Data from Pharmawand - Curated by EPG Health - Date added 30 October 2018

The human body is host to trillions of microbial organisms which live on skin, for instance, on the surface of lungs and on the surface of the gut. This vast ecosystem includes bacteria, yeasts, fungi, viruses and protozoans, outnumbering our own cells 3 to 1. Acquired at birth and during the first couple of years of life, this microbiota or “microbiome” is maintained over a lifetime by interactions with the environment, food, and the drugs we use. There is growing evidence that the balance of communities it contains can directly affect the health of an individual. Take a situation where particular strains of “good” microbes are reduced or even eliminated, for example, allowing new or “bad” strains to take over. Researchers are turning up convincing pointers that altering the microbiome’s population balance in this way could directly impact health. Detailed mechanisms remain to be unpicked, but there is some evidence that the microbiome can influence the risk of suffering from cardiovascular disease, inflammatory or autoimmune diseases, diabetes, obesity, some cancers, or possibly even help trigger conditions like anxiety and depression, or play a role in disorders such as autism.

The last decade has seen an acceleration in interest in tools that can “rebalance” the microbiome, helped by genome sequencing tools. Now peptides, probiotics, bacteria and phages are all being investigated as potential ways to alter the microbiome’s constituency, and to reduce risk of disease [Ref 1].

So far, companies with therapies addressing gastrointestinal and infectious diseases such as Clostridium difficile (C. diff) have captured almost half of all investment. For now, the majority of the large pharmaceutical companies are not directly involved in microbiome R&D. But that's likely to change when positive clinical results start to appear.

Some of the earliest attempts to rebalance an individual's microbiome have involved the transfer of stool samples from a healthy donor into the gastrointestinal tract of the recipient, performed via colonoscopy, by a nasoduodenal tube or as a preparation inside a gel capsule. This is called Fecal Microbiota Transplantation (FMT). The idea is to replace pathogenic bacteria in the gut with healthy bacteria and this has shown promise in the treatment of recurrent and refractory gastrointestinal infections like those caused by C. diff. One study [Ref 2] showed that FMT is more effective than oral vancomycin in preventing further recurrences in individuals who have already had recurrent C. difficile colitis. In fact FMT is being explored in a wide range of indications, utilising a host of bacteria and microbes [Ref 3]. In the longer term, expect this focus to shift towards more specific groups of communities, or individual drugs aimed at suppressing or enhancing specific targets in the microbiome.

Current therapies:

Currently, the FDA only allows the use of FMT without requiring an investigational new drug approval in recurrent C. difficile infection. But there are dozens of clinical studies investigating the impact of FMT on diseases such as diabetes, Crohn's and cirrhosis.

One challenge in using FMT with fecal 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 C. difficile 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. difficile infection. Despite this, Seres now plans to enroll approximately 320 patients with multiply recurrent C. difficile 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:

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. difficile infection, for example, indicating that RBX 2660 is well-tolerated and achieved the primary efficacy endpoint of preventing C. difficile 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. And 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. difficile.

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. difficile 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.

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.

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. difficile 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.   

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.

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.

Phase I and preclinical stage:

Evelo Biosciences is developing cloned compositions of specific strains of naturally-occurring microbes termed monoclonal microbials. EDP 1066 is currently in phase I studies for psoriasis, atopic dermatitis, and ulcerative colitis. EDP 1815 being developed to treat inflammatory diseases. In preclinical testing, EDP 1815 showed immunomodulatory activity on human immune cells and anti-inflammatory activity in discrete tissues, including skin, joints, gut and the central nervous system. Evelo hopes to initiate a clinical trial for EDP 1815 in the fourth quarter of 2018. Meanwhile EDP 1503 is in preclinical trials for oncology – colorectal, renal cell carcinoma, and melanoma.

Axial Biotherapeutics is developing drugs for psychiatric and neurological disorders, in particular a therapeutic to tackle Parkinsons disease using microbiome modification. Meanwhile Nextbiotix is developing microbiome-based therapies using single microbial strains that interact with human cells in the gut to tackle inflammatory bowel disease.

US-based Bloom Science is exploring the way that a ketogenic diet increases the abundance of certain gut bacteria and which also seems to offer protection against epileptic seizure. The company hopes to be able to mimic the diet’s action on the microbiome.

Israeli startup BiomX hopes to tackle inflammatory bowel disease (IBD) which BiomX believe derives from certain gut bacteria. So it is using a phage cocktail to kill these bacteria. BiomX's lead candidate is BX 002, a bacteriophage cocktail developed to target and eradicate pro-inflammatory gut bacteria believed to be implicated in IBD.

Other companies are developing more conventional single molecule therapies. For instance Enterome Biosciences is working in partnership with Nestlé Health Science to develop drug candidates that can influence the health of the microbiome. Its lead product is EB 8108, a small molecule designed to selectively disarm virulent FimH-expressing bacteria without disrupting the gut microbiome aimed at diseases such as Crohn's. EB 8108 is currently in phase I trials. Enterome is also working with Johnson & Johnson to take its other drugs EB 110 and 220 into preclinical and phase I trials for Crohn's disease, and is exploring other pharmaceuticals with Takeda, AbbVie and BMS.

Second Genome, in partnership with Pfizer and Roche, is developing SG 1019, a small molecule P2X7 inhibitor, to target tissue injury and inflammation through inhibition of an inflammasome activation pathway. SG 1019 is in early trials aimed at nonalcoholic steatohepatitis and inflammatory bowel disease.

Over the horizon:

It is generally accepted that intestinal decontamination with non-absorbable antibiotics such as rifaximin is an effective treatment for hepatic encephalopathy. This suggests that gut dysbiosis and the ensuing metabolic consequences involving intestinal absorption of nitrogenous compounds plays a role in the progression of neurocognitive dysfunction.

Cancer is also a target. One study has suggested differences in microbiome in men with cancer compared with benign prostate hypertrophy. It found a higher abundance of Bacteroides massiliensis in prostate cancer and higher Faecalibacterium prausnitzii and Eubacterium rectalie in controls and suggested an influence on micronutrients [4]. Another study identified a 10-microbiome metabolic pathway score that may provide an additional risk factor for prostate cancer, and which is potentially modifiable [5]. Vedanta has developed a bacterial consortia, VE 800, which when combined with checkpoint inhibitors has been found to induce anticancer CD8+ T cells in animal models of melanoma and colon cancer, improving survival and showing infiltration into tumors.

Clearly this emerging field has key questions to answer. The identity of “good” microbes in your gut or on your skin, for instance, is not clear, nor are the relative numbers that typify a “normal healthy” individual. Also what constitutes an unhealthy or “dysbiotic” state: is it characterised by an increase in abundance of “bad” microbes, a decreased abundance of “good” ones, an overall loss of community diversity, or a combination of all three? 

Whatever the answers, microbiome treatments represent a potentially large market. One recent study by Transparency Market Research suggests that the worldwide human microbiome market will be worth $2.2 billion in 2020, reaching $3.2 billion by 2024. Diagnostics and therapeutics are the two main components in this market, with both predicted to hit an annual growth rate of around 9% by 2024.

There are certainly technology gains to be made thanks to genomics instrumentation which is already proving its worth by giving researchers fast methods to analyse the complex genes present in the microbiome. At the same time, however, there are new regulatory hurdles to face, with the FDA and EMA having to decide how best to monitor and control treatments such as FMT and live cell mixtures, as well as refining protocols to standardise testing between treatments [Ref 6].  

References

1) “Microbiome 101: Studying, Analyzing, and Interpreting Gut Microbiome Data for Clinicians” Celeste Allaband et al. Clinical Gastroenterology and Hepatology, online 18 September 2018 https://doi.org/10.1016/j.cgh.2018.09.017.

2) "Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile." Els van Nood et al. N Engl J Med 2013; 368:407-415 DOI: 10.1056/NEJMoa1205037.

3) “Emerging Trends in “Smart Probiotics”: Functional Consideration for the Development of Novel Health and Industrial Applications” Racha El Hage Front Microbiol. 8: 1889. Sep 29. 2017 doi: 10.3389/fmicb.2017.01889.

4) “The role of gut microbiome in the pathogenesis of prostate cancer: a prospective, pilot study.” Golombos, D.M., Ayangbesan, A., O’Malley, P. et al. Urology. 2018; 111: 122–128.

5) “Metabolic Biosynthesis Pathways Identified from Fecal Microbiome Associated with Prostate Cancer” Michael A. Liss European Urology July 11 2018 DOI: https://doi.org/10.1016/j.eururo.2018.06.033.

6) "Faecal microbiota transplantation: a regulatory hurdle?" Frederick Verbeke et al. BMC Gastroenterol. 2017; 17: 128. Nov 28. doi:  10.1186/s12876-017-0687-5.

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