Drug Discovery


References 1Tanoue, T et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature volume 565, pages 600-605 (2019). 2 Gopalakrishnan, V et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science (80-. ). (2018). doi:10.1126/science.aan4236. 3 Evelo Biosciences Reports Positive EDP1815 Interim Clinical Data in Psoriasis Patients at Low Dose in Ongoing Phase 1b Tria. (2019, August 6). Retrieved from http://ir.evelobio.com/news- releases/news-release- details/evelo-biosciences- reports-positive-edp1815- interim-clinical-data. 4 Hsu, B et al. Dynamic Modulation of the Gut Microbiota and Metabolome by Bacteriophages in a Mouse Model. Cell Host & Microbe. (2019). Vol 25, Issue 6, 803- 814. doi:10.1016/j.chom. 2019.05.001. 5 Narasimhaia, M et al. Therapeutic Potential of Staphylococcal Bacteriophages for Nasal Decolonization of Staphylococcus aureus in Mice. Advances in Microbiology. 2013, 3, 52-60. 6 Jeon, J and Yong, D. Two Novel Bacteriophages Improve Survival in Galleria mellonella Infection and Mouse Acute Pneumonia Models Infected with Extensively Drug- Resistant Pseudomonas aeruginosa. Applied & Environmental Microbiology. (2019). 85 (9) e02900-18; doi: 10.1128/AEM.02900-18 9. 7 Leveraging gut microbiota to impact tumor immunotherapy. Retrieved from: http://www.serestherapeutics.c om/sites/default/files/aacr_post er_ser401_final.pdf. 8 Lindenbaum, J, Rund, DG, Butler, VP, Tse-Eng, D and Saha, JR. Inactivation of Digoxin by the Gut Flora: Reversal by Antibiotic Therapy. N. Engl. J. Med. (1981). doi:10.1056/nejm 198110013051403.


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of treatment6. Like many of its peers, Armata is protecting its intellectual property with European and Canadian patents for novel bacteriophages and therapeutic bacteriophage compositions.


Rethinking FMT In the wake of the FDA’s safety alert in June 2019, the days of performing unapproved faecal micro- biota transplantation (FMT) are likely over. However, FMT carried out under an IND is expected to remain a viable approach to manipu- lating the gut microbiome for disease prevention and treatment. It is anticipated that more rigorous testing will become a requirement to both under- stand and inform on the specific bacteria species present in the faecal matter prior to use. When used under an IND and within strict con-


ditions, FMT has proven useful in elucidating inter-patient differences in the response to a given therapeutic. Seres Therapeutics used this approach to validate tumour mouse models of two types – germ-free mice and those treated with antibiotics – that did not respond to an anti-PD1 previously. Following FMT from healthy donors, the germ- free mice responded positively to anti-PD1 treat- ment, due to increased entry of cytotoxic CD8+ T cells into the tumour7. Preclinical studies such as these, using FMT in


concert with mouse models, are helping to inform strategies for the development of microbiome- based therapies that are designed to improve the efficacy of other therapies. In one such example, a Seres live bacteria oral drug candidate (SER-287) is being used in a clinical trial in combination with anti-PD1 therapy in patients with ulcerative colitis.


Understanding transformative effects The potential biotransformation effect of the microbiome is also emerging as a critical issue to consider in drug discovery. Numerous cases have demonstrated the potential for microbial biotrans- formation of a drug, altering its efficacy and/or toxicity. One of the most well-known examples involved the cardiac drug digoxin8. Approximately 10% of patients who took digoxin did not respond to it because their gut microbiomes converted the drug to an inactive form, which was attributed to a single bacterial genus, Eggerthella. The use of antibiotics reversed this effect. The gut microbiome’s ability to transform drug


availability, efficacy and toxicity also was demon- strated with levodopa, which is the leading thera- peutic for Parkinson’s disease and known to have wide variability and efficacy across patients. Scientists at Harvard University identified


Enterococcus faecalis as the potential culprit, link- ing this bacterium to the metabolism of levodopa. E. faecalis absorbs levodopa and converts it to dopamine; another bacterium (Eggerthella lenta) converts the dopamine to meta-tyramine. The investigators hypothesised that the metabolism of levodopa may limit its bioavailability and reduce its efficacy, while causing some of the side effects associated with the drug9. Examples like these bring to the forefront the


complexity of microbiome-based therapy, due to issues such as the potential for biotransformation and the variability of microbiota compositions from one person to the next. As more drugs are characterised by low solubility and/or permeability – spending more time in the gastrointestinal tract and likely having greater interaction with gut microbes – the potential impact of the microbiome on drug metabolism becomes of greater impor- tance for study.


Putting the mouse to best use Microbiome drug discovery holds much promise for the future of disease prevention and treatment, and the mouse model will remain a central tool in this endeavour, enabling investigators to test hypotheses in ways that are not practical in the clinic. The method used in the landmark studies that first linked the gut microbial composition of patients to their response to checkpoint inhibitor therapy – ie, observing a clinical effect then validating it in a mouse model – is a highly viable approach to trans- lational microbiome drug discovery. While homogenous genetics, a comparable phys-


iology and accessibility to a wide range of model types make the mouse a sound choice for micro- biome-related research, it is crucial to address the limitations of the mouse when designing studies for optimum reproducibility and translatability. Several considerations and best practices should be employed when using mouse models in micro- biome-related drug discovery. A key consideration is selection of the most suit-


able model. In addition to the germ-free models that have become almost synonymous with micro- biome research, genetically engineered models that have been used successfully in other work have a role in studying the microbiome, particular- ly its impact on patient response to a given thera- peutic. Where defined bacteria of interest have been identified – as in the case of bacteria consor- tiums – generating a mouse model with a defined microbiome may be the right strategy. This approach affords the flexibility to study a host possessing the microbiota deemed relevant to a


Drug Discovery World Fall 2019


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