From Acne to Immunotherapy: new applications for FMT (Faecal Microbiota Transplantation)

We recently took a detailed view of the human ecosystem and microbiota, examining how peptides, probiotics, bacteria and phages are all being investigated as potential ways to alter the microbiome’s constituency, and to reduce risk of disease.

This time we’ll again put Faecal Microbiota Transplantation (FMT) back under the microscope and look at some of the current challenges and how they are being approached through trials in both Phase II and Phase III.

The challenge of repeatability

One challenge in using FMT with faecal samples from healthy donors is repeatability. So a number of companies such as Seres Therapeutics, working with Nestlé Health, are taking a more focused approach. Seres has developed SER 109 which is based on a mixture of bacterial spores enriched and purified from healthy, screened human donor stools. This approach offers control over the donated microbe population when compared to the more conventional FMT approach.

Seres has initiated a Phase III trial for SER 109, which is aimed at lowering the rate of recurrence for patients suffering from Clostridium difficile (C. diff) infections. An earlier phase II trial failed to meet endpoints, with 44 percent of patients (26 of 59) on SER 109 had their C. diff recur after 8 weeks, compared to 53 percent (16 of 30) of those on placebo. However, Seres suggests it didn’t test a high enough dose of SER 109, and that some patients may not have even had C. diff infection. Despite this, Seres now plans to enroll approximately 320 patients with multiply recurrent C. diff infection for its phase III trial, at sites in both the U.S. and Canada. SER 109 has been designated by the FDA as a Breakthrough Therapy and also has obtained Orphan Drug designation.

Phase II trials:

• Prevention of recurrent C. diff infection

Rebiotix/Ferring are using a broad-spectrum microbiota suspension called RBX 2660 designed to rehabilitate the human microbiome by delivering live microbes into a patient's intestinal tract to treat disease. It has now completed 3 phase II trials, with top line results from a controlled open-label Phase II trial of RBX 2660 (PUNCH Open Label) for the prevention of recurrent C. diff infection, for example, indicating that RBX 2660 is well-tolerated and achieved the primary efficacy endpoint of preventing C. diff recurrence; patients treated with RBX 2660 exhibited a treatment success rate of 78.8% compared with a historical control of 51.8%. So far RBX 2660 has received FDA Fast Track, Breakthrough Therapy and Orphan Drug Designations.

Rebiotix is developing RBX 2660 for other indications too, including pediatric ulcerative colitis, elimination of vancomycin-resistant enterococci (VRE), multidrug-resistant UTI and hepatic encephalopathy. It is also working on RBX 7455, a non-frozen, lyophilised oral capsule formulation, for recurrent C. diff.

• Inflammatory bowel disease

Synthetic Biologics has several products in phase II: SYN 004 (ribaxamase) an oral enzyme tablet engineered to survive the stomach so allowing IV beta-lactam antibiotics to treat infection while ribaxamase protects and preserves the naturally occurring gut microbiome from the onset of antibiotic-mediated primary C. diff infection. It also has SYN 010, a proprietary, modified-release formulation of lovastatin lactone that is designed to bypass the stomach and reduce the body's natural methane production in the GI tract, to treat an underlying cause of the symptoms associated with irritable bowel syndrome with constipation (IBS-C). Both are close to phase III trials.

• Acne vulgaris

Also in phase II is AOBiome Therapeutics’ Ammonia Oxidizing Bacteria (AOB) product candidate for the treatment of mild-to-moderate acne vulgaris. AOBiome's candidate is a first-in-class, topical formulation of a single strain of beneficial AOB, Nitrosomonas eutropha. This treatment has achieved the primary endpoint at Week 12 of a statistically significant reduction in acne severity compared to control. The study also showed a trend in the reduction of the number of inflammatory lesions.

Preclinical trials:

• Cancer immunotherapy

Vedanta Bioscience uses defined bacterial consortium in powder form to alter the microbiome in patients guts. Vedanta has built up a library of more than 40,000 bacterial isolates from around the world to use in its studies. So far it has VE 303 for C. diff infection in phase I, with VE 202 for inflammatory bowel disease (developed in conjunction with Janssen Biotech), VE 416 for food allergy and VE 800 for cancer immunotherapy, all in preclinical stages.

• Superbugs

Matrisys Bioscience plans to use molecules produced by "good" bacteria from healthy human skin to kill disease-causing bacteria such as Staphylococcus aureus (S. aureus) and MRSA. In tests these good bacteria were formulated in a cream and used to successfully kill S. aureus on the skin of patients with atopic dermatitis. The company’s lead product MSB 01 is intended for the treatment of atopic dermatitis. It is also in preclinical development for rosacea and psoriasis.

A look to the future: Probiotic bacteria armed with unique DNA genetic circuits

Boston-based Synlogic’s lead product SYNB 1618 is currently in phase II trials for phenylketonuria (PKU). The company has engineered a probiotic bacteria to carry specialised assemblies of DNA called genetic circuits. These circuits allow the medicines to "sense" a patient’s internal environment and respond by turning an engineered metabolic pathway on or off. SYNB 1618 is designed to function in the gastrointestinal tract and has been engineered to consume phenylalanine, an amino acid that can accumulate to harmful levels in patients with PKU. Against placebo, SYNB 1618 successfully met the study’s primary objectives of safety and tolerability and identified a suitable dose.

See part 1 of our focus on faecal microbionta here: Unravelling the microbiome – health through happy communities.