Nitric oxide cream in pipeline

A nitric oxide-releasing cream to treat psoriasis and atopic dermatitis is in development.

SB414 cream (Novan, Inc.) is a mixture of the stable ointment containing NVN1000 (Novan’s new chemical entity, which is the active pharmaceutical ingredient) and a hydrogel.

The first clinical study of SB414 for the treatment of psoriasis plans to use two separate tubes, but by the time of commercialization the drug product is targeted to be dispensed using a dual-chamber pump.

“When the ointment and hydrogel are dispensed together and mixed, a self-emulsifying cream formulation is created that immediately starts release of the nitric oxide from the polysiloxane macromolecule that harnesses the nitric oxide,” says Stanley Hollenbach, senior vice president of research and development at Novan.

NVN1000 is also the active ingredient for three other nitric oxide-releasing drug products by Novan in development, all of which are different gel formulations as opposed to a cream: SB204 for treatment of acne vulgaris, SB206 for external genital and perianal warts, and SB208 for tinea pedis and onychomycosis.

SB414 differs from these three gels in the release rate of the nitric oxide, 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,” Hollenbach tells Dermatology Times.

In a widely used psoriasis mouse model, SB414 significantly reduced composite psoriasis scores and inhibited the production of proinflammatory cytokines.

For psoriasis, “nitric oxide directly inhibits NF-kB and suppresses proinflammatory cytokines like IL-1β. Additionally, there is direct inhibition of the NLRP3 inflammasome assembly via S-nitrosation of the NLRP3 protein components,” Hollenbach says. “And in so doing, nitric oxide also suppresses IL-17a and IL-17f, which are known to be very influential in the psoriasis disease pathology,” 

For treating atopic dermatitis, SB414 works in a similar fashion. “Nitric oxide downregulates relevant cytokines,” Hollenbach says.

The antibacterial properties of nitric oxide are also of benefit in treating atopic dermatitis. “All of our creams and gels have been able to demonstrate anti-microbial effects, with SB204 and SB414 demonstrating potent bactericidal effects against Staph. aureus,” says Hollenbach, who spoke on SB414 in April at the annual meeting of the Society for Investigative Dermatology in Portland, Oregon

“We believe S. aureus plays a significant role in the initiation and severity of the disease,” Hollenbach says. “Typically, the affected sites of atopic dermatitis patients are populated with an inordinate amount of S. aureus.”

Hollenbach and his colleagues at Novan are intrigued by the preclinical data published recently by Gallo and co-workers at the University of California, San Diego, and the hypothesis that S. 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 is a gas that can penetrate through the epidermal layers,” Mr. Hollenbach says. “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.”

For atopic dermatitis, SB414 was evaluated in a mouse inflammation model of delayed hypersensitivity and in a minipig model of partial thickness skin wounds infected with a methicillin-resistant S. 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,” Hollenbach says.

Novan plans to initiate clinical development of SB414 by the end of June with the filing of an investigational new drug (IND) application, followed by a psoriasis clinical study for mild to moderate disease.

The Phase 2 proof-of-concept trial will likely enroll about 120 patients. At least two SB414 doses will be evaluated against an active comparator and placebo, with therapy administered twice a day for 8 weeks.

A clinical trial for atopic dermatitis could soon follow.

“We believe SB414 could be an effective treatment for psoriasis and atopic dermatitis patients with mild to moderate disease and low body surface area involvement,” Hollenbach says. “And due to the safe, localized delivery, we think it could be used concomitantly with systemic treatments for more severe cases.”

Considering the tolerability that Novan has shown in all of its existing topical products, “we think that the safety of SB414 will be a key differentiator to the other corticosteroid and calcineurin inhibitor topical agents in the marketplace,” Hollenbach says. “However, until we have some clinical data, it is difficult to gauge how SB414 will fit in the total armamentarium of topical anti-inflammatory products.”

Disclosure: Mr. Hollenbach is an employee and shareholder of Novan.