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
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