EXL-01: A Comprehensive Analysis of a First-in-Class NOD2-Targeting Live Biotherapeutic for Immunomodulation in Oncology and Inflammatory Disease

Executive Summary

EXL-01 is a first-in-class, clinical-stage investigational medicine being developed by Exeliom Biosciences. It is classified as a Live Biotherapeutic Product (LBP), consisting of a single, unmodified strain of the commensal gut bacterium Faecalibacterium prausnitzii. Formulated for oral administration in a gastro-resistant capsule, EXL-01 is designed for targeted release in the small intestine to exert a localized immunomodulatory effect. Its mechanism of action is centered on the hyperactivation of the Nucleotide-binding Oligomerization Domain-containing protein 2 (NOD2) pathway in myeloid cells, which drives a context-dependent metabolic reprogramming of monocytes and macrophages. In inflammatory conditions such as Crohn's disease, this reprogramming leads to a potent anti-inflammatory response characterized by the production of Interleukin-10 ($IL-10$). In the immuno-oncology setting, the same mechanism is leveraged to enhance the efficacy of immune checkpoint inhibitors (ICIs) by improving antigen presentation and boosting anti-tumor T-cell activation.

The clinical development program for EXL-01 is extensive and strategically diversified across three therapeutic areas: immuno-inflammation, infectious disease, and immuno-oncology. In Crohn's disease, following a terminated Phase 1 trial (MAINTAIN) that nonetheless demonstrated an excellent safety profile, the program has pivoted to a Phase 2 study (MAINTAIN-POP) focused on preventing post-operative recurrence. For infectious diseases, a Phase 1/2 trial (LIVEDIFF) is evaluating EXL-01's potential to prevent the recurrence of Clostridioides difficile infection in high-risk patients.

The most significant component of Exeliom's strategy is its ambitious immuno-oncology program. Three concurrent Phase 2 trials are underway to assess EXL-01 as an adjuvant to standard-of-care ICIs in cancers with high unmet needs and low ICI response rates: gastric cancer (BIG trial), non-small cell lung cancer (EXLIBRIS trial), and hepatocellular carcinoma (MOTHER trial). A further expansion into renal cell carcinoma is planned in the United States. The emerging safety profile appears favorable, supported by early clinical data and the natural commensal status of F. prausnitzii. This report provides a comprehensive analysis of EXL-01, detailing its scientific rationale, multifaceted mechanism of action, the full scope of its clinical development, and a critical evaluation of its therapeutic potential and associated risks. The coordinated data readout from the oncology trials, expected in late 2026, represents a pivotal inflection point for this novel therapeutic platform.

Profile of EXL-01, a Novel Live Biotherapeutic Immunomodulator

Composition and Advanced Formulation: Beyond Probiotics

EXL-01 is a precisely defined biological drug candidate, classified by regulatory bodies as a Live Biotherapeutic Product (LBP).[1] This classification is fundamentally different from that of a probiotic or dietary supplement. As an LBP, EXL-01 is developed under stringent pharmaceutical guidelines with the intent to treat, prevent, or cure a specific disease, necessitating rigorous evaluation of quality, safety, and efficacy through a formal clinical trial process.[3]

The active pharmaceutical ingredient of EXL-01 is a single, well-characterized, and non-genetically modified strain of Faecalibacterium prausnitzii, a prominent commensal bacterium found in the healthy human gut.[4] The selection of a single strain, as opposed to a consortium of multiple bacteria, simplifies the manufacturing process, allows for a more precise mechanistic characterization, and provides a clearer path for regulatory evaluation.[6]

The drug is formulated for oral, once-daily administration in a gastro-resistant capsule.[4] This advanced delivery system is a critical component of the therapeutic design. It protects the live bacteria from the highly acidic environment of the stomach and the digestive enzymes of the upper gastrointestinal tract, ensuring that a viable dose is released precisely in the jejunum and ileum of the small intestine. This targeted delivery allows the bacteria to interact directly with the dense population of immune cells in the gut-associated lymphoid tissue, which is central to its mechanism of action.[4] As the active agent is a naturally occurring organism, EXL-01 is not classified as a New Molecular Entity (NME).[9] The drug is also referred to by the synonyms EXL 01 and EXL01.[1]

The Scientific Rationale: Harnessing the Power of Faecalibacterium prausnitzii

The therapeutic hypothesis for EXL-01 is built upon a substantial body of scientific evidence linking the abundance of Faecalibacterium prausnitzii to human health. In healthy individuals, F. prausnitzii is one of the most abundant bacterial species, capable of comprising up to 5% of the total fecal microbiota.[10] Its presence is considered a biomarker for a healthy, balanced gut ecosystem.

A significant reduction in the relative abundance of F. prausnitzii, a state of dysbiosis, has been consistently observed in patients with several distinct pathologies. This depletion is strongly associated with inflammatory bowel diseases (IBD), including both Crohn's disease (CD) and ulcerative colitis, where its absence correlates with disease activity and risk of relapse.[4] Similarly, a low abundance of F. prausnitzii is predictive of recurrence in patients treated for Clostridioides difficile infection (CDI), suggesting it plays a key role in maintaining colonization resistance against this pathogen.[10]

Most critically for the drug's oncology program, multiple independent studies of human cancer patients have established a strong correlation between high baseline levels of F. prausnitzii in the gut and a positive clinical response to immune checkpoint inhibitor (ICI) therapies.[1] This association has been documented across various tumor types, including non-small cell lung cancer (NSCLC), metastatic melanoma, and hepatocellular carcinoma.[12] This body of evidence provides a compelling clinical rationale for developing an F. prausnitzii-based LBP as a therapeutic agent to restore this key commensal and thereby modulate host immunity in both inflammatory and oncologic diseases.

Developer Snapshot: Exeliom Biosciences' Focus on Microbiome Therapeutics

EXL-01 is the lead clinical asset of Exeliom Biosciences, a privately held, clinical-stage biotechnology company headquartered in Paris and Dijon, France.[9] Founded in 2016 by leading microbiome researchers, the company is dedicated to developing a new generation of therapies based on the gut microbiome.[16] Exeliom's strategy represents an evolution in the field, moving from broad "microbiome therapy" concepts toward the development of precision immunomodulators that target specific host pathways. The company explicitly describes EXL-01 not merely as a bacterial therapy but as a "novel NOD2-targeting biotherapeutic".[1]

Exeliom has successfully secured significant financing to advance its ambitious clinical programs. The company has raised a total of €24 million (approximately $26 million) in its Series A financing, including a recent extension. This funding is earmarked to support the ongoing Phase 2 studies of EXL-01, particularly in immuno-oncology, and to prepare for the drug's clinical development and expansion into the United States.[15]

Drug Characteristic	Description
Drug Name	EXL-01 (Synonyms: EXL 01)
Developer	Exeliom Biosciences
Drug Type	Live Biotherapeutic Product (LBP)
Active Ingredient	Single, unmodified strain of Faecalibacterium prausnitzii
Formulation	Oral, daily, gastro-resistant capsule for targeted release in the jejunum and ileum
Core Mechanism	Hyperactivation of the NOD2 pathway, leading to metabolic reprogramming of monocytes and macrophages

Mechanism of Action: The NOD2 Pathway as a Central Immunological Switch

Core Mechanism: Hyperactivation of NOD2 and Metabolic Reprogramming of Myeloid Cells

The therapeutic activity of EXL-01 is driven by a sophisticated and highly specific molecular mechanism centered on the innate immune system. The primary molecular target of EXL-01 is the Nucleotide-binding Oligomerization Domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor expressed in immune cells, particularly monocytes and macrophages.[4] The distinct peptidoglycan structure of the F. prausnitzii cell wall acts as a uniquely potent agonist for NOD2, leading to what Exeliom Biosciences describes as a "hyperactivation" of the NOD2 signaling pathway.[4]

This potent NOD2 activation is the initiating event that triggers the drug's core effect: a targeted metabolic reprogramming within monocytes and macrophages.[4] This process fundamentally alters the cellular energy metabolism of these key innate immune cells, shifting their function and subsequent immune output. This metabolic rewiring is the central pivot that allows EXL-01 to function as a true immunomodulator, capable of producing distinct, context-dependent effects rather than simply acting as a general immunosuppressant or immunostimulant.

A crucial pharmacological feature of this mechanism is that it is designed to occur locally within the small intestine, where the gastro-resistant capsule releases the live bacteria. The therapeutic effect does not depend on the bacteria establishing a permanent or significant presence in the colon (colonization) or causing a broad shift in the overall composition of the fecal microbiota. Preclinical and clinical observations have shown that oral administration of EXL-01 does not induce significant changes in fecal microbiota diversity or composition, suggesting a direct and targeted effect on the immune cells it encounters in the small intestine.[1] This attribute simplifies the drug's pharmacodynamic profile, making its effects more predictable and controllable compared to therapies that aim for complex ecological restructuring of the gut microbiome.

In Immuno-Inflammation: Driving Anti-Inflammatory IL-10 Signaling in Crohn's Disease

In the pro-inflammatory microenvironment characteristic of Inflammatory Bowel Disease (IBD), the NOD2-driven metabolic reprogramming of myeloid cells by EXL-01 results in a potent anti-inflammatory response.[11] In vitro studies using human peripheral blood mononuclear cells have demonstrated that EXL-01 has strong anti-inflammatory properties.[11]

Specifically, EXL-01 induces the direct and dose-dependent production of the key anti-inflammatory cytokine Interleukin-10 ($IL-10$) from CD14+ monocytes.[4] This effect has been observed in cells derived from both healthy individuals and IBD patients. Importantly, this robust induction of $IL-10$ occurs without a concomitant increase in pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha ($TNF-\alpha$) or $IL-23$, leading to a highly favorable anti-inflammatory ratio.[11] This selective signaling addresses a critical mechanism underlying intestinal inflammation. Further mechanistic work has revealed that this anti-inflammatory output is directly linked to the metabolic shift, with the production of $IL-10$ being dependent on mitochondrial respiration in the reprogrammed monocytes.[4]

In Immuno-Oncology: A Synergistic Adjuvant to Immune Checkpoint Inhibition

The same core mechanism of NOD2-mediated metabolic reprogramming is leveraged in the oncology setting to achieve a seemingly opposite, yet equally targeted, outcome: enhancing anti-tumor immunity. When administered as an adjuvant to immune checkpoint inhibitors (ICIs), EXL-01 is designed to overcome resistance and boost the efficacy of these revolutionary treatments.[5]

The scientific rationale is supported by extensive data linking a healthy gut microbiome, and F. prausnitzii in particular, to successful ICI therapy.[12] Preclinical studies provide direct evidence for EXL-01's synergistic activity. In vitro, the EXL-01 strain has been shown to improve the function of antigen-presenting cells and enhance the activation and proliferation of T-cells when co-administered with an ICI.[13]

More compellingly, in vivo experiments in a syngeneic mouse tumor model (MCA205) have demonstrated this effect in a clinically relevant context. In these studies, administration of antibiotics was shown to disrupt the gut microbiota and abrogate the anti-tumor efficacy of an anti-PD-L1 antibody. Subsequent oral administration of EXL-01 to these mice was able to partially restore the anti-tumor response to the ICI, resulting in significantly reduced tumor volumes and a significant survival benefit.[21] This restoration of efficacy was also observed at the tumor transcriptomics level, confirming that EXL-01 can modulate the tumor microenvironment to be more permissive to an anti-tumor immune response.[12] This demonstrates that by reprogramming myeloid cells, EXL-01 can help convert previously non-responsive tumors into responders.

The EXL-01 Clinical Development Program: A Multi-Pronged Therapeutic Strategy

Program Overview: Targeting Unmet Needs in Inflammation, Infection, and Oncology

The clinical development strategy for EXL-01 is notably ambitious, spanning three distinct and high-value therapeutic areas: Immune System Diseases, Infectious Diseases, and Neoplasms.[1] This multi-pronged approach leverages the drug's unique, context-dependent mechanism of action to address a wide range of unmet medical needs. The program has advanced to Phase 2 in its lead indications for Crohn's disease and for several solid tumors, including liver cancer, stomach cancer, and non-small cell lung cancer.[1]

The Immuno-Inflammation Franchise: Crohn's Disease

The initial clinical focus for EXL-01 was in Crohn's disease, a chronic inflammatory condition linked to depletion of F. prausnitzii.

The MAINTAIN Trial (NCT05542355): Key Learnings from a Phase 1 Study

The first human study of EXL-01 was the MAINTAIN trial, a Phase 1, multicenter, placebo-controlled study designed to evaluate the safety and preliminary efficacy of EXL-01 in maintaining remission for patients with mild-to-moderate Crohn's disease after induction with corticosteroids.[25]

On October 2, 2024, Exeliom Biosciences announced the early termination of the trial.[9] This decision was not driven by safety concerns but by significant operational challenges, specifically a much lower-than-projected patient recruitment rate.[27] Despite the termination, Part A of the study, an open-label safety run-in involving 8 patients, was successfully completed. This portion of the trial met its primary endpoint, demonstrating an excellent safety and tolerability profile for EXL-01 administered over a six-month period. Notably, no participants discontinued the treatment due to adverse events.[29] The final data from this cohort, including translational data on target engagement, are expected to be presented in the first half of 2025.[19]

The MAINTAIN-POP Trial (NCT06925061): A Strategic Pivot to Post-Operative Recurrence

The operational challenges encountered in the MAINTAIN trial prompted a rapid and strategic re-evaluation of the Crohn's disease program. Rather than abandoning the indication, Exeliom demonstrated agility by pivoting to a new study, MAINTAIN-POP.[27] This ongoing Phase 2 trial targets a different and more logistically accessible patient population: those at high risk of disease recurrence following intestinal resection surgery.

MAINTAIN-POP is a randomized, double-blind, placebo-controlled study aiming to enroll approximately 80 patients across multiple centers in France.[31] The trial will evaluate the efficacy of EXL-01 in preventing post-operative recurrence, with the primary endpoint being a comparison of endoscopic modified Rutgeerts scores at six months post-surgery.[31] This design targets patients at a well-defined, predictable time point, thereby mitigating the recruitment difficulties associated with capturing sporadic flares in a broad mild-to-moderate disease population. The trial is actively recruiting, with topline results anticipated in the first quarter of 2027.[9]

The Infectious Disease Franchise: Preventing Clostridioides difficile Recurrence

Leveraging the known association between low F. prausnitzii levels and CDI recurrence, Exeliom is pursuing an indication for the prevention of this common and often serious hospital-acquired infection.

The LIVEDIFF Trial (NCT06306014): Restoring Colonization Resistance

The LIVEDIFF trial is a Phase 1/2 study designed to assess the safety and efficacy of EXL-01 in preventing CDI recurrence in high-risk patients who have successfully completed a course of vancomycin.[10] The therapeutic rationale is that by reintroducing a high dose of F. prausnitzii, EXL-01 can help restore the gut's natural colonization resistance to C. difficile spores. One proposed mechanism is the bacterium's ability to hydrolyze bile acids that are essential for spore germination.[10]

The trial is structured in two parts: a 6-patient open-label Phase 1 safety cohort (Part A), followed by a 50-patient randomized, placebo-controlled Phase 2 efficacy cohort (Part B).[10] Recruitment for Part A of the trial was completed in March 2025, and the study is ongoing in France.[1]

The Immuno-Oncology Franchise: Overcoming ICI Resistance

The most ambitious and strategically vital component of the EXL-01 development program is its broad investigation as an adjuvant to ICI therapy. In April 2024, Exeliom announced the launch of three concurrent Phase 2 clinical trials in solid tumors characterized by low response rates to standard-of-care immunotherapy, representing a significant unmet medical need.[5] The company expects to share results from these pivotal trials at the end of 2026.[8]

Gastric Cancer: The Phase 2 BIG Trial (NCT06253611)

The BIG trial is a randomized, open-label study enrolling 120 patients with previously untreated, metastatic gastric or gastroesophageal junction cancer whose tumors express $PD-L1$ ($CPS \geq 5$).[4] The trial, sponsored by the GERCOR cooperative group in France, randomizes patients on a 2:1 basis to receive either standard-of-care (nivolumab plus FOLFOX chemotherapy) or the experimental combination of nivolumab, FOLFOX, and EXL-01.[34] As of April 2025, recruitment for the first part of the trial was complete.[1]

Non-Small Cell Lung Cancer: The Phase 1/2 EXLIBRIS Trial (NCT06448572)

The EXLIBRIS trial is an open-label, single-arm study evaluating EXL-01 in combination with nivolumab for patients with advanced NSCLC who are refractory to prior treatment with both an anti-PD-(L)1 agent and platinum-based chemotherapy.[4] This study targets a population with very limited treatment options. Sponsored by the University Hospital of Lille, France, the trial enrolled its first patient in July 2024 and is currently recruiting.[17]

Hepatocellular Carcinoma: The Phase 2 MOTHER Trial (NCT06551272)

The MOTHER trial is investigating EXL-01 as an add-on to standard-of-care first-line immunotherapy for advanced hepatocellular carcinoma (HCC).[4] Patients in the study receive EXL-01 in combination with either atezolizumab plus bevacizumab or durvalumab plus tremelimumab. The trial, sponsored by the Centre Eugène Marquis in Rennes, France, enrolled its first patient in March 2025 and is actively recruiting.[1]

Pipeline Expansion: Renal Cell Carcinoma (NCT07128680)

Exeliom plans to expand its oncology program into the United States with a planned Phase 1 trial in metastatic renal cell carcinoma (mRCC).[9] The study, to be conducted at the City of Hope Medical Center, will evaluate EXL-01 in combination with the ICI doublet of nivolumab and ipilimumab for patients who have received at least one prior line of therapy. The trial is scheduled to begin in December 2025 and marks a key step in the company's international expansion.[9]

Trial Name (NCT ID)	Therapeutic Area	Indication	Phase	Design Summary	Status & Key Milestones
MAINTAIN (NCT05542355)	Immuno-Inflammation	Mild-to-Moderate Crohn's Disease	1	Randomized, Placebo-Controlled	Terminated (Oct 2024) due to low recruitment. Part A completed, demonstrating good safety.
MAINTAIN-POP (NCT06925061)	Immuno-Inflammation	Post-Operative Crohn's Disease	2	Randomized, Double-Blind, Placebo-Controlled	Recruiting in France. Topline results expected Q1 2027.
LIVEDIFF (NCT06306014)	Infectious Disease	Prevention of Recurrent C. difficile Infection	1/2	Randomized, Double-Blind, Placebo-Controlled	Recruiting in France. Part 1 recruitment completed (Mar 2025).
BIG (NCT06253611)	Immuno-Oncology	1st-Line Metastatic Gastric Cancer ($PD-L1$ $CPS \geq 5$)	2	Randomized, Open-Label (EXL-01 + Nivo/FOLFOX vs. Nivo/FOLFOX)	Recruiting in France. Part 1 recruitment completed (Apr 2025).
EXLIBRIS (NCT06448572)	Immuno-Oncology	Advanced NSCLC (Refractory to ICI/Chemo)	1/2	Single-Arm, Open-Label (EXL-01 + Nivolumab)	Recruiting in France. First patient enrolled (Jul 2024).
MOTHER (NCT06551272)	Immuno-Oncology	1st-Line Hepatocellular Carcinoma	2	Single-Arm, Open-Label (EXL-01 + SoC Immunotherapy)	Recruiting in France. First patient enrolled (Mar 2025).
(NCT07128680)	Immuno-Oncology	Metastatic Renal Cell Carcinoma (≥2nd Line)	1	Combination Therapy	Planned to start Dec 2025 in the USA.

Safety, Tolerability, and Pharmacological Considerations

Emerging Safety and Tolerability Profile

Although EXL-01 is still in clinical development and a comprehensive safety database has not yet been established, the available evidence points toward a favorable safety and tolerability profile. The primary source of human safety data is Part A of the terminated Phase 1 MAINTAIN trial in Crohn's disease. In a press release, Exeliom Biosciences reported that the study demonstrated "excellent safety and tolerability" over a six-month treatment period, successfully meeting its primary safety endpoint.[29] This finding was corroborated by the fact that no participants in the study discontinued treatment due to adverse events.[27]

The anticipated safety of EXL-01 is further supported by its biological nature. The active ingredient, Faecalibacterium prausnitzii, is not a foreign pathogen but a highly abundant and beneficial commensal organism that is a natural resident of the healthy human gut microbiome.[11] This inherent characteristic suggests a low likelihood of intrinsic toxicity.

In the context of the immuno-oncology trials, the overall safety profile will be complex and largely influenced by the known toxicities of the combination agents, which include potent chemotherapies (FOLFOX) and immune checkpoint inhibitors (nivolumab, ipilimumab, etc.). Patients in these trials will be monitored closely for well-documented adverse events associated with these agents, including chemotherapy-related myelosuppression and gastrointestinal toxicity, as well as a spectrum of immune-related adverse events (irAEs) such as colitis, pneumonitis, hepatitis, and endocrinopathies.[38] A key objective of these studies will be to determine whether the addition of EXL-01 exacerbates these known toxicities or introduces new safety signals.

Patient Selection and Potential Contraindications from Clinical Trial Protocols

An analysis of the inclusion and exclusion criteria across the various EXL-01 clinical trial protocols provides insight into the populations for whom the drug is being evaluated and reveals potential contraindications. Consistent themes in patient selection emerge, aimed at ensuring patient safety:

• Hypersensitivity: A history of hypersensitivity to EXL-01, any of its excipients, or to soybean or soy-containing products is a standard exclusion criterion, indicating a potential allergenic component in the formulation.[31]
• Immunosuppression: The LIVEDIFF trial for C. difficile infection explicitly excludes patients with significant immunosuppression. This includes individuals with active hematological malignancies, AIDS-stage HIV, recent stem cell allografts, severe neutropenia (aplasia), or those receiving systemic corticosteroids at doses greater than 20 mg of prednisone equivalent per day.[10] This is a common and prudent precaution for therapies containing live microorganisms, to avoid the risk of bacteremia or systemic infection in highly vulnerable patients.
• Concomitant Antibiotic Use: Patients receiving antibiotics at the time of randomization or who are likely to require them shortly after starting treatment are excluded from the trials.[31] This reflects the direct and antagonistic interaction between antibiotics and the live bacterial product.
• Impaired Gastrointestinal Integrity: The Crohn's disease trials exclude patients with certain anatomical or functional gut issues, such as a current stoma, active anal fistulas, or a history of extensive small bowel resection, which could alter the drug's transit and delivery or increase risks.[25]

Drug Interaction Potential: The Critical Role of Antibiotics and the Gut Microenvironment

As a live biotherapeutic product, EXL-01's pharmacology is intrinsically linked to the gut microenvironment, making its interaction with other substances a critical consideration.

The most significant and mechanistically relevant drug-drug interaction is with antibiotics. The preclinical studies that form the basis of the immuno-oncology program demonstrate this relationship clearly: broad-spectrum antibiotics induce a state of dysbiosis that impairs the efficacy of ICI therapy, and EXL-01 is designed specifically to reverse this negative effect.[13] Therefore, concomitant use of antibiotics would be expected to directly antagonize the viability and function of EXL-01. This underpins the exclusion of patients on recent or concurrent antibiotics from clinical trials. This interaction also suggests a potential future therapeutic niche for EXL-01 as a "microbiome-protective" or "efficacy-restoring" agent for cancer patients on ICIs who must undergo necessary courses of antibiotics for unrelated infections.

While specific interaction studies have not been published, other medications known to alter the gut microbiome could also theoretically impact EXL-01's efficacy. These include proton pump inhibitors (PPIs), which alter gastric pH, and laxatives, which affect gut transit time.[42] Furthermore, standard therapies used in IBD, such as 5-aminosalicylic acids (5-ASA) and immunosuppressants like azathioprine, are known to modulate the composition of the gut microbiota and could potentially interact with EXL-01.[42]

Dosing and Administration Across Clinical Trials

The dosing regimens for EXL-01 vary significantly across the clinical programs, reflecting different therapeutic goals and underlying pathophysiologies. This demonstrates a sophisticated, indication-specific approach to the drug's pharmacology rather than a uniform dosing strategy.

• In the LIVEDIFF trial (NCT06306014) for CDI prevention, a high-dose induction followed by a tapering schedule is used. Patients receive 10 oral capsules per day for the first two weeks, followed by 4 capsules per day for weeks 3 and 4, and finally 1 capsule per day for weeks 5 through 8.[10] This "loading dose" strategy is designed to rapidly introduce a large biomass of F. prausnitzii to outcompete C. difficile spores and re-establish colonization resistance.
• In contrast, the trials focused on chronic immunomodulation employ a simpler, continuous low-dose maintenance regimen. In the MAINTAIN trial (NCT05542355) for Crohn's disease, the dose was one oral capsule daily for up to 24 weeks.[25] Similarly, in the MOTHER trial (NCT06551272) for HCC and the EXLIBRIS trial (NCT06448572) for NSCLC, the dose is one oral capsule per day.[36] This approach aims to provide sustained, low-level stimulation of the NOD2 pathway to maintain a modulated immune state over a long period.
• The specific dosage for the BIG trial (NCT06253611) in gastric cancer has not been disclosed in the available documentation.[35]

Trial Name (NCT ID)	Indication	Dosing Schedule	Duration	Pharmacological Rationale
LIVEDIFF (NCT06306014)	CDI Prevention	Tapering Induction: 10 caps/day (wks 1-2), 4 caps/day (wks 3-4), 1 cap/day (wks 5-8)	8 weeks	Rapidly establish high biomass to restore colonization resistance against C. difficile.
MAINTAIN (NCT05542355)	Crohn's Disease	Maintenance: 1 capsule per day	Up to 24 weeks	Sustained, low-level immunomodulation to maintain an anti-inflammatory state.
MOTHER (NCT06551272)	Hepatocellular Carcinoma	Maintenance: 1 capsule per day	Up to 12 months	Sustained immunomodulation to enhance ongoing ICI efficacy.
EXLIBRIS (NCT06448572)	Non-Small Cell Lung Cancer	Maintenance: 1 capsule per day	Ongoing	Sustained immunomodulation to enhance ongoing ICI efficacy.

Critical Analysis and Future Outlook

Strengths and Therapeutic Potential: A Novel Mechanism with Broad Applicability

EXL-01 possesses several key strengths that position it as a highly promising therapeutic candidate with significant potential.

• First-in-Class Mechanism of Action: The drug's activity as a precision immunomodulator that targets the NOD2 pathway represents a novel therapeutic class.[4] This is a departure from less specific microbiome-based approaches, offering a well-defined, scientifically rationalized mechanism that is more akin to a targeted biologic than a traditional probiotic.
• Platform Potential: The unique, context-dependent functionality of its mechanism allows Exeliom to pursue a "platform-in-a-product" strategy. The ability to drive an anti-inflammatory response in IBD and a pro-inflammatory, anti-tumor response in oncology from a single agent is exceptionally rare and gives the product broad applicability across multiple high-value therapeutic areas.[5]
• Addressing High Unmet Need: The immuno-oncology program is strategically focused on one of the most significant challenges in modern cancer care: primary and acquired resistance to ICIs. In indications like gastric cancer, where first-line ICI response rates are only around 35%, a therapy that can convert non-responders to responders would have a transformative clinical and commercial impact.[22]
• Favorable Safety Profile: The foundation of the therapy is a commensal bacterium with a long history of safe co-existence with humans. This, combined with the positive safety data from the Phase 1 MAINTAIN trial, suggests that EXL-01 may possess a wide therapeutic window and a favorable tolerability profile, which would be a major advantage, particularly in combination therapies.[21]

Challenges and Risks: Navigating Clinical Hurdles and LBP Manufacturing Complexity

Despite its promise, the development of EXL-01 faces considerable challenges and risks inherent to pioneering a new class of therapy.

• Clinical Execution Risk: The early termination of the MAINTAIN trial, while not a failure of the drug itself, serves as a stark reminder of the operational complexities of clinical development. Low patient recruitment is a persistent challenge in the industry, and the company's ability to successfully execute its multiple, concurrent, and logistically demanding Phase 2 trials will be a critical test of its operational capabilities.[9]
• Manufacturing and CMC Complexity: The development of an LBP is fraught with significant Chemistry, Manufacturing, and Controls (CMC) challenges that do not exist for small molecules or even many biologics. Ensuring batch-to-batch consistency, maintaining the viability and potency of the live organism from production through to administration, and developing a process that can be scaled up for commercial supply are formidable technical and financial hurdles.[2]
• Regulatory Uncertainty: EXL-01 is an investigational agent and has not received marketing approval from any major regulatory body, including the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or Australia's Therapeutic Goods Administration (TGA).[45] As LBPs are a relatively new class of drugs, the regulatory landscape is still evolving. The long-term requirements for demonstrating safety, particularly concerning potential off-target effects on the host microbiome, remain an area of developing regulatory science.[3]
• Competitive Landscape: While EXL-01's specific mechanism is unique, it operates in two intensely competitive fields. In immuno-oncology, it will compete against a vast pipeline of other novel ICI combination agents. In the microbiome space, it will compete with other LBPs, consortia products, and fecal microbiota transplantation (FMT)-based therapies.

Concluding Assessment and Forward Look

EXL-01 stands out as a scientifically compelling and highly innovative therapeutic candidate. It represents a significant step forward in the evolution of microbiome-based medicine, moving from broad ecological interventions to a targeted, mechanism-driven immunomodulator. Its potential to function as a "platform-in-a-product" across inflammation, infection, and oncology is a testament to its unique biological activity.

The company's primary value driver and greatest strategic bet is unequivocally the immuno-oncology program. The decision to run three concurrent Phase 2 trials is a high-risk, high-reward strategy designed to generate a robust, multi-indication dataset. The coordinated data readout from these trials, expected at the end of 2026, will be a critical, binary inflection point that will likely determine the future of the asset and the company.

Ultimate success will hinge on Exeliom's ability to navigate the dual challenges of demonstrating clear clinical efficacy in these complex trials while simultaneously mastering the formidable technical hurdles of LBP manufacturing at scale. The planned expansion into the U.S. with the renal cell carcinoma trial will be a key test of the company's ability to grow its operational and regulatory capabilities beyond its European base. If successful, EXL-01 has the potential not only to provide a new treatment option for patients with a range of difficult diseases but also to validate a new class of precision microbiome-based immunotherapies.

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