Global Microbiome Therapeutics Landscape: Two Companies Lead Phase III Trials—Who Will Launch the First Microbiome Drug?

In the science fiction film War of the Worlds, alien invaders occupy Earth and capture humans, but are ultimately eradicated by Earth’s oldest indigenous microbes due to their inability to adapt to the environment.

The film may have exaggerated the power of microbes in the face of alien technology, but environmental microbes are to Earth what the human microbiome is to humans: vital and indispensable.

The external environment surrounding humans is constantly filled with a wide variety of microorganisms. From the oral cavity to the anus, this specialized external interface of the human body also harbors thousands of distinct microbial communities. These communities are distributed across the skin, respiratory tract, oral cavity, gastrointestinal tract, and urogenital tract. The dynamic equilibrium among these microbial communities is closely linked to human health status.

Among these, the microorganisms distributed in the human gut have become a research hotspot over the past two decades. The strong association between gut microbiota and human metabolic health has been revealed in recent years; whether it is subhealthy obesity or various metabolic diseases that have already compromised health, the influence of gut microbiota is evident behind them.

With the successive launch of national human microbiome research initiatives, a new wave of enthusiasm for microbiome technology research and development has been ignited. New tools, methods, and technologies for the ecological regulation of human microbial communities are emerging in large numbers, enriching the approaches available to improve the human microecology and prevent infectious diseases.

VCBeat (WeChat ID: vcbeat) has compiled research achievements in human gut microbiota in recent years, aiming to explore the future development trends of the human microbiome industry from these cutting-edge research directions.

Currently, the most common strategy in microbiome-based therapeutic regimens is to restore the dynamic equilibrium of the body’s microbiota, thereby achieving disease treatment. Additionally, there are strategies that involve interventions using specific microbes (such as bacteriophages) or specific drugs (such as antibiotics) to eliminate dysbiotic and harmful microorganisms within the body. Notably, the integration with cutting-edge immunotherapy has emerged as a promising highlight in current microbiome-based treatments, wherein microbial interventions activate immune responses to treat cancer or other specific diseases.

Among the numerous human microbiome therapeutic strategies, Clostridioides difficile infection (CDI) represents the indication with the broadest applicability, potentially making it the first niche sector to yield approved microbiome-based drugs.

Clostridioides difficile infection (CDI) is a severe acute intestinal infection caused by the gastrointestinal pathogen Clostridioides difficile. Clinical manifestations primarily include diarrhea, abdominal pain, nausea, and fever. CDI has become one of the three most urgent antibiotic-resistant bacterial threats in the United States and remains a leading cause of healthcare-associated infections in U.S. hospitals.

According to reports from the Centers for Disease Control and Prevention (CDC), approximately 700,000 people in the United States are infected with Clostridioides difficile infection (CDI) each year, and 500,000 patients receive antibiotic treatment for CDI. The recurrence rate is approximately 20% to 30%, and nearly 60% of these patients are at risk of multiple recurrences. Furthermore, CDI causes up to 29,000 deaths annually in the United States, with nearly $4.8 billion spent on emergency care facilities for CDI. The CDC has listed CDI as an urgent public health threat.

However, to date, therapeutic options for Clostridioides difficile infection (CDI) have been limited to oral antibiotics. The scarcity of available antibiotics, coupled with patients’ pathological conditions that hinder adequate drug delivery to the intestinal lumen, has resulted in significant clinical limitations. These challenges underscore an urgent market need for a highly effective treatment regimen for severe gastrointestinal infections.

“The one who tied the bell must untie it.” The essence of *Clostridioides difficile* infection lies in the dysbiosis of the human gut microbiota. In addition to using novel antibiotics to eradicate the pathogen, microbiome therapy aimed at restoring the dynamic equilibrium of the gut microbiota can also achieve therapeutic goals, making it a prominent focus of current research in the human microbiome field.

International Microbial Therapies for CDI and Associated Companies

Crestovo is a biopharmaceutical company based in Massachusetts, USA. In 2017, it merged with Finch Therapeutics, another human microbiome research company, to jointly develop microbiome-based therapies for Clostridioides difficile infection. Finch Therapeutics focuses on developing novel microbiome therapeutics to address significant unmet clinical needs. The company’s proprietary technology platform enables the development of biologic drugs that help restore microbiome function, thereby treating diseases caused by dysbiosis or microbial disruption.

Previously, the microbiome drug developed by Finch Therapeutics received FDA Fast Track designation for the treatment of autism spectrum disorder with gastrointestinal symptoms in children.

Finch Therapeutics, in collaboration with Crestovo, has developed CP101 (PRISM 3), a leading microbiome therapy utilizing Full Spectrum Microbiota™ (FSM™) derived from the human gut microbiome. This orally administered, enteric-coated capsule delivers an intact microbial community for the treatment of recurrent Clostridioides difficile infection.

It is reported that CP101 has also been granted Fast Track Designation and Breakthrough Therapy Designation by the FDA. Furthermore, in the ongoing Phase II clinical trial, 74.5% of patients with recurrent CDI achieved sustained clinical cure by Week 8.

“These results are encouraging, indicating that CP101 has the potential to meet the need for an oral therapy capable of breaking the cycle of CDI recurrence and preventing the disruptive impact of recurrent Clostridioides difficile infection on patients’ lives,” said Dr. Jessica Allegretti, Principal Investigator of the PRISM 3 clinical trial. “This validates the feasibility of microbiome restoration approaches, marking a key milestone in the field and providing a reference for developing similar therapies targeting many other conditions caused by microbiome disruption.”

Notably, CP101 demonstrates therapeutic potential in the treatment of chronic hepatitis B. The company is initiating a program to evaluate CP101 for this indication, investigating whether it can restore the gut microbiome in patients with chronic hepatitis B and support the activation of immune responses. Modulation of the immune system by the microbiome underpins the mechanism of action of approved hepatitis B therapies, such as pegylated interferon.

Rebiotix is a clinical-stage microbiome company based in Minnesota, USA, dedicated to leveraging human microbiome technology to treat challenging diseases. The company’s Microbiota Restoration Therapy (MRT) platform produces stable therapeutic agents designed to deliver diverse live microbes into the patient’s gut, thereby restoring the human microbiome for therapeutic purposes.

In 2018, Rebiotix was acquired by the Swiss biopharmaceutical group Ferring Pharmaceuticals. Founded in 1950, Ferring Pharmaceuticals is a global leader in the specialized fields of reproductive medicine, women’s health, gastroenterology, and urology. Following the acquisition, the two companies will jointly explore the association between the human microbiome and disease to develop more innovative therapies for various diseases.

RBX2660 is an advanced investigational microbiome therapy developed by Rebiotix. It is a non-antibiotic therapeutic agent for the treatment of recurrent Clostridioides difficile infection (CDI), composed of a suspension of gut microbiota and administered via enema.

It is reported that RBX2660 has received Fast Track designation, Breakthrough Therapy designation, and Orphan Drug designation from the U.S. FDA. The company is currently actively conducting Phase III clinical trials for RBX2660, which is poised to become the world’s first approved human microbiome therapeutic.

In addition, Rebiotix’s MRT technology platform has many other pipelines under development, such as RBX7455, a non-frozen lyophilized oral capsule formulation that can also be used to prevent the recurrence of CDI.

Seres Therapeutics is a microbiome technology company based in Massachusetts, USA, dedicated to developing novel multi-functional bacterial consortia that cure diseases through functional interactions with host cells and tissues.

The company has developed an investigational oral microbiome therapeutic, SER-109, for Clostridioides difficile infection (CDI). This agent reduces CDI recurrence by breaking the vicious cycle of recurrent infections and restoring the diversity of the human microbiota, thereby achieving sustained clinical efficacy.

SER-109 is manufactured by fractionating target bacteria derived from the stool of healthy human donors, followed by further inactivation of potential pathogens. However, this therapy is fundamentally distinct from fecal microbiota transplantation (FMT), as it consists of highly purified spore-based commensal bacteria.

Currently, SER-109 has been granted Breakthrough Therapy Designation and Orphan Drug Designation by the FDA. In August 2020, Seres Therapeutics announced the results of its Phase 3 clinical trial: compared with the placebo group (41%), treatment with SER-109 for eight weeks significantly reduced the proportion of patients with recurrent CDI to 11%, exceeding the efficacy threshold previously agreed upon with the FDA.

Acurx Pharmaceuticals is a biopharmaceutical company based in New York State, USA, dedicated to developing novel antibiotics for hard-to-treat infections. In 2018, the company acquired the ACX-362E pipeline from GLSynthesis. ACX-362E is a novel antibiotic that inhibits DNA synthesis in Gram-positive bacteria, including Clostridioides difficile and Enterococcus species, thereby exerting its antibacterial therapeutic effect.

It is reported that ACX-362E was granted Fast Track designation by the FDA in 2019, and the company is currently actively conducting Phase II clinical trials of ACX-362E.

Deinove is a French biotechnology company that specializes in developing innovative antibiotics and bio-based active ingredients for cosmetics through disruptive approaches, aiming to help address the challenge of antibiotic resistance, while also exploring sustainable production models for the cosmetics and nutrition industries.

The company has developed DNV3837, an intravenous antibiotic for the treatment of Clostridioides difficile infection (CDI). This agent, which is a prodrug of the molecule DNV3681, treats infections caused by Gram-positive bacteria. Upon conversion to its active form, DNV3681, the drug crosses the gastrointestinal barrier and accumulates in the intestinal lumen, thereby precisely targeting the site of infection.

The FDA has granted DNV3837 the Qualified Infectious Disease Product (QIDP) designation and Fast Track status. The company is currently actively conducting Phase II clinical trials of DNV3837 to evaluate its efficacy under pathological conditions (through symptom monitoring, stool analysis, etc.) and to further consolidate safety and pharmacokinetic data for this antibiotic candidate.

Beyond Clostridioides difficile infection (CDI), the application landscape for human microbiome-based therapeutics holds vast potential. Internationally, numerous biopharmaceutical companies are leveraging principles of the human microbiome to develop biologics for conditions such as inflammatory bowel disease, cancer, and graft-versus-host disease. VCBeat (WeChat ID: vcbeat) has compiled a brief overview for our readers.

Other International Microbial Therapies and Application Scenarios

Inflammatory Bowel Disease (IBD) is an idiopathic inflammatory disorder of the intestine, clinically characterized by diarrhea, abdominal pain, and potentially hematochezia.

In a broad sense, inflammatory bowel disease (IBD) can refer to various types of intestinal inflammatory conditions; however, in the narrow sense, it specifically denotes ulcerative colitis (UC) and Crohn’s disease (CD).

Ulcerative colitis is a continuous inflammation involving the mucosal and submucosal layers of the colon; the disease typically begins in the rectum and gradually extends to involve the entire colon. Crohn's disease can affect any part of the gastrointestinal tract, characterized by discontinuous, transmural inflammation, most commonly involving the terminal ileum, colon, and perianal region.

In the past, inflammatory bowel disease (IBD) was predominantly observed in Western developed countries and was considered rare in China; however, its incidence in China has shown a significant upward trend in recent years. The peak age of onset for IBD is between 15 and 25 years, although it can also occur in children and the elderly. There is no significant difference in incidence rates between males and females.

Currently, pharmacological treatments for inflammatory bowel disease (IBD) primarily focus on aminosalicylates, glucocorticoids, immunosuppressants, and antibiotics, with no biologics yet developed from the perspective of microbiome-based therapeutics. Internationally, however, pharmaceutical companies have begun exploring IBD treatments through microbiota modulation, as exemplified by Vedanta Biosciences and Intralytix.

Intralytix is a biotechnology company based in Maryland, USA. The company has developed a proprietary phage technology and became the first company in the world to receive FDA approval for phage-based products intended for food safety applications. It boasts the world’s largest portfolio of phage products and holds several patents related to phage technology.

Vedanta Biosciences, founded in 2010, is a leader in clinical-stage microbiome therapeutics. It has developed a novel therapy for immune-mediated diseases based on consortia of human microbiome-derived bacteria.

The two companies have different strategies for IBD, but both are fundamentally based on innovative therapies developed using the principles of the microbiome.

VE202, developed by Vedanta Biosciences, is an investigational live biotherapeutic product (LBP) administered orally., composed of a defined bacterial consortium. The drug is manufactured under GMP conditions from a purified clonal bacterial cell bank, yielding a standardized pharmaceutical product in powder form, thereby eliminating the need to rely on directly sourced fecal donor materials with inconsistent composition. It is reported that VE202 can induce immune tolerance in the gut, potentially offering a therapeutic approach for inflammatory bowel disease.

Vedanta Biosciences is actively conducting a Phase I clinical trial of VE202, enrolling 105 healthy volunteers for single- and multiple-dose studies, and evaluating two variants of VE202 (consortia composed of 11 and 16 bacterial strains, respectively).

In June 2020, Vedanta Biosciences announced the results of its Phase I clinical trial for VE202: VE202 was safe and well-tolerated at all doses in patients with inflammatory bowel disease (IBD), demonstrating durable and dose-dependent colonization. The company plans to initiate Phase II clinical studies in IBD patients within the next 12 months.

Unlike Vedanta Biosciences, Intralytix’s strategy for IBD leverages the company’s core expertise—bacteriophages.Bacteriophages are a normal component of the microbiome; these virus-like organisms have naturally evolved to target and eliminate specific bacteria. Compared with antibiotics, they can treat bacterial infections without compromising the survival of beneficial gut bacteria, thereby fine-tuning the human microbiome and addressing the growing problem of antibiotic resistance.

In July 2015, Intralytix announced an initial collaboration with Ferring Pharmaceuticals on phage-based therapies for inflammatory bowel disease (IBD). Through the expanded partnership, the two parties will jointly develop phage-based drugs to modulate the microbiome of the female reproductive tract, human gut, oral cavity, and skin.

Brain cancer has long remained a formidable challenge in oncology, as barriers such as the blood-brain barrier hinder conventional small-molecule drugs from reaching the disease site for precise targeted therapy.

Internationally, a French biopharmaceutical company is attempting to overcome glioblastoma (GBM) through microbial immunotherapy.

Enterome is a clinical-stage biopharmaceutical company founded in 2012 that leverages its proprietary technologies in microbiota and immune-mediated inflammation to develop next-generation cancer therapies. The company operates two technology platforms: OncoMimics and EndoMimics.

The OncoMimics platform develops microbiome-derived peptide antigens that closely mimic antigens expressed by tumor cells. By rapidly activating memory T cells capable of triggering gut bacterial responses, as well as tumor-targeting cytotoxic cells, it facilitates the development of appropriate anti-tumor therapeutics.

Currently, the platform has established two immunotherapy pipelines: EO2401 and EO2463. EO2401, targeting glioblastoma, is currently undergoing Phase 1/2 clinical trials; EO2463, targeting B-cell malignancies such as lymphoma and leukemia, is in the preclinical candidate drug development stage.

The EndoMimics platform is primarily dedicated to developing innovative therapies for inflammatory diseases. Its portfolio includes EM101, a next-generation biologic agent targeting type 2 diabetes and inflammatory bowel disease.

Notably, the company has developed EO2401, an innovative cancer immunotherapy candidate based on microbial antigens. When used in combination with immune checkpoint inhibitors, this drug can treat progressive or first-recurrence glioblastoma multiforme (GBM). GBM is an aggressive form of brain cancer for which there is currently no cure.

EO2401 is an innovative, off-the-shelf immuno-oncology candidate developed using Enterome’s OncoMimic technology platform. EO2401 combines three OncoMimics found in aggressive cancers, such as glioblastoma.

EndoMimics has announced the initiation of the first clinical trial for EO2401, evaluating its safety, tolerability, immunogenicity, and preliminary efficacy in combination with checkpoint inhibitors for patients with glioblastoma (GBM). The study will enroll 32 patients across 10 clinical sites in Europe and the United States, with initial clinical data expected to be disclosed in 2022.

Graft-versus-host disease (GvHD) is a severe complication induced by hematopoietic cell transplantation (HCT) and is currently a major cause of transplant failure and transplant-related mortality. Clinical manifestations typically include fever, exfoliative dermatitis, vomiting, diarrhea, and abdominal pain, which may progress to intestinal obstruction.

First-line therapy for both acute and chronic graft-versus-host disease (GvHD) consists of corticosteroids; however, the efficacy of corticosteroid monotherapy is limited, with a response rate of approximately 50%. Currently, there is no standard second-line regimen for the treatment of acute or chronic GvHD, and long-term combination therapy with other immunosuppressive agents is typically required.

This gap may be filled at the level of microbiome therapeutics. The French biopharmaceutical company MaaT Pharma has developed a high-concentration microbiome-based biotherapeutic for graft-versus-host disease (GvHD), which holds promise for alleviating GvHD symptoms in patients.

MaaT Pharma is a biotechnology company founded in 2014. The company aims to treat serious diseases caused by human microbiota dysbiosis by restoring the balanced symbiosis between patients and their host microbiota.

MaaT013 is a microbiome-based biotherapeutic agent developed by the company for the treatment of acute graft-versus-host disease (GvHD). Formulated as an enema, it contains a complete ecosystem with highly diverse and abundant microbial components, and can be stored for up to 24 months.

It is reported that the drug has been granted orphan drug designation by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). MaaT Pharma is actively conducting Phase II clinical trials and has already provided compassionate use access to 11 enrolled patients, all of whom have demonstrated some level of response: five achieved a complete response, and two showed a favorable local response 28 days after the initial dose.

Commenting on these results, Dr. Florent Malard, the founder, stated, “We have strong reasons to believe that restoration of the gut microbiota exerts its effects by modulating patients’ immune systems, ultimately achieving suppression of intestinal graft-versus-host disease (GvHD). Our compassionate-use trials have also demonstrated that some patients experienced complete resolution of symptoms following treatment.”

Furthermore, to support the further expansion of MaaT Pharma’s product portfolio into additional indications, the company has also established GutPrint, a robust discovery and analytics platform.^®, for evaluating candidate drugs, identifying new disease targets, and determining biomarkers for microbiome-associated diseases.