Skin Microbiome Medicines in Development to Treat Skin Diseases: Discussion with Keay Nakae, CFA

The skin supports a delicate ecosystem of microbial elements. Although the skin usually provides a barrier, several dermatologic diseases have been linked to these microbes and how they interact with the internal body environment. Understanding changes in the microbiome within disease pathophysiology means understanding the potential to treat these dermatologic diseases by restoring equilibrium. With the rising popularity of holistic and natural treatment options such as prebiotics and probiotics, more natural therapies are under study to find alternative treatments to these skin disorders through manipulation or supplementation of the microbiome.

What Are Skin Microbiomes?
The skin is home to a diverse variety of microorganisms, most of which are harmless and even beneficial. The development of molecular methods to identify microorganisms has led to an emerging view of the resident skin bacteria as highly diverse and variable. An enhanced understanding of the skin microbiome is necessary to gain insight into microbial involvement in human skin disorders and to enable novel promicrobial and antimicrobial therapeutic approaches for their treatment.

Many companies are starting to emerge as leaders in the skin microbiome sphere, with some taking a unique approach to using the skin’s natural microbiome to treat many common skin conditions, such as:

• Monoclonal microbials, or single strains of bacteria derived from the human microbiome selected for anti-inflammatory properties
• Live biotherapeutic product (LBP), which consists of three therapeutic strains of a gram-negative bacteria that were specifically selected for their impact on key parameters of inflammatory skin disease
• Removal of the bad bacteria from the microbiome through a phage-based approach

Traditional Treatments and Steroid Use vs the Microbiome Option
 

Atopic dermatitis (AD) is an inflammatory skin condition that, depending on severity, can cause enormous suffering and discomfort. Currently, corticosteroids and systemic immunosuppression, which is the usual standard of care alongside basic skin care for difficult-to-treat cases of this disease, have many undesirable side effects. Children in particular are of increased susceptibility to side effects from steroids, and one study out of Italy found 81% of parents have a fear of topical corticosteroids.¹ Research is currently focused on evolving dermatologic treatments toward a more steroid-free future, or at least development of steroid-free options that work just as well.

“Seventy percent of the kids who have [AD] aren’t going to be on [steroids] because the parents understand that there are safety issues,” said Keay Nakae, CFA, senior research analyst at Chardan, a health care investment bank based in New York City, NY. “This leaves a great medical need. Microbiomes are nonsteroidal, which means a more natural product that can be applied topically, which means no steroids will enter the bloodstream and risk affecting a child’s growth.”

This is where skin microbiomes come in to play and provide a much more appealing treatment path for children and even adults. The idea is that by managing the skin’s natural bacteria, the skin’s own ecosystem can essentially cure itself. “These bacteria have the ability to do things when they interact with the skin that is associated with reducing inflammation, which is the key issue in diseases such as [AD] and psoriasis,” Nakae said. He then added that these good bacteria are intended to not only reduce inflammation but also help heal the skin. “Wound healing is important; it’s not just about clearing out bad bacteria but also having repair, helping to really address the disease on the skin,” he added.

There are a handful of microbiome medicine companies that are currently in the middle of clinical trials, some of which are in phase 2 of their research. The EDP1815 compound is in phase 2 and phase 1b clinical studies as a treatment for psoriasis. Another compound, the LBP FB-401, previously completed a phase 1b/2a trial that showed some very promising results for AD. That said, according to Nakae, what has been missing in the microbiome until last year was efficacy, and this has been due to clinical trials lacking a control arm. The phase 1b/2a trial of FB-401 was a single arm study with a small sample size. In early September 2021, it was announced that FB-401 failed to demonstrate a benefit in a subsequent larger, randomized, placebo-controlled phase 2b study of AD. “Given that microbiome medicines are an emerging therapeutic approach, these types of clinical failures are going to occur along the way,” Nakae said.

Nakae is enthusiastic about a phage-based approach in acne with BX001, which has completed phase 2 clinical research, and BXOO5, which has completed preclinical research in atopic dermatitis. “This approach is to solely get rid of the bad bacteria, rather than introducing bacteria to rebalance the microbiome,” he said. Bacteriophages (phages) are viruses that can infect and kill bacteria in a highly specific manner. In a phage-based approach, researchers will leverage the evolutionary process by which viruses “learn” to kill specific bacteria over time. Different phage combinations will target a subset of strains of a specific bacterium that is associated with a targeted disease. Depending on the disease, there is a known bacterial composition, and the phages are selected to kill a specific bacterium within that composition that is thought to be causal of disease.

Staphylococcus aureus, also known as the bacteria that is implicated in the dreaded itch-scratch cycle, is arguably the most dangerous of all the common staphylococcal bacteria. When a patient scratches the skin in response to inflammation, they break the natural skin barrier, which in turn makes the deeper layers of the skin vulnerable to bacteria that would not normally be able to penetrate that outer barrier. This allows S aureus to enter the skin, make the AD worse, and thus cause more scratching. “What is understood in terms of the microbiome is that it may be possible to design a therapeutic for patients that were developing a colonization of S aureus,” Nakae said. “If knock down of the inflammatory response with a nonsteroidal treatment can be achieved, this could facilitate moving away from the traditional treatment of steroids.”

Microbiomes: Only for AD?
In addition to AD, researchers are also looking into skin microbiomes when treating acne by targeting specific disease-associated bacteria. Currently, there are many over-the-counter treatments for acne and the market is so saturated that newer companies are finding it tough to break into it. Some newer companies are starting to stray away from topical acne treatments and look toward marketing microbiome treatments through cosmetics companies. “The strategy here will be to pursue commercialization [of microbiomes as an acne treatment] as a cosmeceutical,” Nakae said. “Once this is on the market, it could potentially unlock another important example of phage evolution and their ability to take down negative bacteria.”

But skin conditions are not the only thing that researchers are looking to treat with microbiomes. Cystic fibrosis, some forms of cancer, inflammatory bowel disease, and even primary sclerosing cholangitis may all be treated using phage cocktails and microbiome therapy. “A number of different diseases have associated ‘bad’ bacteria,” Nakae said. “And if you have a disease where bacteria can be knocked down for a patient’s benefit, those are the types of indications that [researchers] are looking to pursue.”

So when can we truly expect these clinical trials to move into actual products on the market? It may be a bit sooner than we all originally thought. “We could see 2022 as the year for emergence of the microbiome more broadly,” Nakae said. “And since big pharma is involved, there’s going to be a lot of attention if it takes off.”

Reference

1. El Hachem M, Gesualdo F, Ricci G, et al. Topical corticosteroid phobia in parents of pediatric patients with atopic dermatitis: a multicentre survey. Ital J Pediatr. 2017;43(1):22. doi:10.1186/s13052-017-0330-7