Drug Discovery
space, Vedanta and Evelo, have obtained exclusive licences (from the University of Tokyo and the University of Chicago respectively) for specific applications of the bacteria used in their drug cocktails. Vedanta is advancing its oral biologic candidate
VE800 to clinical trials based on positive preclinical research findings in syngeneic tumour mouse mod- els. A study by Dr Kenya Honda, scientific co- founder of Vedanta, demonstrated the VE800 cock- tail of 11 human-derived bacteria boosted produc- tion of interferon-gamma-producing (IFNy+) CD8+ T cells, which improved anti-tumour immunity and response to immune checkpoint inhibitor therapy in germ-free tumour models1. Previous landmark studies of the microbiome’s
impact on checkpoint inhibitors focused on differ- ences in the gut microbial compositions of respon- der patients versus non-responders – identifying clinical effects of the gut microbiome and validat- ing them in mice transplanted with human micro- biota. For instance, Gopalakrishnan et al observed a correlation between an effective response to anti- PD-1 therapy and the diversity and composition of the gut microbiota, using a melanoma mouse model2. In contrast, the recent Vedanta study iden- tified a defined collection of bacterial strains capa- ble of improving anti-tumour response. Given that the 11 identified strains are not present abundantly in healthy humans, the findings have significant implications for the use of bacterial consortiums as efficacious therapeutics. These preclinical findings paved the way for studying the impact of VE800 on immune checkpoint inhibitor efficacy in the clinic, an effort that Vedanta and BMS are now jointly undertaking. Similarly, Evelo is in clinical trial phase with sev-
eral monoclonal microbial drug candidates – oral- ly-delivered single strains of microbes – after posi- tive preclinical results. Its EDP1503 demonstrated activation of several systemic immune pathways that complement immune checkpoint inhibitors, with an increase in CXCL9 and CXCL10 produc- tion in the tumour microenvironment and enhanced NK and T cell infiltration to the tumour site. These findings set the stage for an Evelo- Merck clinical trial collaboration in which EDP1503 will be studied in combination with Ketyruda in a variety of tumour types, including metastatic melanoma, colorectal and triple-nega- tive breast cancer. Monoclonal microbial drug can- didates also are in testing for psoriasis, showing positive initial results. In August 2019, Evelo released data from a cohort of patients with mild to moderate psoriasis treated with EDP1815, a
Drug Discovery World Fall 2019
monoclonal microbial drug based on Bifidobacteria. After 28 days, patients showed a statistically significant (p<0.05) reduction in aver- age lesion severity score (LSS), while those receiv- ing a placebo had a mean increase in LSS of 0.25 points3.
Harnessing the power of bacteriophages Another emerging strategy in microbiome drug dis- covery is the use of bacteriophages (also called phages) as a tool for manipulating the microbiome for therapeutic purposes. The gut microbiome is known to harbour bacteriophages that interact both with each other and the human host. Researchers studied the effects of bacteriophages on the microbiome in gnotobiotic mice colonised with defined human gut bacteria, incorporating 10 species that represent the major phyla in the gut microbiome. The mice were subjected to predation by cognate lytic phages, capable of infecting and killing a bacterial cell, then multiplying and attack- ing nearby bacterial cells. Using metabolomic pro- filing, investigators discovered that the bacterio- phages had altered the microbiome of the colonised gnotobiotic mice which in turn impacted the gut metabolome4. The results demonstrate how the antagonistic effects of bacteriophages can mod- ulate bacterial colonisation and potentially impact the host, adding to the growing body of evidence that manipulating the microbiome may be an effec- tive therapeutic approach. Armata Pharmaceuticals is among several com-
panies leveraging bacteriophages as potential ther- apeutics, focusing on antibiotic-resistant infections such as Staphylococcus aureus. Preclinical work in mouse models has shown the effectiveness of phages against S. aureus. Two phages (K and 44AHJD) evaluated for efficacy against S. aureus in a mouse nasal colonisation model were found to lyse >85% of the clinical isolates tested5. Data pre- sented at the IDWeek 2018 conference demonstrat- ed the efficacy of Armata’s lead candidate, AB- SA01, in the clinic as well. When AB-SA01 was used as an adjunct to antibiotics in 13 patients with severe S. aureus infections, 83% of patients achieved complete resolution or significant improvement of baseline signs and symptoms. Another Armata investigational therapeutic
based on bacteriophages (AB-PA01), targets the drug-resistant Pseudomonas aeruginosa. In two mouse models of pneumonia, treatment with the phages B -R656 and B -R1836 significantly decreased the bacterial load in the lungs (>6 log10 CFU and >4 log10 CFU, respectively) on day five
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