As 2025 draws to a close, I would like to take a moment to reflect on the key events and trends shaping our industry — and how they position us for the year ahead.

Despite a continued challenging economic environment across biotech, the past 12 months have brought meaningful progress for the microbiome field. We have seen encouraging developments in microbiome therapeutics, alongside impressive resilience from companies committed to addressing unmet medical needs for patients.

At the same time, new patterns are emerging with the rapid development of — and growing demand for — Next-Generation Probiotics.

Here at Biose Industrie, I am proud of how our teams navigated these dynamics while delivering strong results. In 2025, we onboarded more than 200 new client strains across our U.S. and EU facilities, produced 450 certified active-substance batches, and delivered 250 certified finished-product batches.

With early signs of renewed investor interest and new European public-funding initiatives building momentum into 2026, I am optimistic that our industry is preparing for a new wave of opportunity — not only next year, but well beyond.

Clinical and Regulatory Milestones

If there is one feature that has truly defined 2025 for the microbiome field, it is the strength of the Phase II and III therapeutic readouts.

MaaT Pharma’s Xervyteg® (MaaT013) demonstrated a three-fold increase in one-year survival among patients with GI-aGvHD in the pivotal ARES Phase III trial creating waves for the microbiome field and making headlines globally. These results supported submission to the EMA under an MAA — positioning Xervyteg® as potentially the first microbiota therapeutic in hemato-oncology.

Siolta Therapeutics announced positive topline results from the Phase 2 ADORED study of STMC-103H, its lead oral microbial therapy. Infants completing one year of treatment showed a clinically meaningful reduction in the risk of developing atopic dermatitis and food allergy, including a 77% reduction in physician-diagnosed food allergy, with consistent benefits across secondary endpoints.

In the metabolic space, Bloom Science reported that BL-001, an investigational oral therapy, achieved statistically significant placebo-adjusted weight loss at 28 days in a Phase 1 study.

We also saw compelling long-term data published in Nature Communications. In a cohort of adolescents originally enrolled in an FMT study eight years earlier, participants in the treatment arm were, on average, 11 kg lighter than placebo recipients four years post-intervention.

Looking ahead, 2026 is poised to be a milestone year, with anticipated topline data from Vedanta’s Phase 3 RESTORATiVE-303 study, potential EMA marketing authorization for Xervyteg®, and possible FDA accelerated approval for Infant Bacterial Therapeutics’ IBP-9414 in the United States.

In addition, the EMA’s positive Pediatric Investigation Plan decision for AOB Pharma’s B244 in atopic dermatitis and pruritus enables AOBiome to move toward an initial MAA submission following completion of its pivotal and extension studies.

Finally, Exeliom Biosciences continues advancing multiple Phase 2 programs evaluating a Faecalibacterium prausnitzii-derived LBP to prevent post-surgical recurrence in Crohn’s disease and as an adjuvant across several oncology indications with data expected in early 2027.

Promising Financial Indicators

2025 also brought encouraging financial signals for the microbiome and next-generation probiotics sector:

MRM Health successfully closed a €55M Series B round — a landmark raise that drew widespread attention across the European biotech ecosystem. SNIPR Biome likewise completed its Series B at $35M, bringing its total funding to more than $90M to continue advancing its pipeline.

The acquisition of The Akkermansia Company by Danone in July marked a significant inflection point for the next-generation probiotics market, underscoring growing strategic interest from major consumer health players.

Beyond these transactions, we observed several early-stage financings as well as two announcements with important implications for the years ahead:

• Novo Nordisk and Novonesis entered into a partnership to explore the role of the gut microbiome in metabolic health — with the dual aim of informing product development and identifying predictive biomarkers for obesity prevention.
• Wellcome Leap launched the FORM (Foundations of a Resilient Microbiome) program — a $50M initiative designed to investigate the causal link between early-life microbiome dysfunction and neurodevelopmental conditions such as autism.

Together, these developments reinforce gr owing investor confidence and highlight the strategic relevance of microbiome science across pharma and consumer health.

The EU Biotech Sector

As the CEO of a company with facilities in France and the US and Treasurer of the European Microbiome Innovation for Health, I have been well-positioned over the past years to monitor both the EU and US markets closely.

The EU has traditionally controlled the biotech market through tighter regulations and reduced market exclusivity periods, a strategy that inadvertently signalled a ‘hostile’ environment for R&D and drove significant capital migration to the United States. This ‘production drain’ was starkly validated by the recent Draghi report, which identified the chronic investment gap as a primary threat to European stability within the biotech industry.

However, it is great to see important steps being taken that will greatly increase the EU’s competitive position moving in to 2026 with the announcement of The Biotech Act and the €10 billion BioTechEU initiative. By introducing regulatory sandboxes, simplifying clinical trials, and creating a massive capital injection, the European Commission aims to strengthen the EU biotech sector with the objective to restore a regulatory and industrial environment capable of sustaining innovation within Europe.

The Consolidation of Live Biotherapeutics Products & Next Generation Probiotics

To properly understand the current microbiome landscape, it’s essential to understand how it now spans two converging and increasingly interconnected sectors:

Live Biotherapeutic Products (LBPs) are fully regulated biological medicines developed under stringent GMP conditions and supported by advanced CMC packages, and multi-phase clinical trials.

Next-Generation Probiotics (NGPs) by contrast, are positioned within the Consumer-health space but are increasingly underpinned by strain-specific clinical data, multi-omics characterisation, and precision formulation strategies. Companies such as Pendulum, Design for Health, Verb Biotics, and Clostra Bio are generating robust real-world datasets feeding therapeutic discovery.

Increasingly, microbiome companies are considering a dual strategy, leveraging their expertise in LBPs to launch NGPs. This approach allows companies to generate early revenue and gather solid scientific evidence while navigating the lengthy pathway for biological drugs.

Despite distinct regulatory frameworks, both LBPs and NGPs rely on shared biology and industrial foundations such as fermentation and formulation technologies, analytical methods, manufacturing infrastructure, supply-chain management, and downstream quality and data systems. This convergence is giving rise to a unified industrial ecosystem, and ample market opportunities for Biose. making NGPs a primary focus area for our company’s strategy moving forward.

It’s all about the Science

Albeit I am writing this letter as Biose’s CEO, I am a scientist at heart and especially excited to see recent advances in both basic and population-level research.

What were once viewed largely as associative “gut–organ” links are now increasingly supported by mechanistic evidence, moving the field from correlation toward causality.

Studies published this year have shown that specific gut-derived metabolites do not merely circulate through the body, but actively influence immune function in peripheral tissues such as the skin and lungs, effectively acting as systemic signalling molecules.

At the same time, researchers are beginning to characterise microbial communities in biological sites that were long considered sterile or biologically marginal. Emerging data indicate that low-biomass environments — including intratumoral niches and the ocular surface harbor distinct microbial signatures capable of modulating disease progression and influencing responses to existing therapies.

As research increasingly moves beyond the gut, women’s health has emerged as one of the most compelling areas where microbiome science is now delivering robust, mechanistic insights.

Over the past years, several academic groups and industrials— including work conducted by Seed Health, Freya Biosciences, Biocodex, and teams at Massachusetts General Hospital — have significantly contributed to elevating vaginal microbiome research to the level of global health priorities, with initiatives that have reached major institutional stakeholders such as the Gates Foundation.

Recent publications have moved the field beyond descriptive abundance profiling, demonstrating how Lactobacillus crispatus–dominated ecosystems form structured, protective biofilms that actively reinforce epithelial integrity and limit pathogen invasion. These findings provide a mechanistic framework explaining why L. crispatus–rich microbiota is consistently associated not only with protection against bacterial vaginosis, but also with improved reproductive and gestational outcomes.

In parallel, growing clinical and translational evidence continues to strengthen the rationale for strain-specific approaches in women’s health. Recent peer-reviewed studies published in 2024–2025 have further documented the functional properties of Lacticaseibacillus rhamnosus Lcr35, including its capacity to modulate host–microbe interactions across multiple indications, from mucosal protection to systemic metabolic and inflammatory pathways, moving away from generic probiotic concepts toward well-characterized, clinically validated strains.

Conclusion

The microbiome field is coming out of a transition period, being defined by in-human data, industrial maturity, and clear regulatory pathways. With some important milestones expected and signs of a recovering financing landscape I remain bullish entering 2026.

At Biose we look forward to another year of continuing to support leading microbiome companies around the world with their mission of developing the next generation of microbiome products for patients with unmet medical needs.

Supporting our clients with this mission is the very foundation of our business and as such, I’d like to close this year’s wrap-up with the words of Adam Wilkinson, Vice President of Pre-Clinical Development at Microbiotica:

“Working in partnership with the Biose team, we are delighted to have successfully navigated the challenges of process development and scale-up of two LBPs in parallel. Manufacturing of biologics can be challenging at the best of times, but the development of multiple processes to be scaled up to cGMP standard poses significant challenges, and seamless open collaboration between our project teams has been essential to success”

Wishing everyone a very Happy New Year filled with joy and success.

Yours Sincerely,

Adrien Nivoliez
Chief Executive Officer, Biose Industrie

The post Microbiome at a Turning Point: This Year’s Breakthroughs and Next Year’s Big Bets appeared first on Biose Industrie.

Core Values

By embodying these values—commitment, agility, responsibility, and expertise—Biose demonstrates its dedication to advancing healthcare and improving patient outcomes. As we continue to grow and evolve, these values will remain at the core of everything we do, guiding our actions and shaping our future success.

Commitment

At Biose Industrie, Commitment is more than just a word – it’s our guiding principle. We understand the critical role we play in bringing life-saving therapies to patients worldwide. Every member of our team is deeply committed to excellence in everything we do, from developing innovative biopharmaceutical process solutions to delivering exceptional manufacturing services. Our unwavering dedication ensures that we meet and exceed the expectations of our clients and partners, making a meaningful impact on global healthcare.

Agility

In the fast-paced biopharmaceutical industry, agility is paramount. At Biose Industrie, we embrace change as an opportunity for growth and innovation. Our agile approach enables us to quickly adapt to evolving market dynamics, regulatory requirements, and technological advancements. Whether it’s scaling up production to meet increased demand or pivoting our strategies in response to new developments, we remain agile and responsive, ensuring that we stay ahead of the game and deliver value to our clients.

Responsibility

As a trusted partner in the biopharmaceutical supply chain, Biose Industrie recognizes the immense responsibility we have to patients, healthcare providers, and the broader community. We hold ourselves to the highest standards of ethical conduct, environmental stewardship, and social responsibility. Our commitment to responsible manufacturing practices, product quality, and regulatory compliance ensures the safety, effectivness, and reliability of the therapies we help bring to market. We are dedicated to making a positive impact on society and upholding the trust placed in us by our stakeholders.

Expertise

Expertise is the cornerstone of our success at Biose Industrie. With decades of collective experience in the biopharmaceutical industry, our team of experts possesses unparalleled knowledge, skills, and technical know-how. From process development and analytical testing to cGMP manufacturing and regulatory affairs, we leverage our expertise to deliver tailored solutions that meet the unique needs of each client. Our relentless pursuit of excellence drives continuous improvement and innovative solutions, positioning Biose Industrie as the leading CDMO in the biopharmaceutical sector.

Business team

Adrien NIVOLIEZ

Interim CBO

Rishi TRIVEDI

Business development director - US & India

Alexander LEPAGE

Business developement director - Europe & Latam

Richard ELLIS

Global business developement director - CDMO services

Management team

Adrien NIVOLIEZ

CEO

Samuel BRISSEZ

VP process

Emmanuelle BARDET

VP quality & QP

Caroline DAUSSET

VP analytics

Bertrand CLAUX

VP human resources

Paul-Marie CHASSAING

VP finance

Nadine DAOU

VP US operations

Company History

2023

Adrien NIVOLIEZ becomes the Chairman and CEO of BIOSE Industrie and the company continues as the world leading CDMO

350 employees

February 2023

BIOSE Industrie raises a joint investment of €80M by L-GAM and the French State through the French Tech Souveraineté scheme and creates 200 jobs

2021

BIOSE Industrie is granted €5M by the French State as part of the France Relance scheme

September 2020

Creation of new offices in Boston, USA

150 employees

July 2020

With the support of Cathay Capital, BIOSE Industrie invests €40M in its Aurillac plant

January 2020

BIOSE and BIOSE Industrie merge to become BIOSE Industrie

60 employees

2017

Adrien NIVOLIEZ becomes the CEO of BIOSE Industrie

2015

2011

Creation of PROBIONIOV, a subsidiary of LYOCENTRE, with a new commercial department in Clermont-Ferrand and the R&D department in Aurillac

2008

Creation of a Research and Development (R&D) department

2007

Stanislas DESJONQUERES becomes the CEO of LYOCENTRE

2005-2007

Consolidation of the manufacturing facilities at the Aurillac plant

1997

Acquisition of LYOCENTRE by Hubert DESJONQUERES, implementing a policy of commercial and industrial revitalization

1975

Creation of the Aurillac plant

1958-1978

Development of the Saint-Simon plant

1951

Creation of LYOCENTRE

The post About us appeared first on Biose Industrie.

By Adrien Nivoliez

Chief Executive Officer, Biose Industrie

As the year draws to a close today, I’d like to reflect on the microbiome landscape in 2024:

Unfortunately, conditions remained particularly challenging for pre-revenue biotechs raising funds for microbiome-based therapeutic programs, and this was felt by the market with several programs discontinued, a handful of biotechs closing their doors, and even some microbiome industry-specific service providers shutting down.

Despite this, 2024 was an extremely significant and historical year for the field as we had indisputable scientific evidence that defined Live Biotherapeutics work!

Infant Bacterial Therapeutics’ Phase 3 readout demonstrated a 27% reduction in all-cause mortality for infants with necrotizing enterocolitis. Beyond its significance for the market as potentially the first FDA and EMA-approved single-strain LBP, Infant Bacterial Therapeutics’ product saves babies’ lives!

This, for me, is far more important than any short-term hurdles our industry is currently facing and is what should also be more important for everyone else too. At the end of the day, it is now a fact that defined LBPs have the potential to save lives, and IBT’s Phase 3 study comprising 2,153 premature infants is testimony to just that.

Of course, there were other important milestones reached by a number of companies progressing microbiome science in and out of the clinic, some sizeable fundraises, new spin-outs, and important clinical data. Furthermore, it was great to see some very sizeable public investment commitments.

Below, I share some highlights throughout 2024 and some of the things that I am particularly excited about coming up in 2025:

Fundraising in the Microbiome

Despite 2024 being a difficult year for early-stage biotechs, there were some significant investments across the microbiome field, such as:

• $12M raised by Kanvas Biosciences, Siolta Therapeutics, and Z-Biotics.
• A $10.4M strategic grant from the Bill & Melinda Gates Foundation into Freya Biosciences.
• £27M raised by EnteroBiotix.
• Additional funding rounds: $9M for Holobiome, $4.2M for Ancilia Biosciences, and $2M for Neobe Therapeutics.
• €20M funding for SNIPR Biome from the European Innovation Council.

On the public funding side, the Dutch government allocated €200 million specifically for microbiome research through the establishment of the Holomicrobiome Institute.

M&A and Partnerships in 2024

2024 also witnessed strategic mergers and acquisitions:

• The formation of the Cmbio brand through the merger of Clinical Microbiomics, CosmosID, MS-Omics, DNASense, and Microba’s Research Services Unit.
• Probi’s acquisition by Symrise.
• Lactobio’s acquisition by L’Oréal.

One standout partnership was between the Novo Nordisk Foundation, Wellcome Trust, and the Bill & Melinda Gates Foundation, with a $300M commitment aimed at advancing global health equity. Notably, the microbiome was highlighted as a key area of focus for addressing nutritional and immunological health challenges.

Clinical read-outs

As already mentioned, Infant Bacterial Therapeutics (IBT) reported positive Phase 3 results for their candidate targeting infant necrotizing enterocolitis, showing a 27% reduction in all-cause mortality. If approved, this would represent the first FDA approval of a single-strain Live Biotherapeutic Product (LBP).

• Maat Pharma presented positive 18-month data for MaaT013, showing a clear overall survival advantage in acute Graft-versus-Host Disease (aGvHD) for 140 patients at the 2024 Annual congress of the European Society for Bone and Marrow Transplantation. As we enter 2025, I am particular excited for MaaT Pharma’s official phase 3 Ares read-out!
• MRM Health announced positive Phase 2a results for pouchitis and ulcerative colitis, significant indications with substantial market potential.
• EnteroBiotix reported successful Phase 1b results for their program in liver cirrhosis.
• Seres Therapeutics shared positive Phase 1b safety and clinical results.

Additionally, during the Microbes in Women’s Health Congress in Copenhagen (April 2024), I had the opportunity to present alongside leading KOLs Caroline Mitchell and Jacques Ravel on the development of two multi-strain LBPs, LC106 and LC115, targeting bacterial vaginosis (BV). These drug products, each containing multiple Lactobacillus crispatus strains, were designed based on insights from stable vaginal microbiomes.

2024 also saw two landmark Nature publications:

• Eligo Bioscience’s study on genetically modifying bacteria in the gut with nearly 100% efficiency.
• Immunobiome’s research on microbiome-based cancer therapies, focusing on iron deprivation in the tumor microenvironment.

Some other promising 2025 clinical read-outs I am excited about include:

• Genome & Company’s Phase 2 trials for GEN001, targeting stomach cancer and biliary tract cancer
• Microbiotica’s Phase 1b trial for MB097, targeting advanced melanoma in patients who have failed to respond to immunotherapies
• Biomica’s Phase 1 trial for BMC128, focused on patients with non-small cell lung cancer (NSCLC), melanoma or renal cell carcinoma (RCC) who previously progressed on immunotherapy
• CJ Biosciences’ Phase 1/2 trial for CJRB-101, investigating its efficacy in solid tumours including NSCLC and melanoma
• Everimmune’s Phase 1/2 trial for EV997, evaluating safety and preliminary efficacy in combination with immune checkpoint inhibitors for solid tumour
• Exeliom Biosciences’ Two additional Phase II studies evaluated EXL01 in hepatocellular carcinoma in combination with an ICI and one in postoperative Crohn’s disease.

New spinouts on the scene

Despite the challenging fundraising landscape, 2024 saw the emergence of several promising biotech spinouts:

• Ostia Biosciences (University of Toronto) – Developing probiotics producing novel antimicrobials, with trials starting in early 2025.
• 32 Biosciences (Ginkgo Bioworks) – Focused on diagnostics and therapeutic modulation of bacterial virulence.
• Taylored Biotherapeutics (UCalgary) – Targeting the gut-brain axis for mental health applications.
• Florey Biosciences (Harvard Wyss) – Innovating with engineered yeast strains to address antibiotic-induced microbiome disruptions.
• Concordance Therapeutics are developing smart bacteria that localize to disease sites in the gut, consuming toxic metabolites and converting them into anti-inflammatory compounds.

The Consumer Microbiome Market

In 2024, the consumer microbiome market experienced significant momentum, driven by groundbreaking innovations and product launches from key players in the field. Next-Generation Probiotics (NGPs) continue to gain traction, offering targeted solutions for metabolic health, gut health, and women’s health.

Companies like Pendulum Therapeutics have showcased the potential of precision probiotics with products designed to address metabolic pathways. Similarly, Z-Biotics has expanded its footprint with innovative GMO-based probiotic solutions, addressing emerging consumer needs in metabolic health. Seed Health, on the other hand, has made notable progress in women’s health with their vaginal synbiotic, setting new standards for efficacy in microbiome-focused solutions.

These developments underscore the growing maturity of the NGP market, where science-backed innovation continues to drive both clinical and commercial success on a global scale.

Biose’s year in review

Reflecting on 2024, I am incredibly proud of the achievements of our team at Biose Industrie:

• 600+ bacterial strains manufactured.
• 80+ drug substance batches and 25+ clinical drug product batches produced.
• 10 million finished products delivered globally.
• New major and fantastic clients onboarded, reflecting our growing global reputation.

Looking ahead, we are actively preparing for a Pre-Approval Inspection (PAI) by the FDA. This preparation is closely aligned with the clinical advancements of our clients’ programs and represents a critical milestone in enabling commercial manufacturing of approved therapies.

We will also be expanding of our Boston laboratory in 2025 to serve as a small-scale GMP Phase 1 product manufacturing suite, complementing its state-of-the-art R&D services.

Furthermore, we are heavily investing in cutting-edge technologies to enhance both efficiency and scalability. This includes advanced fermentation techniques, optimized anaerobic production processes, innovative lyophilization strategies, and real-time quality monitoring systems to guarantee precision at every stage of production.

Signing off

Despite difficulties and challenges faced by the microbiome field, 2024 will remain for me as a pivotal and extremely significant year for our industry, as it is the year in which defined LBPs showed therapeutic reality.

With significant clinical trial results, significant investments from the public and private sectors, new company formations and good science continuing to emerge, it is important that stakeholders of the industry continue to focus on their end goal, which is ultimately bringing new therapies to patients in need.

I can say with certainty that this is the goal which continues to drive the team at Biose Industrie to maintaining the gold standard in bacterial manufacturing.

With this, I would like to wish all our friends, colleagues, clients and collaborators a very successful 2025!

Yours Sincerely

Adrien Nivoliez

CEO

Biose Industrie

The post Microbiome Wrapped 2024 – A Year in Review & What’s Next appeared first on Biose Industrie.

Head of Programs for LBP Development & Manufacturing

A few weeks back, Nadine, Richard, Adrien, and I had the pleasure of attending the Boston-based microbiome drug development conference “Microbiome Connect USA 2024”. Spanning 3 days the event promised the chance to connect with the microbiome field, and learn about its latest innovations, and it did not disappoint!

Women’s & Infant Microbiome Pre-day

Arriving at the conference, November 14^th, we attended the Women’s & Infant microbiome pre-day, a day of talks and panels dedicated to the work being undertaken to improve women’s health treatments and outcomes for infants. The talks ranged from regulatory considerations for microbiome-based technologies in paediatric use from the FDA to discussions on single-strain vs multi-strain approaches for vaginal dysbiosis.

Caroline Mitchell’s presentation was a personal highlight of the pre-day, providing a detailed analysis of microbiome interventions for bacterial vaginosis (BV). Mitchell described the lack of efficacy and innovation for existing bacterial vaginosis treatments, pointing out that options have remained stagnant since the 1980s, with antibiotics being the main treatment. Antibiotic usage leads to high rates of BV recurrence and rarely restores the vaginal microbiota to a healthy L. Crispatus dominance, Mitchell explained. The presentation explored a range of research projects which are developing antibiotic, microbiome-modulating alternatives, mentioning work by her eponymous lab as well as the Kwon Lab, Freya Biosciences, and the VMRC. It was exciting to see Biose’s partnership with the VMRC to develop an L. Crispatus derived LBP for BV be mentioned. The LBP is currently being tested for safety and efficacy in a phase 1 trial with results expected in 2025.

Day One – A Post Regulatory Approval Microbiome Market

On the morning of Day 1, we entered the buzzing conference room where Vedanta kicked off the official day one with a presentation on the future of the microbiome drug landscape. Dan Couto, Vedanta’s Chief Operating Officer, explored the field’s recent events including the closure of several developers, significant investments, and M&As. This led nicely into a panel discussion with MTIG, Rebiotix, BiomeBank, and Seres Therapeutics who discussed the field’s future in the context of the recent regulatory approvals.

Following the morning session, the agenda split into two tracks: “Emerging Pipeline & Therapeutic Updates” and “Bioprocessing & Data Strategies”. Emerging Pipeline & Therapeutics Updates covered a range of modalities for targeting a range of microbiomes, including a multi-strain product for targeting the lung microbiome from Biose partner Alveolus to a small molecule regulator of the gut microbiome by Axial Therapeutics. On the other track, Bioprocessing & Data Strategies presentations focused on the manufacturing side of microbiome drug development exploring CMC and cGMP manufacturing considerations and challenges, including one I was privileged to give on Biose’s world leading expertise in drug manufacturing.

My presentation described our global customer base, and how we leverage EU and US based facilities to ensure a close working relationship with our clients. I explained our end-to-end services, which extend from WGS data analysis for strain identification to regulatory support for CTD filing. A key focus of the talk was a scale-up case study on one of our clients. This project begun at our technology transfer facility in Boston. Where we worked to scale an extremely oxygen sensitive microbe from our clients’ flask-scale up to a 2000L reactor. This journey took several iterations, working up increasing scale and regulating the process until the microbe grew reliably and robustly. This kind of speciality work is only possible due to our extensive experience working with microbes, beginning in 1951!

The day ended with a screening of “Designer Shit”, followed by a panel discussion of the film. The movie followed the journey of Director Saffron Cassady, as she examined the world of faecal microbiome transplantation as a potential treatment for Ulcerative Colitis.

Day Two – Money, Microbiome and Manufacturing

At a time of uncertain investment for the biotech field at large, the morning panel of day two felt appropriate, focusing on what biotechs can do to engage investors and ensure their financial future in the market. Joyance Partners, Seventure, and Corundum Systems Biology all gave their input on this question giving a rounded view of investment strategy to the room full of microbiome researchers.

Once again, the program split into the two tracks, with Emerging Pipelines and Therapeutics continuing to showcase the diverse modalities biotechs are using to improve health outcomes, this time broadening to include clinical reads-outs for indications including rare liver disease, eczema, and cancer. Bioprocessing & Data Strategies shifted its focus to cover the “data” side of the track, with talks on multi-omics, proteomics, and biomarker development.

After three days of meeting with existing and new clients, listening to leading researchers discuss their work, the event came to a close. We all had a wonderful experience at Microbiome Connect and we cannot wait to return next year.

Presentation highlights:

Presentations we particularly enjoyed included:

• “Ambition to Provide Premature Infants With Approved Medication” – Robert Molander, COO, Infant Bacterial Therapeutics. Molander opened by describing the market opportunity for an effective infant necrotising enterocolitis (NEC) treatment, highlighting the high economic burden of the disease along with the high frequency. Their phase 3 candidate IB-9414 leverages reuteri to reduce inflammation and prevent dysbiosis in premature infants to prevent NEC development. Their phase 3 is currently the largest preterm randomised trial to date, IBT expect results for IB-9414 in 2024.
• “Development of AX -5006, a Small Molecule Inhibitor of CsgA Aggregation as a Potential Disease -Modifying Treatment for Parkinson’s Disease” – Becca Senter, Ph.D, Vice President, Head of Preclinical Research and Development, Axial therapeutics – Senter discussed Axial’s work on gut-brain candidates including small molecules to target autism-associated irritability, parkinson’s disease, and oncology. The presentation focused mostly on their lead candidate, AX-5006. Senter presented compelling results from Axial’s preclinical work which indicated that AX-5006 inhibits CsgA aggregation in mice models to alleviate Parkison’s motor-related symptoms. AX-5006 plans to enter the clinic in 2024.
• “AI-enabled, Metabolomics-based Drug Discovery Engine for Inflammatory Disease” – Hannah Wastyk, CEO, Interface Biosciences – Wastyk introduced Interface’s platform of AI-powered drug discovery, which combines the cultivation of important microbes in a proprietary growth media with an AI tool “CausalVision” to screen for microbe-produced metabolites with casual relationship to disease phenotypes. Interface’s first candidate is a topical Rx small peptide, RC13, which targets atopic dermatitis. Wastyk presented pre-clinical results which showed improved wound-healing in a scratch model and in vivo antibiotic activity.
• “Reinventing Humanity’s Relationship with Microbes” – Cheri Ackerman, CEO, Concerto Biosciences. Ackerman opened with a description of Concerto’s kChip technology, a high-throughput discovery platform for measuring microbe-microbe interactions. Ackerman explained the application of the kChip to discover a new candidate, ENS-003, to target vulvovaginal candidiasis. The LBP will modulate albicans, by down-regulating it’s virulence and shifting it to a commensal state. Concerto are currently screening the top performing bacterial combinations which regulate C. albicans.

Preclinical showcase presentation – Dr. Egle Katkeviciute, CSO and co-founder, Recolony – Katkeviciute presented their work to develop two anti-cancer candidates. The first is an LBP, RCLBP01, based on commensal bacteria which modulates T-cell activity to aid tumour clearance. Due to the approach only using commensal bacteria the therapeutic has high tolerability compared to other anti-cancer approaches. The company will be filing for an IND in 2025. Along with this LBP approach, Recolony are also developing a small molecule based on a RCLBP01-produced metabolite. Recolony forecast filing an IND for their small molecule late 2026.

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Last month, Biose industrie had the privilege of speaking at Microbiome Connect: Asia. The two-day congress took place in Seoul, Korea, and was attended by microbiome enthusiasts across academia and industry alike. Given the rapidly growing APAC microbiome market, Biose were thrilled to hear from APAC voices on topics ranging from regulatory firsts to clinical updates.

Day One

The opening panel, “New Frontiers in Microbiome Therapeutics” discussed avenues for collaboration between the APAC and global market.  Genome & Company’s CEO, Jisoo Pae, joined the CEOs of BiomMe, Sang Sun Yoon, and GwangPyo Ko, KoBioLabs, to engage in a thought-provoking conversation covering national government initiatives across APAC countries, and the future of microbiome therapeutics research. Korea was identified as an “easier” territory to develop microbiome therapeutics within due to the regulatory leniency. The discussion also touched upon the importance of engaging with a CDMO in the early stages of drug development, loss of therapeutic efficacy of combined bacterial strains, and the importance of selecting the right target disease candidate. On the latter point, the cancer market was highlighted as being a promising target for LBP development.

The morning of day one placed regulatory considerations at centre-stage. Servatus’ Samantha Coulson, head of clinical research, explained the company’s platform and proceeded to discuss regulatory differences between LBP and probiotics. The key differences being, LBPs are approved by regulatory authorities based on clinical trials whereas probiotics are treated like food supplements. The intended use of the product was also cited as a clear differentiator, with LBPs having intended therapeutic use in a patient population. Coulson also highlighted the safety considerations of bacterial products, stating translocation of LBPs across mucosal barriers are an important risk associated with the modality. This led onto BiomeBank’s presentation regarding their world first authorisation for a donor-derived microbiome-based product. Mirjana Rapaic, Head of regulatory affairs, provided a vibrant talk on Biomebank’s journey to market authorisation, including their work to establish a CMC biological dossier and BiomeBank’s GMP manufacturing capabilities.

Day Two

Day two opened with “The Path to Commercialization”, a session discussing requirements for the LBP field to scale.  The session opened with a discussion between Corundum system biology, and Metagen Therapeutics on investment and market dynamics. Sou Miyake, Director of Business development, and Taku Nakahara, CEO, Metagen Therapeutics explained that globally the fundraising climate for the biotechnology is currently difficult but suggested that Japan is proving more open to investing in the field.

Following the panel, Biose’s Program Leader, Taous Saraoui–mazed, PhD took to the stand to discuss CMC challenges for LBP development.  Taous explained Biose’s background as the global LBP drug developer with its activity split between an Aurillac Lab and facility, and a technology transfer laboratory in Boston. Biose’s expertise as an end-to-end solution provider for R&D, DS & DP manufacturing was explored by describing Biose’s program pipeline. Taous showcased key elements of Biose’s offering, highlighting it’s integrated regulatory expertise, integrated QC laboratory, and integrated ICH compliant incubators for stability studies and storage.

Pipeline presentations

The rest of day-two consisted of clinical updates and platform presentations. The range of therapeutic targets being explored by the presenting companies was vast:

• Genome & Company described their SB-121 candidate targeting autism spectrum disorder-associated symptoms. SB-121 is a Lactobacillus and dextan microsphere which modulates host oxytocin signalling. Given the role of oxytocin in regulation of social behaviour the rationale is that stimulating oxytocin signalling with SB-121 will reduce ASD-associated maladaptive behaviours. Results from their phase 1b showed SB-121 was safe and well tolerated in patients, and improved ASD-associated maladaptive behaviours as measured by vineland-3 and social preference testing.
• ImmunoBiome’s presentation focused on their IMB002, LBP candidate, targeting inflammatory disorders including inflammatory bowel disease and rheumatoid arthritis. ImmunoBiome chose their candidates and targets using their proprietary Avatiome platform that simulates host-microbiome immune interactions. Their IMB002 candidate, a Bifidobacterium strain, induces regulatory T-cell response and suppresses inflammatory immune response. CsgG has been identified as a key effector molecule in this process. ImmunoBiome has been granted IP protection for the novel Bfidobacterium strain and its derived polysaccharides in Korea, Japan, Indonesia, and the USA respectively. Biose are currently conducting toxicity studies on IMB002.
• GI Biome focused on their GB-X01 phase 1 candidate which targets colorectal cancer. GB-X01 showed anti-tumorigenic effect as stand-alone treatment in colorectal cancer model mouse, showing a reduction of the tumour volume and tumour weight compared to control. When used as an add-on therapy, GB-X01 enhances the anti-tumour effect of bevacizumab while minimizing the efficacy variation between tests subjects. GB-X01 induces intra-tumoral activity of NK cells in a colon cancer model, which presented a unique option to be used in combination with NK cell therapy – where the biggest challenge for efficacy is intra-tumoral infiltration. In addition to having an additive effect to chemotherapy, GB-X01 also reduces side effects associated with chemotherapy, such as diarrhoea. GI Biome are currently running a phase 1 study to determine the tolerability and dose for GB-X01, as well as exploring endpoints.

Conclusion

Microbiome Connect: Asia was an excellent opportunity to connect with the global microbiome drug development field. The quality of research was excellent, and the discussions held were important and necessary to further the field. We look forward to the next iteration of the conference and are grateful we were able to present.

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Biose Industrie is a world-leading contract development manufacturing organisation, dedicated to LBP process development and production. Since the company was founded in 1951 in Aurillac in the Cantal area of France, Biose Industrie has demonstrated its ability to develop a unique and innovative competence in industrial microbiology in compliance with pharmaceutical standards and regulations (ANSM, EMA, FDA).

With over 1000 batches in production and 100 in the clinical stage, Biose Industrie has experienced constant growth since 2017, working with biotechnology and pharmaceutical companies to develop microbiome-based medicinal products. This growth results from the rapidly growing microbiome therapeutics market, which has applications in a wide range of therapeutic areas including gastroenterology, oncology, gynaecology, dermatology and metabolic disorders.

In this context, a joint investment by the French State through the “French Tech Souveraineté” scheme, a system operated by EPIC Bpifrance and managed by Bpifrance as part of its France 2030 investment plan, and L-GAM, would allow them to acquire joint control of Biose Industrie in order to finance the next investment plan which will increase the company’s industrial capacity, for drug substance and drug product, in Aurillac. The investment will total €80 million, resulting in 200 additional staff hires within the next 4 years to scale Biose’s workforce to total 500 employees. In addition, to the further expansion of applied R&D facility near Boston US.

For this new phase of growth, Biose Industrie has high ambitions focused on three priority areas: (i) maintain and develop its technological and industrial advantage versus competition, (ii) continue recruiting staff in high numbers and (iii) expand its international presence where the company already has many clients.

On completion of the transaction, which remains subject to all applicable regulatory authorisations, “French Tech Souveraineté” and L-GAM will become shareholders alongside Adrien Nivoliez, the future President of Biose Industrie, the Fonds Souverain Auvergne-Rhône-Alpes managed by Siparex.

As an industrial partner (CDMO – Contract Development Manufacturing Organization) naturally intent on serving our clients, we are proud to contribute with them to improving the health of all the patients affected by their research programmes”, commented Adrien Nivoliez, CEO of Biose Industrie. “Central to our plans to grow, lies a heartfelt desire to continue to expand with our clients to ensure that we are in a position to meet all their needs. I am extremely excited to see the success and finalisation of the financing of this new stage in the company’s growth and I emphasize once again the company’s high ambitions

About Biose Industrie

Originally called Laboratoires Lyocentre and established in 1951, Biose Industrie was bought by the Desjonquères family in 1997, who pursued its historical development as a CDMO specialized in the industrial manufacturing of microorganisms compliant with pharmaceutical standards and regulations for human health. Today Biose Industrie’s turnover is largely generated by international sales, over half of which are in the USA. Locally, Biose Industrie is at the forefront of the industrial scene and employs over 300 people.

About L-GAM

L-GAM (www.l-gam.com) is a long-term oriented investment firm with capital commitments in excess of €1 billion. L-GAM was established in 2013 with the backing of the Princely Family of Liechtenstein and several families from Europe, Asia and the USA. Its unique and differentiated business model is based on long-term, industrial-like investment focus and a flexible mandate to provide investment solutions throughout the capital structure. L-GAM focuses on partnering with small and medium sized companies across Europe. L-GAM has invested , among others, in Jardiland (France), Faist ChemTec (Germany), Grupo BC (Spain), Cyber Group Studios (France), Woolrich (Italy and USA), Amplitude Laser Group (France), Centro Medico Santagostino (Italy), Ancorotti Cosmetics (Italy), Vinventions (Belgium) and Cotta (Liechtenstein).

About French Tech Souveraineté

The “French Tech Souveraineté” scheme was launched by the French government in June 2020 and is an investment scheme aimed at both promoting and protecting business development in France. The government has injected a total amount of €650 million into the scheme to support French technological companies developping technologies of the future of national interest and that could be prey to large foreign companies or overtaken by competitors with stronger financial means. The “French Tech Souveraineté” agreement designates EPIC Bpifrance as the operator of the scheme and Bpifrance Investissement to manage the implementation and monitoring of investment files.

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Kisaco Research’s flagship Microbiome Connect event returned to Boston in November. Joined by a range of microbiome companies and researchers, the event covered both the R&D and manufacturing considerations for microbiome drug development. From freeze-drying techniques for LBP development to synthetic therapeutic approaches, the conference platformed a diverse topic roster.

Some highlights of the event include:

Innovative therapeutic platforms

Focused on a systems approach to targeting the microbiome was Concerto Biosciences. Cheri Ackerman, CEO of Concerto Biosciences, presented on Concerto’s high-throughput interaction platform. Highlighting the work Concerto have done to characterise the skin interactome, Cheri explained how this complex mapping revealed lead candidates for ENS-002. ENS-002 is a defined group of microbes that reduces S. aureus virulence and is poised for in-human trials. The lead candidate “restores protective microbial interactions” to “rehabilitate” the skin microbiome.

Axial Therapeutics opts instead for a small molecule approach to target the gut-brain axis. Stewart Campbell, CEO, explained Axial aims to launch three new clinical programs, focusing on CNS and Oncology indications, in the next 18 months. Campbell explained Axial’s platform is based on Dr. Sarkis Mazmaian’s ground-breaking work into the gut-brain axis. The company showcased data on their phase 2 candidate, AB-2004, which treats irritability associated with autism spectrum disorder. The data highlighted improved irritability and anxiety scores in the cohort.

Leading the development of lung-targeted microbiome drugs, Alveolus’s Vivek Lal presented on their resMIT platform – “Respiratory Microbiota-based Inhaled Therapeutics”. Vivek outlined the rationale for targeting the lung microbiome to develop drugs. He discussed the non-sterile nature of the lower airways and the implication of the pro-inflammatory MMP-9 cascade in Chronic Lung Disease. Alveolus is gearing up to launch into clinic to address neutrophilic inflammation in COPD and BPD indications in 2023.

MaaT Pharma’s, CBO, Savita Bernal detailed their Microbiome Ecosystem Therapy platform. Having generated both native and co-cultured LBP candidates, MaaT’s MET platform marries a cGMP capability with their proprietary gutPrint metagenomics. Savita described the positive relationship between gut microbiome diversity and survivability of cancer patients. Data showcased MaaT013, the company’s phase 3, full ecosystem, candidate improved Graft-vs-Host-Disease patient survival in their HERACLES phase 2 clinical. Described mechanisms for the therapeutic effect of MaaT103 implicate epithelial barrier integrity, microbiome diversity, and inflammation regulation.

For their ApyraMed platform, MVBiotherapeutics leverages the ATP-degrading capabilities of apyrase to increase protective igA production. ApyraMed candidates are recombinant live bacteria which express exogenous antigens and apyrase. Fabio Grassi, CEO, demonstrated anti-biotic treated mice treated with MV-003 were resistant to C. diff colonisation when compared to the control. The ApyraMed platform has applications in immuno-oncology and antibiotic-associated dysbiosis. The company plans on developing this product up to phase 2 to license afterwards.

Manufacturing LBPs

Biose Industries’ Head of Programs, Claire Derlot, Ph.D. gave a presentation on LBP CMC challenges. Derlot outlined Bioses’ leading LBP manufacturing services starting from analytical R&D all the way up to commercialisation. With Biose Industrie’s integrated QC lab, QP Pharmacists for LBP FMP certification and release, summed with its ICH compliant incubators for short to long term stability studies, it showcased Biose as a titan of microbiome manufacturing.

Nicolas Pichon, head of biomanufacturing, Servatus covered single-use vs multi-use manufacturing technologies, as well as describing how Servatus set-up a smart and hybrid production facility. Pichon described single-use vs multi-use reactors as a matter of choice. Merits of single use were: a smaller footprint, infrastructure versatility and quick turnover. Multi-use in contrast was explained to facilitate a larger capacity (up to 20000L) and be resistant to supply chain disruption. Key considerations for deciding between the two modes of manufacturing equipment were: scalability, supply chain management, flexibility, cost, and process complexity. Pichon then explained Servatus’ hybrid approach to manufacturing. Using both single and multi-use equipment, he suggested with this approach, process optimization can be continuous.

Pharmabiome took to the stage to describe their proprietary “COMIT” consortia manufacturing platform – “continuously co-cultivated minimal microbiome therapeutics”. The COMIT platform prioritises microbe interactions to produce a multi-strain drug product.  Tomas de Wouters, CEO, described how their process results in high reproducibility, increased yield, high product stability compared to other approaches.

Regulatory considerations

Diving into the need for standards for live microbial products was Kit Goldman, Ph.D., Senior Director for Dietary Supplements and Herbal Medicines, from the US Pharmacoepia. Kit reiterated the FDA’s previously outlined guidance on drug substance and drug product specifications. The quality parameters for live microbial products were described as: relative percentage of strains, enumeration, purity, and stability. Kit described the challenging nature of working with Live microbial products and suggested appropriate methods for meeting regulatory parameters. Goldman contrasted the merits of different enumeration methods including flow cytometry, NextGen sequencing, and qPCR. Another challenge outlined by Kit was defining the ratio of viable:dead cells in a product. Viable but non-cultivatable cells (VBNCs) were explained to be microbes unable to form colonies, but which retain metabolic activity. The “functional” but non-colony forming nature of VBNCs make testing for their presence via plating difficult.

Paul Carlson, Principal Investigator, of the FDA, outlined the regulatory considerations for microbiome-based therapeutics. He detailed the process of filing for an investigational drug application (IND) for microbiome-based therapeutics (FMT and LBPs). Carlson described the challenges in the regulation of FMT, identifying product safety and characterisation as key issues. Regarding FMT, questions such as “What organisms should we test for?” and “what is a good potency assay?” were outlined. The recent FDA safety alerts related to FMT were used to highlight FMT’s intrinsic potential for health risks.

Carlson then described the chemistry, manufacturing and controls (CMC) for LBPs. Drawing from the FDA’s published guidelines, he explained CMC for LBP INDs should include but not be limited to: strain information, antibiotic resistance profiles, cell banking system info, the drug substance/drug product manufacturing process, stability data, manufacturing controls and release testing, and bioburden testing. Carlson described intended use, as being critical in determining a products categorisation as an LBP as compared to a probiotic. The process of filing for an IND utilizing commercially available LBPs was explained; applicants can request a waiver for the requirement for CMC information, which if granted allows for the label on a commercially available LBP to be used in substitute of traditional CMC information.

Conclusion

We enjoyed meeting with new and familiar faces at Microbiome Connect: USA 2022. We look forward to attending more microbiome events and working researchers pushing microbiome therapeutics to commercialisation.

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In 2002 the first study using molecular methods to analyse vaginal microbiome make-up was conducted. In which, researchers evaluated the bacterial flora of post-menopausal women by PCR techniques. Since then, through the adoption of more advanced molecular methods like 16S metagenomics, our understanding of the complexity and dynamism of the vaginal microbiota has evolved significantly. And whilst research is early for this microbiota niche it is implicated in a range of indications.

These include:

• Bacterial Vaginosis (BV) – Affecting roughly 20% of child-bearing women, bacterial vaginosis is indicated by a loss of Lactobacilli species and an overabundance of anaerobic species. The resulting dysbiotic microbiota leads to symptoms like altered vaginal discharge, and discomfort. Antibiotics are often used to treat BV, although given their microbiome disrupting effects, alternatives are being examined.
• Vulvovaginal candidiasis (VVC) – Not just consisting of bacterial strains, the vaginal microbiome naturally contains fungi (mycobiome) and viruses (virome) too. During periods of dysbiosis, an overgrowth of albicans often occurs, leading to Vulvovaginal candidiasis – the most common vaginal fungal infection. In vitro studies have demonstrated vaginal mucosal cells treated with L. Crispatus strains reduce C.albican adhesion capabilities, presenting live bacterial supplementation as a potential alternative to traditional antifungal treatments in the future.
• Urinary Tract Infection (UTI) – UTIs are most commonly caused by coli strains. It has been recorded that the quantity of UTI-causing bacterial strains in the vagina increases significantly preceding symptoms, highlighting the role of the vaginal microbiota as a starting point for the condition.
• HIV – Whilst the mechanism is unclear, a link between a dysbiotic vaginal microbiota and incidence of HIV acquisition has been identified. One hypothesis for this is the dysbiotic microbiota disrupts the vagina’s epithelial barrier, resulting in closer proximity between HIV particles and the host’s immune cells. This is supported by a recent paper, in which metaproteomic analysis demonstrated women dominated by vaginal lactobacilli had higher abundance of bacterial lactate dehydrogenase which is positively associated with increased epithelial barrier proteins.

The health implications of a disrupted vaginal microbiome are clear, but what factors lead to perturbed community composition?

• Sex – Studies have identified associations between sexual practices and vaginal microbiota disruption. For instance, women who have sex with women (WSW) show an increased risk for developing BV. One study found sex with a new partner increases the diversity and quantity of BV-associated strains in WSW. Other sexual factors shown to alter microbiome composition include unprotected penile receptive sex, vaginal sex after anal sex, and oral receptive sex. The mechanism for microbiota disruption varies sex practice to practice. For example, penile receptive sex may negatively impact vaginal flora due to the cytokine upregulating and pH lowering of semen.
• Antibiotic exposure – Unsurprisingly antibiotic treatment can deplete bacterial species in the vagina thus disrupting community balance, leading to disease states.
• Birth control – Some research has identified a positive role of progestin-based hormonal contraception on vaginal microbiota composition, finding decreased incidence of BV and increased lactobacilli dominance in users. There have been mixed findings regarding the impact of copper intrauterine devices on vaginal microbiome composition.

Although, the vaginal microbiome drug landscape is in its beginning stages, there is lots of innovation taking place in the sector. Hailing from Cambridge, Massachusetts LUCA Biologics inc. is developing its first drug candidate to target UTI and will enter the clinic this year for a phase 1b clinical. Raising $2.8 million in funding in 2019, the Seed Health backed company will develop live biotherapeutic products for indications including: preterm birth and bacterial vaginosis. Working on a platform of “living medicines”, LUCA  sources its strains from a 1000+ strain and gene catalogue assembled from Dr Jacques Ravel’s research group. Described in Nature, Dr Ravel’s VIRGO catalogue includes 0.95 million non-redundant genes (Ravel et Al. 2020). LUCA will no doubt be a front runner in the vaginal microbiome field, supported by Dr Ravel’s world-leading expertise.

Currently within phase 2, Nexbiome Therapeutics’ LBP candidate, BGY-1601, aims to treat acute vaginitis.

Also targeting the vaginal microbiome Osel inc. are developing a live biotherapeutic product to prevent BV and rUTIs. Osel’s LACTIN-V contains the bacterial strain Lactobacillus crispatus CTV-05, selected for its role in maintaining microbiota community composition. Lactovbacillus crispatus being shown to be depleted in women with BV, this drug aims to restore lactobacillus dominance. In a Lancet published paper, LACTIN-V treatment of BV was associated with lower proinflammatory cytokine IL-1α and soluble E-cadherin, an indicator of epithelial barrier integrity.

Ferring, Rebiotix and MyBiotics are collaborating on live microbiota formulations to address BV. In 2021 the groups released an announcement outlining a multi-year strategic collaboration. MyBiotics’s CEO, David Daboush explained the project would combine their “MyCrobe” culturing platform with Ferring and Rebiotix’s development experience.

Gedea Biotech aims to develop “the first antibiotic-free treatment” for BV prevention. Citing the growing public health threat of antibiotic resistance as a driver, Gedea’s BV candidate, pHyph, hopes to address an unmet medical need. Founded in 2015, Gedea have conducted multiple studies to validate their product and will be embarking on a study into VVC soon.

Approaching the vaginal microbiome in a subtractive approach is Intralytix, who are examining the applications of phage to treat BV.

Some researchers are avoiding drugs altogether and are instead adopting approaches akin to fecal microbiome transplantation to modulate vaginal microbiome health. Vaginal microbiome transplantation is being examined for applications in treating rUTI and BV. A recent paper from Massachusetts General Hospital, Boston, outlines a protocol for an “FDA-approved donor screening protocol and detailed methodology for donation collection, storage, screening, and analysis of VMT material” contributing to the work needed to standardise this novel practice.

Ma, B., France, M.T., Crabtree, J., Holm, J.B., Humphrys, M.S., Brotman, R.M. and Ravel, J. (2020). A comprehensive non-redundant gene catalog reveals extensive within-community intraspecies diversity in the human vagina. Nature Communications, [online] 11(1), p.940. doi:10.1038/s41467-020-14677-3.

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In the past decade, scientists have looked at how these hard-working organs may be influenced by the bacteria and other microorganisms residing in the digestive tract, or gut. Although the kidneys themselves are considered sterile, evidence is accumulating that the gut microbiota influence kidney function in several ways.

The microbiota-gut-kidney axis is the bidirectional relationship between the gut microbiota and the kidneys. The ‘crosstalk’ between these two body systems takes place in two main ways:

• Effects of microbial metabolism on kidney function: Changes to the gut microbiota impact the sets of metabolites produced in the gut. Some of these, including short-chain fatty acids, are sensed by the kidneys and influence renal function; meanwhile, some gut microbial metabolites can contribute to the generation of uremic toxins.
• Effects of gut microbes on kidneys via the immune system: Chronic kidney disease (CKD) and other renal diseases are associated with a permeable gut barrier. Bacteria or metabolites entering systemic circulation through a “leaky gut” trigger immune activation and systemic inflammation that can affect kidney function. Gut microbiota may have other effects on the kidney via complex interactions with the immune system: for instance, lymphocytes, monocytes, and other immune cells produced at the bone marrow are activated by the gut microbiota at peripheral lymphoid organs such as gut-associated lymphoid tissue (GALT); altering these dynamics may impact local kidney inflammation and contribute to kidney disease.

Renal diseases associated with alterations in gut microbiota

Gut microbiota alterations occur in patients with various renal diseases and conditions. In chronic kidney disease (CKD), studies show individuals with CKD have altered gut bacteria: in one study, increased bacteria from the taxa Klebsiella and Enterobacteriaceae were observed, with reduced Blautia and Roseburia. As the disease progressed, Thalassospira and Akkermansia (which is normally associated with health benefits) were increased. Another study showed very subtle gut microbiota changes in early-stage CKD.

A 2020 meta-analysis of studies also determined that individuals with kidney stones have altered gut microbiome composition, although no consistent pattern was observed.

In end-stage renal disease (ESRD), gut microbiota composition seems to be altered as well. One group found 190 operational taxonomic units (OTUs) altered in those with ESRD versus controls; furthermore, patients with ESRD appear to have an expansion of bacterial taxa that possess tryptophanase and urease genes. The plasma from ESRD patients tends to have higher concentrations of urea, which gut microbes help convert into ammonium hydroxide; the latter disrupts the proteins that keep tight junctions in the gut together.

Paralleling several other cancers, scientists have found that gut microbial composition is associated with the efficacy of immunotherapy drugs for renal cancer.  An important study from 2020 used shotgun DNA sequencing to analyze fecal microbes in people with renal cell carcinoma, backed up by preclinical models, and found that fecal microbiota composition was a driver of response to immunotherapy drugs.

Gut-kidney axis therapeutics

Although kidney-related indications are not the most common ones in the microbiome space, several companies are advancing gut microbiome-targeting drug products that target kidney disease. Osel Therapeutics, in addition to its live biotherapeutic product (LBP) targeting bacterial vaginosis and urinary tract infection in women, is also developing an LBP focused on renal cell carcinoma: CBM-588. Interestingly, CBM-588 is a butyrate-producing strain of Clostridium butyricum that has long been used in Japan in non-drug applications for digestive symptoms. The company is now bringing it through Phase 1 trials with the aim of improving clinical outcomes in both advanced renal cell carcinoma and hematopoietic stem cell transplantation. The company published an open-label study that showed promising results for this LBP drug candidate in improving clinical outcomes for patients with renal cell carcinoma who were treated with nivolumab–ipilimumab.

Everimmune is advancing Oncobax AM, a microbiome-focused therapeutic based on Akkermansia muciniphila and aimed at improving responses to immunotherapy in renal cancer (as well as lung cancer).

Kibow Biotech is a company with a number of prebiotic and probiotic dietary supplements on the market, including a kidney health supplement (Renadyl™) that has been available to consumers for over 20 years. The company recently decided to transition the supplement to a live biotherapeutic product targeting chronic kidney disease stage IV. The product consists of 3 probiotic strains that use nitrogenous wastes as nutrients, reducing their buildup in the digestive tract. In its drug iteration, the product will have to meet new standards for safety, efficacy, and manufacturing quality.

Notitia Biotechnologies has an approach focused on restoring key groups of bacteria called “foundation guilds”, either by providing the guilds directly or promoting their growth in the gut microbiome. The company has a candidate for early/end-stage diabetic kidney disease, which has completed a Phase 1 trial.

Finally, Qu Biologics lists kidney cancer is among the conditions being targeted by its Site Specific Immunomodulators (SSIs), which aim to recruit immune cells to a specific organ or tissue to normalize immune function. The SSI targeting kidney cancer is derived from components of inactivated urogenic E. coli and is administered by subcutaneous injection.

Although the drug products being advanced to target the gut microbiota for kidney health are relatively few, they represent hope to those affected by kidney diseases, including cancer. Continued advancements in understanding how the pathogenesis of kidney disease relates to the gut will very likely bring about novel microbiome-focused therapies.

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Describing the microbiome

A presentation by Alexandra Zhernakova of University Medical Centre Groningen, “The role of host genetics and environment in shaping the gut microbiome”, provided an overview of factors that influence the human gut microbiome as observed in large-cohort association studies. Although both genetics and environment influence the gut microbiome, the environment is by far the most important. Researchers have been able to explain around 18.7% of the inter-individual variation in the gut microbiome, with major effects from medicines, food items, and host factors such as diseases. Zhernakova cited some studies that focus on genetic contributions to microbiome composition, although power is a major problem for microbiome genome-wide association studies; 50-100K samples are needed to detect more loci.

Olaf Larsen of University of Amsterdam and Yakult provided a broad view of what we still need to know about the human microbiome in his presentation “Microbiota Management: A One Health Perspective”. To understand whether the recent rise in chronic diseases is attributable to depleted microbiomes, we need to answer questions such as: What are the critical determinants of ecosystem structure and stability? And what are the associated functionalities of the ecosystem? He says keystone taxa may be drivers of structure and functionality (see here). He gave an example of how it is possible to model microbial guilds for the creation of efficient fecal transplant analogues.

Therapeutics

A variety of approaches to microbiome-focused therapeutics were described in the conference presentations. Perhaps the most straightforward approach was described by Ana Montalban-Arques of Recolony: providing specific strains of bacteria that are lacking in those with colorectal cancer (CRC) compared to healthy individuals, for anti-tumor effects. The bacteria in question are two commensal Lachnospirales strains, delivered in gastric resistant capsules.

Sin-Hyeog Im from ImmunoBiome gave an example of how LBPs can target the immune system directly. His presentation, “Mechanism of Anti-cancer Activity of IMB001 in Enhancing Cancer Immunotherapy”, described the company’s immunostimulatory anti-cancer LBP, IMB001, which works through the priming of T-cells by macrophage in the tumor microenvironment.

Recombinant live biotherapeutic products (LBPs) were described by Maria Lluch Senar of Pulmobiotics in “Pioneering live biotherapeutics in the respiratory tract”. The company is developing genetically modified organisms for respiratory diseases, which are bacteria expressing several therapeutic proteins. Each therapeutic candidate uses a chassis – either MycoChassis or LactoChassis –and they do insertion of genetic platforms on the chassis genome. The company is currently developing therapeutics for five different indications.

The presentation “Advancing a portfolio to Late-Stage: The Synlogic Experience”, by Vasu Sethuraman of Synlogic,covered the concept of “synthetic biotics”. Differentiated drug candidates are created using programmable, precision genetic engineering combined with a well-characterized probiotic chassis. The company has Phase 2 trials are ongoing for its two most advanced candidates, SYNB1618 and SYNB1934 for phenylketonuria. In addition, they are advancing a candidate for another rare metabolic disease, homocystinuria.

Spencer Diamond, microbiologist from Banfield Lab, presented on a recent publication in Nature Microbiology in collaboration with Doudna Lab, showing a strategy for editing genomes of specific organisms living within microbial communities. The technique consists of two parts: first, they used something called environmental transformation sequencing (ET-seq) which delivered nontargeted transposon insertions to a microbial community, allowing them to track which constituents of the community were manipulable. Then, having identified the organisms responsive to genetic manipulation, they applied all-in-one RNA-guided CRISPR–Cas transposase (DART) systems to insert DNA. In this way they successfully manipulated the genes of individual members of a microbial community, without the need for culturing. This could be an important tool in the microbiome field, and in the near future will be used primarily for research purposes.

Christian Grøndahl of SNIPR Biome spoke on “Applying CRISPR to treat life-threatening diseases”. The team uses the approach of CRISPR-armed phages to achieve selective bacterial killing and modification of the microbiome, either destroying bacterial genes or adding genes. The company’s pipeline is focused on applications in oncology and immunology, with partnerships in cardio-metabolism. One example is SNIPR001, which targets antimicrobial resistance (specifically, fluoroquinolone-resistant E. coli infections) in people with hematological cancer, via selective bacterial killing while preserving the gut microbiome.

A “full ecosystem approach” was described by Isabelle Adeline of MaaT Pharma in her presentation “The guts to fight cancer”. Maat Pharma develops standardized, high-diversity microbiome ecosystem therapies for hematological malignancies and cancer applications. They currently have promising Phase 2 data for their product addressing acute Graft-vs-host-Disease; and in hemato-oncology, they also have MaaT013 and MaaT033, which aim to restore gut microbiota and improve survival in patients with liquid tumors.

Regulatory Affairs

Céline Druart of the host organization PRI spoke on “Revision of the EU BTC & Pharma legislations: An evolving regulatory landscape for microbiome-based medicinal products”. She noted that Microbiome-based Medicinal products (MMPs) are a wide spectrum of products with varying levels of characterization and control. MMPs are a type of Biological Medicinal Product, and she suggests that in the absence of a specific regulatory framework for MMPs, it is prudent to rely on applicable and relevant regulatory concepts for biological medicinal products and advanced therapeutic medicinal products, even if MMPs don’t fit perfectly within the scope of these guidelines. Druart also covered probable future changes to the European regulatory framework: ongoing revision of the Blood, Tissues & Cells legislation and the general Pharma legislation. This means substances of human origin (SoHO) will have an additional layer of legislation to take into account.

Austin Udocor of DNA Genotek / Novosanis / Diversigen gave a specific example of a regulatory journey in his presentation “The first FDA authorized device for fecal microbiome sample collections: Our journey through a new regulatory pathway and what it means for microbiome innovations”. The company used the De Novo Pathway for new technologies. After they were granted the De Novo in 2021 for Omnigene Gut Dx, the device became the first and only FDA-authorized device for gut microbiome profiling. Udocor explained that authorized devices matter because (1) they allow standardization so data can be compared between different companies and institutions around the world; and (2) they increase analytical validity, so a company can show that the microbiome data is based on good science. He advised companies to include regulatory strategy in initial product development, since “regulatory requirements are product requirements”. Not only did he recommend early engagement with Notified Bodies or Competent Authorities, but also being prepared to reply to unfavourable responses if the intended purpose for use is novel.

Intellectual Property

Michèle Paquier of Eligo Biosciences presented on “Intellectual Property Practical and strategic considerations”. She cautioned that intellectual property (IP) often comes into play too late – such as when an employee / inventor leaves the company, or confidentiality issues arise with collaborators. Paquier says IP should be considered from the beginning. It is useful to secure both product and method claims, since the combination puts the company in a stronger position in case of patent challenge; furthermore, it offers more flexibility for licensing. A product’s level of characterization and level of distinction from “natural product” (in the US in particular) are key to optimal worldwide patent protection.

Manufacturing

Claire Derlot, Head of Programs at Biose Industrie, hosted a panel discussion titled “Identifying and overcoming Manufacturing Challenges for LBPs” together with Romain Daillere of EverImmune, Adam Wilkinson of Microbiotica and Prof Sin-Hyeog Im of Immunobiome. The panelists discussed:

• Strain Safety & stability: How does a company select the right candidate and the potency marker? Biose Industrie brings their expertise to help confirm those elements, and brings additional value regarding phage investigation or strain stability markers.
• CMC process: Panelists shared tips for process development with GMP-suitable Raw Materials / Culture medium selection, as well as the impact of the manufacturing process on potency and the impact of the collection phase / lyophilization stress.
• Drug Product formulation: Participants discussed which target and which Drug Product form.
• Stability: They covered how to define expiry and factors that go into labelling.
• GMP Live Biotherapeutic Product Drug Substance and Drug Product characterization
• IND filings

During the event, Biose Industrie CEO Adrien Nivoliez also co-hosted an interactive round table discussion on “Patenting the Microbiome and its Influence on Investment”, together with Georges Rawadi and Kristin Thompson, Chief Business Officer at eureKARE. These industry experts gave young biotech leaders in the field the opportunity to interact informally and ask questions around investment and IP strategies.

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