Will Big Pharma get the bug for microbiome therapies?
The microbiome therapeutics field is dominated by many innovative small and medium-sized enterprises (SMEs), all focused on driving the development of a single or a small pipeline of biotherapeutics. This has resulted in an impressive range of innovative products in development, often targeting conditions which conventional “small molecule” drug discovery projects have failed to adequately address.
While we are seeing growing engagement from ‘Big Pharma’, it is difficult to conclude that it has fully embraced the field. In 2018 we saw the first acquisition of a microbiome company, with the purchase of Rebiotix by Ferring. However, most Big Pharma is perhaps more tentatively venturing into the microbiome field via collaborations (eg, MSD and 4D Pharma, Takeda and Finch Therapeutics).
Is this a problem? Possibly not. However, what Big Pharma does have vast amounts of experience in is getting products approved and to the market. More engagement from Big Pharma may make it easier and faster to establish a “well-trodden” path to market for microbiome-related therapeutics, potentially making it easier for all in the field to get products to market. But what is most likely to tempt Big Pharma to engage even more with the microbiome field?
The options
The options can roughly be split into three categories:
- "Drugs from bugs”: bacteria are adept at producing bioactive molecules that can manipulate the physiological processes of their hosts. Such bioactive molecules can be isolated, characterised and in some cases present therapeutic potential, for example, as immune-suppressive agents for treating autoimmune disorders.
- “Bugs as drugs”: a range of microbiome-based therapeutics are in development that use live bacteria to treat an array of disorders, extending from gastrointestinal disorders to those of the skin and concerning the central nervous system. If one is relaxed about the term “bugs”, bacteriophage-based therapeutics may be squeezed into this option.
Such therapeutics can be provided in the form of faecal microbiota transplant compositions (which can include intact whole microbial communities derived from faecal matter), defined “cocktails” of selected bacterial species/strains (eg, bacterial consortia), or single strain compositions—provided here in the order of complex to less complex. Microorganisms may be natural or engineered.
- “Bugs for drugs”: the microbiome is increasingly being recognised as having a profound effect on drug metabolism, absorption and overall efficacy. This opens the potential for manipulation of the microbiome in order to change the effect conventional small molecule therapeutics or biotherapeutics may have on the patient being treated.
Big Pharma has always been relatively conservative. Consequently, while they may be willing to speculate to a certain extent, the principal focus always tends to fall on the least risky endeavours. Currently, although we are close, there have been no clinically approved ‘bugs as drugs’ on the market in the US or Europe.
“It is perhaps ‘bugs for drugs’ that, from our analysis, could represent the most immediate and profound attraction to a Big Pharma development team.”
Microorganisms are inherently more complex and less predictable than small molecule therapeutics. This is perhaps why, for the most part, Big Pharma have left specialist SMEs to forge the path of development in this area, particularly with respect to the most complex compositions on offer.
However, as we will no doubt see successful ‘bugs as drugs’ products launch in the coming years, this will likely change the risk profile and so the attitude of Big Pharma to this application of microbiome technology. While ‘drugs from bugs’ present a clear and immediate attraction to the Big Pharma, it is perhaps ‘bugs for drugs’ that, from our analysis, could represent the most immediate and profound attraction to a Big Pharma development team considering entering the microbiome space.
Looking for the low risk, easy win
What does a low risk, easy win venture look like to a Big Pharma development team?
When a proprietary drug has established itself as one that provides tremendous profits for its owner, it is important to determine the end date of the exclusivity period for sale of that product—the so-called “exclusivity cliff”. This of course probably corresponds to a “profits cliff”. There is no question therefore that any strategies to extend the period of time to that cliff, or even to reduce the gradient of the cliff, will bring significant financial value—thus the ideal low risk, easy win venture.
As an example of such strategies in action, we can look to Seroquel (quetiapine), an oral antipsychotic. Seroquel was one of the big revenue earners for AstraZeneca (AZ). In 2010, AZ is estimated to have netted $5.3 billion from sales of the drug.
The exclusivity cliff for this drug was set for March 2012. AZ identified an innovative formulation of the drug (Seroquel XR) that provided a sustained release of the product. This enabled patients to switch from the conventional twice-a-day dosing regimen to taking it only once a day, thereby making it easier to achieve good patient compliance for that regimen—a very important consideration for the targeted patient group.
Some studies showed that treatment with Seroquel XR was associated with a lower risk of sedation and postural hypotension than with the standard instant release form. Seroquel XR therefore became the new standard of care. Consequently, even after the exclusivity cliff arrived, and despite lower costs for immediate release generic products, generics manufacturers found it difficult to dislodge AZ’s Seroquel XR from the market due to its superior clinical performance.
In this example, it was a release profile that was the tool used to positively effect change of the exclusivity cliff. Pharmaceutical development teams have an array of tools within their toolbox, for example, enhanced stability technologies; combination therapies with benefits to efficacy levels or reduction in off-target effects; and directing treatment to super-responders.
As the exclusivity cliff looms, a large amount of energy goes into investigating each of the available tools and their associated IP and regulatory strategies, in order to model the likely effect of the application of each tool on the exclusivity cliff.
It is apparent that microbiome technologies offer, in certain cases, a new tool to add to this toolkit. If a microbiome innovator can demonstrate to Big Pharma that it has a good understanding of one of the Big Pharma’s blockbusters, the exclusivity cliff associated with that blockbuster, and a good argument that the innovator’s microbiome product can positively influence the cliff, that microbiome company will likely have the full attention of the Big Pharma in question.
What can ‘bugs for drugs’ offer?
The microbiome can affect our bodies’ responses to conventional therapeutics. As early as the 1950s, gut microbes were reported to affect cholesterol metabolism. More recently, gut microbes have been reported to activate drugs, such as sulfasalazine; to inactivate drugs, such as digoxin; and to direct the metabolism of drugs down a path that results in the production of toxic metabolites (eg, sorivudine/brivudine).
Much interesting work in this field is coming out of labs such as the Zimmermann group at the European Molecular Biology Laboratory and the Cabreiro Lab at Imperial College London. The Cabreiro Lab has shown that the presence of certain bacterial species can improve or suppress the effects of fluoropyrimidines, a colorectal cancer therapeutic, through metabolic drug interconversion involving bacterial vitamin B6, B9 and ribonucleotide metabolism.
Find a bacterium with a favourable metabolic activity on a drug, and you may have found a way to improve the drug profile, either by increasing efficacy or decreasing adverse off-target effects. Alternatively, if you find a drug whose therapeutic potential cannot be fully realised because of a particular enzyme secreted by some gut microbe, if you can also identify a bacterial consortium that can reduce the population of that enzyme in the gut or influence the enzyme production by the microbe, you may be able to significantly increase the efficacy of the drug itself.
Any of these effects may be the basis of a tool for affecting the exclusivity cliff of the drug in question through the creation of a protectable innovative drug and bug combination therapy. From this, a range of formulation technologies, and innovative drug regimens may also be identified to optimise the combination treatment. Yet more tools for affecting the exclusivity cliff?
We are already seeing such combination microbiome therapeutic technologies being fought over in the patent courts, underlying the growing realisation of substantial value from such innovations. The University of Chicago US Patent No. 9,855,302 is directed to treating cancer with a combination of bifidobacteria and checkpoint inhibitors and is exclusively licensed to Evelo Biosciences.
In April Genome & Company, a Korean microbiome company, won US post-grant review proceedings invalidating the patent before the US Patent Trial and Appeal Board. Genome & Company had partnered with Merck KGaA and Pfizer in January 2020 to develop its proprietary microbiome product in combination with avelumab, an anti-PD-L1 antibody initially in development for small-cell lung cancer. This is clearly an emerging focus for microbiome.
4D Pharma and Biomica are further prominent microbiome companies developing microbiome products as an effective adjunct to augment checkpoint inhibitors.
The combination of bacteria and inhibitor exploits the finding that certain bacteria are able to enhance the antitumour activity of checkpoint inhibitors such as anti-PD-L1. If this enhancement is sufficiently powerful such that the combination treatment becomes the new standard of care, compared to anti-PD-L1 administered alone, and the sale of such checkpoint inhibitors are significant, the owners of anti-PD-L1 therapeutics would likely be very interested in this new technology for increasing the value of their anti-PD-LI therapeutics portfolio.
Based on Merck and Pfizer’s collaboration with Genome & Company, there already is significant interest.
Perhaps the holy grail of any ‘bugs for drugs’ innovator would be a combination therapy where the microbiome component provides such a substantial benefit that the combination becomes a true standard of care, to the point that the regulators stipulate direction on the label of the drug that that microbiome component must be taken in association with the established drug.
One can imagine this being the case when the combination eliminates a significant life-threatening side-effect of the drug when taken alone. In such a scenario, even after exclusivity for the basic drug is gone, generics would not be permitted to sell that drug without a label inducing infringement.
The gradient of the exclusivity cliff would not merely be lessened, but the whole cliff may be moved forward in time.
Summary
If you are Big Pharma and looking to delay the exclusivity cliff, do not overlook microbiome as a potential powerful part of your toolkit.
If you are a microbiome company looking to identify a new target for your research, it may be worthwhile looking for microbiome products that have synergies with drugs already on the market and learning as much as you can about the commercial realities of that drug.
Craig Thomson is a partner at HGF. He can be contacted at: cthomson@hgf.com
Leena Contarino is a partner at HGF. She can be contacted at: lcontarino@hgf.com
Andrew Wells is a partner at HGF. He can be contacted at: awells@hgf.com
