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Ithaka Life Sciences Ltd (Ithaka) is a provider of business advisory and interim management services to the life sciences sector.

Tuesday, 29 April 2014

Re-equilibrating the Microbiome

We all know that the bacterial cell population of the human body outnumbers the body’s own cells by about ten to one, but it now seems that the health of that bacterial population may have a direct bearing on the health of the host, particularly around the guts.  Interventions that can re-equilibrate the gut flora have the potential to treat a number of distressing and persistent conditions.  Re-infection of the intestines and bowel of a patient with a faecal sample from a healthy donor (Faecal Microbiota Transplantation or FMT) has become of so much interest to health providers in recent times that both the FDA and NICE have felt compelled to issue new guidance documents for its use in the last two months.  Questions arise as to how it works, what conditions it could treat, and how it can be delivered and regulated.

Discussion of this potential treatment seems to be held back for two very different reasons: on one hand, the general public regards it as bizarre and unpleasant, and it suffers from a general schoolboy humour (Private Eye published a cutting in its “Funny Old World” section only last week, where the humour lay merely in the concept itself); on the other hand, the reasons behind the actual therapeutic effect remain unclear, with no identifiable active ingredient, no large-scale clinical trials published, and the perhaps unfair perception that it is quackery.  It thus falls between two stools.

While the concept of FMT has been around for a number of years, it has been given real impetus recently by the massive rise in genome sequencing power, which has allowed the effects of various conditions to be mapped via the changes in the gut flora – this microbiome sequencing has been a feature of a number of publicly-funded initiatives worldwide and is also one of the main targets of Craig Venter’s latest vehicle, Human Longevity Inc.’s Biome Health division.  The initial promise of FMT has been for the treatment of C. difficile infections, where a previously minor and unregarded bacterium takes advantage of external factors, particularly over-dosing of antibiotics, to out-compete and swamp the other occupants of the gut.

However, it seems that the population make-up of the gut flora could also play a significant factor in the development of other intestinal and bowel diseases, including Crohn’s disease, ulcerative colitis and inflammatory bowel disease (IBD).  Whilst treatment for C. difficile infections could be the starting point for greater clinical use of FMT, and provide the confirmation of efficacy and method of action, it is the promise of treatment for these other long term, distressing and debilitating diseases that most excites clinicians.

This promise has led to the setting up of a service, called OpenBiome in October 2013, at the Microbiome Health Research Institute of MIT, to create a frozen storage facility for donated stool samples, screened for enteric bacterial pathogens, viruses and parasites.  These can then be supplied to physicians wishing to try the procedure on patients infected with C. difficile.  OpenBiome charges $250 for a 250 mL sample, more than enough to treat the patient and considerably cheaper than a further course of antibiotics-of-last-resort.

The Regulatory position for FMT is changing rapidly.  FDA originally treated FMT as any new investigational drug, requiring physicians to request an IND for any use.  In May 2013, this was changed to allow physicians to exercise enforcement discretion, opening up the field for further development.  Further new draft guidelines, issued in February 2014, seem to close this window again, requiring not just informed consent of the patient, but also that the FMT product is obtained from a donor “known to” the patient or the healthcare provider, and that the stool donor and stool are qualified by screening and testing first.  This new guidance seems to prevent the use of the anonymous donor samples from OpenBiome, unless the “known to” restriction is interpreted very broadly.

NICE’s own guidelines on FMT for recurrent C. difficile infections, issued in March 2014, require UK clinicians to keep records of both donor and recipient, as well as to screen for pathogens.  This seems closer to the rules regarding tissue donation for transplantation.  Defining the treatment and its most appropriate regulatory regime are still to be finalised.  The best delivery method also remains unclear – enema, nasal feeding tube, and enteric-coated capsule have all been used or considered.

The microbiome of the average human gut contains thousands of different micro-organisms, in variable amounts and with their own niches.  16S ribosomal RNA sequencing has identified many bacteria which have never been isolated, and which may not ever be able to be cultured separately in the laboratory.  Understanding the synergy of the populations will be an enormous task.  A recent publication on the microbiome of 447 patients with Crohn’s disease showed diminished microbial diversity and over-representation of certain bacterial species compared with 220 control samples, and that certain species were particularly associated with deep intestinal ulcers, although the researchers could not determine whether this was causative or simply colonisation of an already existing suitable environment.  Given the interdependencies within the microbiome and the spread of human conditions caused by their perturbation, it may be that the essentially empirical nature of FMT may become the standard of care for many years, before we truly appreciate the exact causes and treatments for diseases such as ulcerative colitis.

However, given that there are well-documented cases of patients with recurrent C. difficile infections, close to death after up to nine courses of antibiotics, being completely cured with FMT, then this is clearly a treatment which is going to become both more widely applied and better accepted.

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