clinical trials in patients with mild to moderate psoriasis. The plan is to enroll 120 patients who will receive at least two SB414 doses twice a day for eight weeks. The treatment group will be compared against an active comparator and placebo.
The hope is that Novan’s product will turn out to be a safer and more effective alternative to existing treatments, such as corticosteroids and calcineurin inhibitor topical agents.