The gastrointestinal (GI) tract, skin and respiratory tract contain vast resident microbial communities, and imbalance or reduced diversity in these populations can contribute to immunological diseases. Research suggests that compromised biodiversity in the gut may influence the pathogenesis not only of GI indications, but those of respiratory and dermatological diseases as well. These connections are known as the gut-lung and gut-skin axes.

GlobalData’s upcoming report, Thematic Research: Microbiome-Targeted Therapeutics in Immunology, indicates 23 microbiome-targeting therapeutics currently being developed in the US, UK and 4EU (France, Germany, Italy and Spain) for GI, dermatological and respiratory conditions. Each of these therapies aims to address disease by manipulating the microbiome. Figure 1 summarises all pipeline products in Phase I, II and III development.

Most microbiome-targeting agents in the pipeline are in the early stages of development, with roughly half in Phase I and half in Phase II. Out of the 23 drugs, 13 are being investigated for GI indications, with the majority targeting ulcerative colitis (UC), whereas six and four are being developed for dermatological and respiratory conditions respectively. Many of the microbiome-targeting drugs for dermatological and respiratory indications are oral formulations, likely targeting these diseases via the gut-skin and gut-lung axes respectively.

The market is currently dominated by small and mid-size biotech, but Big Pharma players such as Takeda and Johnson and Johnson have shown increasing interest in this space lately, with the development of the Phase II agent Sibofimloc (NCT03943446) and Phase I agent JNJ-72537634 (NCT03931447) respectively. Four therapies are in late-stage Phase II trials, namely 4D Pharma’s Blautix for irritable bowel syndrome (IBS), AOBiome’s B-244 for acne vulgaris and atopic dermatitis (AD), Evelo Biosciences’ EDP-1815 for psoriasis, and Seres Therapeutics’ SER-287 for UC. Of these agents, key opinion leaders interviewed by GlobalData were particularly enthusiastic about the prospects of 4D Pharma’s Blautix and AOBiome’s B-244, as both agents have already demonstrated promising data in Phase Ib or in early Phase II trials.

IBS is a non-inflammatory GI condition equally separated into three sub-categories, namely IBS-C (constipation-predominant), IBS-D (diarrhoea-predominant), and IBS-M (mixed with constipation and diarrhoea). Decreased biodiversity and imbalance of bacterial levels in the gut microflora are involved in IBS manifestation, which is what Blautix is aiming to address. The therapy is an oral formulation that releases single strains of commensal Blautia hydrogenotrophica that consume H₂ gases causing bloating during the disease. The drug also induces acetate production (which promotes gut health) and increases microbiome diversity, ultimately trying to tackle both the cause and effect of the disorder.

Blautix is currently being evaluated in a Phase IIb trial (NCT03721107) but has shown encouraging efficacy and safety results in a previous Phase Ib trial. What is most promising about this candidate is that it is under investigation for both sub-groups of IBS-C and IBS-D patients, which have had very different therapeutic regimens until now. If successful, Blautix would be the first marketed product capable of treating both conditions.

The product could, consequently, also be effective in treating IBS-M patients (one third of IBS cases) who have so far had no treatments approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Blautix could ultimately have a strong impact on the market by being the first microbiome-targeting therapy for IBS and the first treatment approved for both IBS-C and IBS-D, which could potentially grant it the exclusive market share of IBS-M patients.

B-244 is a topical product under development by AOBiome for the treatment of acne and AD. The therapy contains ammonia-oxidising bacteria Nitrosomonas eutropha D23. B-244 converts ammonia into nitric oxide (NO) to reduce pH, effectively killing the bacteria implicated in these two dermatological diseases. GlobalData expects this product may gain popularity if marketed as a more ‘natural’ alternative to topical retinoids in acne or corticosteroids in AD.

So far, B-244 has displayed good efficacy and tolerability for both acne and AD. It is currently in a Phase IIb trial (NCT04490109) for mild-to-moderate AD and has already been evaluated in a Phase IIb trial for mild-to-moderate acne (NCT02832063). Although AOBiome read out positive data for NCT02832063 in 2017, the company has seemingly stalled the development of B-244 in acne, possibly prioritising the drug’s launch in AD. If successful in clinical trials, B-244 will be the first skin microbiome-targeting drug to enter the market. GlobalData believes its unique mechanism of action and potential to manage two distinct conditions may lead to strong uptake by patients.

The microbiome is a space with high potential, a fact underlined by the complete absence of any microbiome-targeting treatments on the market. The current pipeline holds numerous potential candidates, with the majority still in the early stages of drug development and only four in late-stage trials for GI, dermatological and respiratory indications. Products such as Blautix and B-244 in particular are microbiome-targeting candidates setting high expectations by either meeting the unmet needs of difficult-to-treat patients or by addressing multiple indications.