Dr. James McIlroy

5th Year MBCHB University of Aberdeen

Founder of EnteroBiotix

Faecal Microbiota Transplantation (FMT) Novel approaches to an ancient therapeutic strategy

Personal fees and other from EnteroBiotix Limited Consultancy from Biotechspert Limited

Disclosures

“It is suggested that this simple yet rational therapeutic method should be given more extensive

clinical evaluation.”

- Mr Ben Eiseman, 1958

4th century: Ge Hong described use of human faecal suspension by mouth for diarrhoea and food poisoning “Zghou Hou Bei Ji Fang” Handy Therapy for Emergencies

16th century: Li Shizhen prescribed fermented faeces for abdominal diseases with diarrhoea, abdominal pain, fever, vomiting and constipation; “yellow dragon soup” “Ben Cao Gang Mu ” Compendium of Materia Medica

Instillation of bacteria from a healthy

person into another person to cure

illness associated with

dysregulations of bacteria

Donor sample with healthy

bacteria

Administered by a doctor

Faecal Microbiota Transplantation (FMT)

Restoration of imbalances of

bacteria

Dysregulations of intestinal microbiome homeostasis are associated with a multitude of aliments

Brain

- Stress

-Autism

-Multiple Sclerosis

Unhealthy (dysbiosis) Healthy (symbiosis)

Infection Diet Hygiene Xenotbiotics

Lungs

- Asthma

Liver

- NAFLD

- NASH

Intestine

- IBD

-IBS

-C.diff

- MDRO

Genetics

Adipose Tissue

- Obesity

- Metabolic disease

Systematic Diseases

- Type 1 Diabetes

- Atherosclerosis

- Rheumatoid Arthritis

Adapted from Levy et al Nature Reviews Immunology 17, 219–232 (2017)

Adapted from: Aviv Cohen. Dig Dis Sci 2016 62:5, 1131-1145 Bakker Microbiol Spectr 2017 75:4 Credit: Dr Simon Goldenberg

The gut microbiota in health and disease

Causality Level of complexity Course of disease Responders / non-responders Influence of genetics, diet concomitant medication

Microbiota and disease causality

20%

40%

60%

After first episode After first recurrence After two or more recurrences

Kelly CP, LaMont JT. N Engl J Med. 2008;359(18):1932-1940; Johnson S. International Journal of Antimicrobial Agents 33 (2009) S33-S36. Deshpande et al. ICHE 2015 36:4, 452-60

- Age ≥65 years1-4, 1

- Severe CDI1,4

- Previous episode of CDI1,3-5

- Co-morbidities including renal failure1,4,6,7,10

- Exposure to concomitant antibiotics4, 10

- Infection with particular strains e.g RT

027/B1/NAP1

- Exposure to PPIs8,10

- Previous hospital admission9

1 Kyne et al. Lancet 2001; 357: 189-93 2 Bauer et al. Clin Microbiol Infect 2009; 15: 1067-79 3 Bauer et al. Lancet 2011; 377: 63-73 4 Hu et al. Gastro 2009; 136: 1206-14 5 McFarland et al. Am J Gastroenterol 2002; 97: 1769-75

The gut microbiota in disease – C.difficile

6 Do et al. CID 1998; 26: 954-9 7 Bauer et al. Clin Microbiol Infect 2011; 17: A1-4 8 Kwok et al. Am J Gastro 2012; 107: 1011-9

9 Eyre et al. CID 2012; 55: 77-88 10 Deshpande et al. ICHE 2015 36:4, 452-60

Slide credit Dr. Simon Goldenberg

The microbiota affects C.difficile invasion

Chang JY, et al. J Infect Dis 2008:197;435-8

Time

Adapted from Serestherapeutics

Patients with recurrent CDI have decreased phylogenetic richness

van Nood et al. N Engl J Med 2013;368:407-415

31%

FMT Vancomycin

Faecal transplants – theory, evidence

93%

10.1056/NEJMc1803103

Faecal Microbiota Transplantation (FMT): theory, evidence

Adapted from: Finch Therapeutics

Ruminococcus and

Lachanospiraceae

(Clostridium cluster IV

and XIVa)

Clostridium clusters

IV, XIVa and XVIII

Clostridium cluster IV,

Clostridium cluster

XVIII

IV, XIVa and XVIII are consistently associated with remission

Moayyedi et al. Rossen et al. (TURN trial) Paramsothy et al.

As a research tool

McIlroy J et al. Aliment Pharmacol Ther. 2018;47:26–42.

- Optimal route of administration?

- Optimal processing protocol (aerobic/anaerobic)?

- Optimal dosage?

- Donor characteristics?

- Optimal donor screening protocol?

- Donor patient compatibility?

- Optimal cyroprotectant (glycerol vs PEG vs DSMO vs custom mixes)

- Long term sequelae?

- Suitable for paediatric populations?

- Bowel lavage?

- Encapsulation?

Faecal Microbiota Transplantation (FMT): challenges

Doctors have to source

suitable donors

Then they have screen donors for transmittable

diseases

Then they have to process samples using

budget equipment and limited staff

FMT is currently administered through

invasive medical procedures

The entire process can take more than

three months

Faecal Microbiota Transplantation (FMT): challenges

• ISO:9001 controlled donation • Active donor registry

• cGMP ready facility set up • Trained & Qualified Staff • Isolator technology

• Several batches produced and quality released

• Capsule in development

• First Minister/CMO opening • NHS Tayside collaboration

• Applied for GMP License • Inspection June 18

EnteroBiotix at a glance

Progress & Achievements

Achieved in 2017/2018

Meet the unmet clinical need for safe access to FMT

Support FMT based research and clinical trials

Progress product pipeline through clinical development

Strategy

Create cocktail of bugs

Healthy human

FMT

Healthy human

Microbial signatures, colonisation etc

Diseased human

Adapted from Lawley and Forster Nature Biotechnology 33, 47–49 (2015)

Future perspectives

Identify microbes that drive patient outcomes

IBD IBD

Roseburia

Faecalibacterium prausnitzii

Butyrate producing species

Proteobacteria

Fusobacteria

Mucin degrading species

Specific changes in IBD

ISO

Best in class donor programme

Closed system enabling collection device

Ex-vivo engineering system

• Staff trained to ISO/GMP • MHRA license Q2 18

• Prototype built • CE mark 2019

• High through put closed system processing

Enhancement

• Progress to pre clinical POC

Phase 1 (executed) Phase 2 (Series A)

We are building a best in class platform to enhance microbiota samples

Ex-vivo engineering

Confidential

Summary

- FMT is a relatively safe and powerful treatment option for

recurrent CDI

- FMT is a powerful research tool when combined with stratification of

responders and the interrogation of the associated microbial changes

in patients

-

-

-

Licensed facilities will expand access for patients in hospital,

EnteroBiotix seeking to be supplying hospitals by Q2 2018

Encapsulation expected to aid the design of placebo controlled trials and

further expand access. EnteroBiotix seeking to supply capsules by Q4 18

Advances in technology set to allow for precision microbiome engineering

and there are many novel technologies moving towards clinic

Thank you

Questions?

Stool tests EnteroBiotix (undertaken by Scottish National Reference Laboratory in Glasgow) C.difficile (toxin A/B EIA). Ova and parasites (concentrated and unconcentrated wet preparation examination using microscopy and auramine phenol stain). Giardia antigen. Cryptosporidium antigen. Bacteriology stool culture (for listeria, Salmonella sp, Shigella sp, Campylobacter sp, E Coli VTEC, Vibrio species) Norovirus, Rotavirus, Adenovirus antigen PCR (soon to add Sapiovirus and Astrovirus) Entamoeba histolytica Test (to differentiate from E.dispar) Vancomycin-resistant enterococci (VRE) Carbapenem-resistant Enterobacteriaceae (CRE) Extended-spectrum beta-lactamases (ESBLs) Blood tests EnteroBiotix (undertaken by NHSBT in England) Strongyloides serology Architect HBsAg Architect anti-HBc Architect anti-HCV Architect HIV Ag/Ab (HIV 1+2) Architect Syphilis Ab HTLV 1/2 Ab HCV RNA HIV RNA HBV RNA HEV RNA CMV EBV Hepatitis A IgM