The top 4 challenges for microbiome companies – NIZO
Posted 8th May 2019 by Joshua Sewell
Microbiome research is abundant and profoundly inspiring. Whether focusing on cancer drug response, or the more classical field of gut discomfort solutions, we are clearly on the brink of some long-anticipated breakthroughs. But despite the promise, companies in the field face challenges.
This blog focuses on four of these challenges. I believe we can actively work together to ensure these will not become problematic for the industry.
Why companies are investing in the microbiome domain
Microbiome research is highly interesting. On the one hand, this is because of therapy response to orally administered drugs and, on the other, because of the impact of dysbiosis of the microbiome ‘organ’ on the host. This research might well enable us to develop prophylactic products and therapeutics that are as profitable as antibiotics but cause no side effects or are more efficacious.
Hence, since 2010 investments in the microbiome space have increased every year and now amount to EUR 1.5 Billion, according to Global Engage.
2018 saw an even more active engagement of strategic investors with microbiome start-ups. Partnership deals with Rebiotix, 4D Pharma and Microbiotica are first examples of these. This development seems to indicate that the pharmaceutical sector is beginning to believe in and understand the role of the microbiome in therapeutics.
Whereas many companies focus on IBD, metabolic disease and oncology, others carefully choose a niche to operate from, such as Parkinson’s, psoriasis and a number of rare diseases. If they succeed in establishing a position, they are looking at great business potential. But the stakes are high. Only a handful of companies will thrive.
Below are four major challenges that microbiome companies, especially start-ups, face and that are specifically related to the way we work in this science-based field. We might be able to counter these.
1. The ‘research challenge’
The first challenge is research-related: there is more to curing and preventing complex diseases than moderating the microbiome.
Make no mistake: university groups worldwide have done significant research on many diseases and afflictions that impact people’s lives. A lot of good treatments have been developed, barring side effects. However, it seems unlikely that we will be able to cure, let alone prevent, complex diseases by merely increasing (the functionality of) one or more specific species or strains.
It is important to remember that other factors often play a more prominent role in disease occurrence and progression. For instance, the immune system of the host, or ‘environmental factors’, such as diet, heat, and stress.
To develop a balanced therapy or prophylactic solution, it is crucial to take a broader approach and look into such other aspects as well. Rather than single microbiome therapies, combination therapies such as adjunctive microbiome modulation approaches we see in novel cancer treatments are more likely to benefit patients who do not respond sufficiently to first-line or second-line therapies.
2. The ‘translational challenge’
The second challenge brings into view the difficulty of tying preclinical and clinical phase results together.
We all know the pioneering companies that are now beyond preclinical stages in IBD/Crohn’s. Unfortunately, translating preclinical data into the clinical phase has always been a discussion point.
After all, predictable preclinical models are often non-existing. (How to mimic a ‘living’ microbiome on your plate?) Furthermore, the behaviour of mice is always different from that of the human host, so quickly moving into the human phase is easier said than done.
In my opinion, the scientific community should make haste with the development of reliable and cost-effective in vitro/ex-vivo models for relevant diseases and healthy states for gut and skin. Alternatively, they should focus on healthy volunteer study models with relevant set-ups to test the capacity of microbiome modulators to bring significant changes to microbiome composition/functionality. If nothing else, these models could help therapies to ‘fail fast’, preventing companies from moving into expensive human clinical trials that are bound to be unsuccessful.
3. The ‘regulatory challenge’
In the news, we read of the plans for the increase of GMP-capacity to accommodate the LBP-market needs. However, I believe the actual production of such future therapeutics will be a costly business, due to GMP regulatory hurdles related to the difficulty in repetitively culturing consistent batches of live therapeutics.
Do we really need live bacteria in such therapeutics, or can we suffice with the extracts or inactivated cells (postbiotics) to achieve the same effect? Recent research on a well-known gut commensal has shown that its inactivated version also shows beneficial effects (in mice, that is). Moreover, an alternative route, which is regulatory wise and probably even cheaper and faster, is to consider prebiotic-like concepts that are able to stimulate specific bacterial groups in the microbiome. A more food-based approach could be feasible.
4. The ‘formulation challenge’
Culturing live bacteria is challenging on its own and groups like NIZO have invested recently in capabilities and equipment for screening and upscaling of strict anaerobic gut commensals. However, downstream processing and the creation of proper formulations – other than freeze-dried ones – are largely unexplored.
Currently, nine out of ten LBPs in development use freeze-drying technology to create batches for animal or human studies. For some of these, one can argue that freeze-drying may not be the best downstream processing technology to use given that shelf life tests often reveal batch-to-batch variations. These complicate attempts at creating stability.
Furthermore, reproducibility of measurements performed on live bacteria in such powders proves to be challenging. Moreover, every individual strain behaves differently under stress loads that occur in downstream processing – each strain is likely to have its own optimal downstream processing condition.
So far, this area has had less attention, and in my opinion, more research is required: apart from freeze-drying, alternative technologies will be needed that gives greater stability or reduce production costs. The question is: how do we integrate such development work early in the pipeline?
This ‘formulation challenge’ should be addressed more profoundly in a joint industry initiative.
Improving the chance of success and increasing investor interest
It is vital to consider the above challenges at an early stage of the research design, as well as further on in the research pipeline.
Not only will such insights help start-ups improve their chances of success. It will also resonate well with potential investors that are knowledgeable in the microbiome field.
As stated above, not all of these challenges can be addressed by single companies, as there are overarching issues that affect most start-ups. One of these is the ‘translational challenge’ that deals with the absence of reliable and cost-effective preclinical models. Solutions are the development of new in vitro and ex vivo models and/or uniform human volunteer models for establishing Proof-of-Concept. The other issue to conquer cooperatively is the ‘formulation challenge’.
While many academic groups and CROs are dealing with the cultivation of ‘unculturable’ strains, less attention is paid to alternative DSP and formulation technology for live bacteria apart from freeze drying. A solution is to bring together the greatest minds to jointly work on the development of alternative drying techniques for certain species and strains.
These two challenges need to be addressed in a broader, joint effort including academia, CROs, industry, and investors, to allow all those entrepreneurs in food and pharma to have a larger chance of success in this emerging field.
Nils Hijlkema is Business Leader Microbiome Partnerships at NIZO, an exhibitor and content sponsor at the Microbiome & Probiotics Series: Europe.
The Microbiome R&D and Business Collaboration Forum: USA programme creates a collaborative environment and networking opportunities across the full range of microbiome and probiotics research. The agenda is available to download here.