Based on some neat guesstimating1, the number of bacteria in the gut roughly equals the number of cells in our bodies, so it’s no surprise that such a substantial (around 200g in a 70kg adult) and metabolically active biomass might have a pervasive influence on wellbeing.
A growing body of evidence supports the notion that the makeup of the bacterial communities (“microbiomes”) resident in our gut, mouth, skin, (and possibly even the brain) can influence biological processes associated with a variety of gastrointestinal, metabolic, neurological and immunological diseases and perhaps even cancer treatment outcomes. Whether alteration of the healthy microbiome (“dysbiosis”) merely correlates with disease states, or truly represents a causative or contributory factor potentially addressable through targeted intervention, remains largely unknown, although this, and other big unknowns, have not dampened enthusiasm for the commercial exploitation of the microbiome in drug and consumer product development.
During the past decade, well-funded, not-for-profit US and European initiatives have advanced gene sequencing and profiling techniques to the point where the largely unknown and uncultivatable organisms that comprise the human microbiome can be characterised at genome level (“metagenomics”). According to a recent commentary2, exploration of the human microbiome has turned up some 5000 microbial species, representing 2000 genera, 25 phyla and some 316 million genes. Of the many important “unknowns”, 40% of identified genes have no match in functional gene databases.
While comprehensive definition of the normal/healthy microbiome is a challenge, even a partial understanding of the dysbiosis-disease axis might usefully translate into a means of disease treatment or prevention. Several strategies aimed at beneficial modification of the microbiome are in play: small molecules; natural or genetically modified single bacterial strains (a 21st century take on probiotics), or alteration of the ecosystem through introduction of host of microbial strains. Small biopharma companies have taken point on microbiome product development, although not without early buy-in from global players, notably Johnson & Johnson, Takeda, AbbVie, Allergan and Nestlé Health Sciences.
The microbiome-focused product pipeline is still relatively slender, but over a dozen candidates have reached Phase II or III clinical development, in the main for gut-associated indications. Phase III evaluations of SER-109 (Seres Therapeutics) and RBX-2660 (Rebiotix), respectively an orally administered, donor-derived bacterial spore preparation and a mixture of donor-derived microorganisms, administered by enema, are ongoing: both are indicated in the prevention of Clostridium difficile infection. Recent interim data from a Phase III study of RP-G28 (Ritter Pharmaceuticals), a synthetic oligosaccharide “prebiotic” intended to encourage the growth of lactose-utilising bacteria in the gut showed no benefit over placebo in reduction of the symptoms of lactose intolerance.
No new therapeutic field is without its problems, but the successful commercialisation of microbiome products faces particular challenges. Not least is intellectual property, since, by and large, patent law does not permit claims concerning live organisms or naturally occurring materials. And, should Company A make claims around the benefit arising from one microbial strain or a defined collection of microbes, Company B may be able to claim comparable benefit in the same indication using a totally unrelated strain or collection. Building a proprietary position may require good use to be made of claims around manufacture and formulation. While patent law will undoubtedly evolve with the field, it’s a safe bet that microbiome product development will prove to be of benefit to lawyers3.
“Living drugs” are not easy to reliably manufacture at scale and will necessarily need to be standardised with respect to composition and potency to satisfy regulatory agencies, a tall order when dealing with complex microbial mixtures. Regulators will also need to be made comfortable with respect to product safety (donor derived faecal transplantation has resulted in at least one death) and, given the undoubted variability in the microbiome, and differences between individuals, clinical studies will need to conducted in rigorously defined and matched treatment and control patient populations .
Ritter Pharmaceutical’s recent study failure notwithstanding, the least risky path to market is arguably that based on small molecule modification of the microbiome through inhibition or enhancement of microbial metabolite production or disruption of microbe-host interactions. Clinical studies of small molecule inhibitors of microbial methane production (SYN-101: Synthetic Biologics) and ammonia production (KB195: Kaleido Biosciences) are underway: small molecule disruption of microbe-host interaction, for example by upping the numbers of regulatory T cells in the gut to damp down inflammatory bowel disease, is still largely at translational stage. Whether small molecule approaches can produce consistent outcomes in the face of continual change in the microbiome remains to be established.
An intriguing, and potentially exploitable, facet of the microbiome is its effect on existing drug treatments. A recent study found that a collection of gut bacteria was capable of metabolising almost two thirds of a panel of 271 orally administered, chemically diverse drugs4.
A connection between gut bacteria and metabolism of L-DOPA, the mainstay of medical management in Parkinson’s disease was first noted in the 1970s. A bacterial enzyme, tyrosine decarboxylase, looks to play a part and treatment with enzyme inhibitors was shown to increase systemic levels of L-DOPA in animals, an approach that might be able to reduce variability in L-DOPA responses in patients. Animal studies have indicated that several commonly prescribed antidepressants influence gut microbiome composition and that these changes may influence the response to drug treatment.
The response to checkpoint inhibitor therapy in cancer patients remain largely unpredictable, but a correlation between the abundance of certain gut bacteria and the outcome of treatment with anti-PD1/L1 checkpoint inhibitors has been observed in melanoma, non-small cell lung cancer and renal cancer patients. Intriguingly, different bacteria are implicated in each of the different patient groups5.
Perhaps the real money is to be made outside of disease cure and prevention. Cosmetics and consumer health companies are actively pursuing microbiome-related innovation, with L’Oreal partnering in March this year with uBiome, a microbial genetics company which sells microbiome sampling kits and analyses, with $199 buying you a three-time point exploration of your gut microbiome. Then again, perhaps not. On October 2nd, 2019, uBiome announced its intention to liquidate the company, despite closing an $83 million funding round last year6.
2Multiple levels of the unknown in microbiome research. Thomas AM and Segata N. MC Biology (2019) 17:48 https://doi.org/10.1186/s12915-019-0667-z. Online 2019 June 12th.
3Patenting the microbiome: trends, challenges and insights. Sabatelli AD, Vincent NG and Puleo DE. Pharm Pat Anal. 2017 Nov;6(6):273-282. https://doi.org/10.4155/ppa-2017-0028 Online 2017 Oct 24th.
4Microbes make metabolic mischief by targeting drugs. Lewis K and Strandwitz P. News & Views Nature 570, 453-454 (2019) https://www.nature.com/articles/d41586-019-01851-x online June 17th 2019.
5Microbiota and cancer immunotherapy: in search of microbial signals. Gharaibeh RZ and Jobin C. Gut 2019;68:385-388.Online Feb 7th 2019. http://dx.doi.org/10.1136/gutjnl-2018-317220.
6Troubled poop-testing startup uBiome announces plans for liquidation. Endpoint News online October 2nd 2019 http://tinyurl.com/y3r46vzc