Using the Skin Microbiome to Control Atopic Dermatitis

A topical atopic dermatitis (AD) treatment derived from skin bacteria demonstrated safety and preliminary evidence of clinical activity in a proof-of-principle study.

After seven days of treatment, MSB-0221 significantly reduced Staphylococcus aureus colonization in S. aureus-associated AD and inhibited expression of mRNA for the S. aureus toxin PSM-alpha. The compound inhibited inflammation-inducing toxin irrespective of its activity against S. aureus. A post hoc evaluation limited to patients with confirmed S. aureus killing suggested improvement in local eczema severity.

Patients treated with MSB-0221 had fewer AD-related adverse events (AEs) as compared with patients treated with a topical delivery substance (vehicle) without S. hominis (ShA9), a naturally occurring skin bacteria incorporated into MSB-0221, reported Richard L. Gallo, MD, PhD, of the University of California San Diego, and colleagues in Nature Medicine.

“Besides its effect on decreasing the redness and itch in a subset of patients, and dramatically and rapidly decreasing the colonization by Staph aureus, one of the unique aspects of this is that it’s specific for this organism,” said Gallo, co-founder of MatriSys Bioscience, the company that is developing MSB-0221. “It was not detrimental to other members of the microbiome that could help restore balance.”

The research platform that selected MSB-0221 and elucidated its mechanism of action has led to identification of additional beneficial skin bacteria that might be used to treat other inflammatory skin diseases, he added. The platform has helped create the potential for a precision medicine approach to inflammatory skin diseases.

Background

AD often is associated with colonization and proliferation of S. aureus, which induces a proteolytic breakdown of the epidermal barrier and dermal immune dysregulation, Gallo and colleagues noted. The colonization leads to increased production of proinflammatory cytokines and suppression of antimicrobial peptides (AMPs), causing additional dysregulation of the skin microbiome and perpetuation of the disease cycle.

In addition to intrinsic AMPs, some strains of skin commensal, coagulase-negative staphylococci (CoNS) produce bacteriocins that selectively inhibit nonresident pathogenic bacteria, such as S. aureus, the authors continued. Most patients with AD lack the protective strains of CoNS.

Investigators hypothesized that reintroducing a protective strain of CoNS would have therapeutic activity in AD. Preclinical studies showed that ShA9 killed S. aureus in the skin of mice and inhibited expression of proinflammatory PSM-alpha. The results provided support for a phase I, first-in-human randomized trial of MSB-0221.

The study included 54 adults with moderate-to-severe AD involving the ventral arms and culture-confirmed colonization of S. aureus. The patients were randomized 2:1 to MSB-0221 or vehicle, applied twice daily for seven days. Patients in both groups had clinical assessments before the start of randomized treatment and at the end of the study.

Skin swabs were obtained for analysis on days one, four, and seven. Additional clinical assessments occurred one, two, and four days after the final application of randomized therapy, and skin swabs were obtained at the same time. The primary endpoint was the safety of MSB-0221 on day eight, as compared with the control group.

Results; Looking Ahead

AEs were assessed by patient self-report in a daily diary. The results showed that 83.3% of patients in the control group reported at least one AE as compared with 55.6% of patients treated with MSB-0221 (P=0.044). The per-patient rate of treatment-emergent AEs was 0.19 for the MSB-0221 group and 0.34 for the control arm (P=0.075).

More than 90% of AEs in both groups were mild and consisted primarily of events associated with the clinical course of AD, including eczema, pain, and swelling. No serious AEs occurred in either group.

Data for biologic and clinical activity showed that MSB-0221 significantly reduced colony-forming units of S. aureus during treatment and in the 96-hour follow-up afterward, as compared with the control group (P=7.9 x 10^-4 to 3.5 x 10^-5). In vitro growth inhibition of S. aureus by ShA9 correlated with changes in skin colonization during treatment and afterward.

Investigators also observed a correlation between ShA9 killing of S. aureus strains isolated from patients, S. aureus survival on lesions, and improvement in the Eczema Area and Severity Index (EASI) among patients randomized to MSB-0221 (P=0.008) but not the control group (P=0.48).

Additional analyses showed an inverse correlation between PSM-alpha expression and expression of ShA9 auto-inducing peptides, which have an inhibitor effect on S. aureus, independent of S. aureus killing. Reduced expression of PSM-alpha mRNA also correlated with improvement in EASI score on day seven.

Gallo told MedPage Today that the next step in evaluating MSB-0221 will be a 150-patient, randomized, placebo-controlled phase II trial with a treatment duration of 12 weeks.

The findings are consistent with a fairly extensive history and recognition of the involvement of the skin microbiome in AD, said Bruce Brod, MD, of the University of Pennsylvania in Philadelphia.

“We don’t fully understand all of the ramifications, but there seems to be at least a subset of patients with atopic dermatitis whose disease is influenced and exacerbated by certain bacteria, such as Staph aureus,” said Brod, who is a spokesperson for the American Academy of Dermatology. “There is still sort of a chicken-and-egg aspect to the relationship. Did the skin inflammation come first or the Staph aureus?”

“This is a proof-of-concept study that provides some evidence that shifting the balance of another bacteria that’s not pathogenic might have some therapeutic benefit in some patients with atopic dermatitis,” he added. “It provides support for larger studies looking at safe bacteria to shift the flora to a more favorable environment. At this point, it’s just another piece of a puzzle that could one day lead to different therapies. It’s probably not the whole picture, but in some patients, it may play a significant role.”