Entrepreneurship

Entrepreneurship @ Fleur

Fleur represents a novel therapeutic approach to Type 2 Diabetes Mellitus (T2DM) and obesity management through engineered probiotic bacteria that express and secrete wild-type glucagon-like peptide-1 (GLP-1) directly within the human gastrointestinal tract. Unlike synthetic GLP-1 receptor agonists that require weekly injections and produce systemic side effects, Fleur delivers localized, physiologically-appropriate GLP-1 through an oral probiotic yogurt drink format.

The platform addresses a massive market opportunity at the intersection of the $28.65B global weight loss supplement market and the $39.74B global probiotic drink market, with initial focus on the U.S. serviceable obtainable market of $1.42B. With superior unit economics (81.2% gross margin, 1-month payback period) and a scalable go-to-market strategy, Fleur is positioned to capture meaningful market share while addressing critical unmet medical needs.

Market Opportunity & Problem Statement

The Global Health Crisis

Obesity and diabetes represent converging epidemiological crises:

• 42.4% of U.S. adults over age 20 are classified as obese
• Nearly 3 billion people worldwide are living with overweight or obesity
• 38.4 million Americans are diagnosed with diabetes
• 90-95% of diabetes cases are Type 2 Diabetes Mellitus (T2DM)
• No known cure exists, and biological mechanisms remain largely unknown and complex

Fleur Pitch Semifinal for the McCloskey New Venture Competition

Current Treatment Landscape & Limitations

The existing therapeutic arsenal demonstrates significant shortcomings across multiple dimensions:

Metformin (Oral Tablet)

Mechanism: Increases insulin sensitivity and decreases hepatic glucose production
Limitations: High consumption rate leading to digestive system stress, diarrhea, lactic acidosis, and vitamin B12 deficiency

Incretin Mimetics (e.g., Ozempic/Semaglutide)

Mechanism: GLP-1 receptor agonists that stimulate insulin release and slow gastric emptying
Limitations: Weekly injections, extended systemic half-life, neurological side effects including brain fog, optic nerve complications, depression, anxiety, and ADHD-related symptoms

Insulin Injections

Mechanism: Direct insulin replacement therapy
Limitations: Daily dosage requirements, off-peak effects where insulin affects blood sugar at suboptimal times

Sodium-Glucose Cotransporter 2 Inhibitors (e.g., Farxiga)

Mechanism: Promotes glucose excretion through urine
Limitations: Risk of urinary tract infections and dehydration

The Cost Barrier

Current injectable treatments represent a significant financial burden, with monthly costs ranging from $886 to $1,349:

• Ozempic: $936/month
• Wegovy: $1,349/month
• Saxenda: $1,349/month
• Victoza: $1,000/month
• Trulicity: $886/month

This pricing structure places effective treatment beyond the reach of many individuals who would benefit most from therapeutic intervention.

Cost Barrier for Injectable Treatments

Treatment Sustainability Crisis

Clinical data reveals that current regimens lack sustainability due to strong side effects:

Gastrointestinal complications:

Side Effects of Some Current Weight Loss Treatments (Forbes)

Severe complications include acute pancreatitis, kidney injury, gallbladder injury, diabetic retinopathy, and gastroparesis. The delayed gastric emptying caused by semaglutide also increases the risk of pulmonary aspiration during anesthesia.

The Unmet Need

Less than 10% of individuals express willingness to use injectable weight-loss drugs, despite their effectiveness. This substantial gap between clinical need and treatment acceptability creates a massive opportunity for alternative delivery mechanisms and more natural therapeutic approaches.

The Scientific Foundation

Understanding GLP-1 Physiology

Glucagon-like peptide-1 (GLP-1) is one of many important hormones naturally produced in the gut in response to eating food. It has two well-established roles in the body: signaling to the pancreas to produce insulin and signaling to the brain to influence satiety and food intake.

The hormone functions through a sophisticated signaling cascade:

• Pancreatic Signaling: GLP-1 stimulates glucose-dependent insulin secretion from pancreatic β-cells while simultaneously suppressing glucagon release

• Gastric Regulation: Slows gastric emptying, prolonging nutrient absorption and enhancing satiety

• Neural Modulation: Communicates with the brain stem and hypothalamus to regulate appetite and energy balance

• Metabolic Effects: Reduces hepatic steatosis, decreases lipid content, and improves insulin resistance in peripheral tissues

GLP-1 Physiology

The Problem with Synthetic GLP-1 Receptor Agonists

Modified synthetic GLP-1 receptor agonists such as Ozempic (semaglutide) are designed with an extended half-life, requiring only one dose per week. However, this design feature causes the medication to flood the bloodstream systemically.

In contrast, natural GLP-1 degrades quickly and remains mostly localized to the pancreas and intestine. When synthetic agonists reach the brain in elevated concentrations, they interfere with satiety and reward signaling systems, leading to neurological side effects. GLP-1 receptors in the brain activate various neural regions involved in energy-balance control, and excessive stimulation can disrupt normal neurological function.

Evidence for Engineered Probiotic Approach

Studies have demonstrated the possibility to engineer, express, and secrete glucose-sensitive GLP-1 in various bacterial strains. Animal trials have validated significant anti-diabetic effects:

Key Supporting Research:

• Monkey model validation: Luo et al. (2021) demonstrated antidiabetic effects of engineered Lactobacillus plantarum-pMG36e-GLP-1 in primates, showing the approach translates to higher-order mammals

• Obesity attenuation in mice: Wang et al. (2021) showed that engineered bacteria MG1363-pMG36e-GLP-1 attenuated obesity induced by high-fat diet in mice

• Glucose-responsive insulin secretion: Duan et al. (2015) engineered commensal bacteria to reprogram intestinal cells into glucose-responsive insulin-secreting cells for diabetes treatment

GLP-1 Animal Trials

These foundational studies establish the scientific validity of using engineered probiotics as a delivery vehicle for therapeutic peptides in the gastrointestinal tract.

The Fleur Solution

Core Innovation

Fleur's concept addresses the limitations of current therapies through a biomimetic strategy that leverages the body's natural GLP-1 production mechanisms:

Delivery Mechanism

Utilize a probiotic oral delivery system to populate the gut microbiome long-term with natural (short-lasting) GLP-1 producing bacteria. This approach builds upon established commercial probiotic drinks (Yakult, Kombucha, Chobani), making both testing and production feasible.

Bacterial Platform Selection

Studies have found success with engineering Lactococcus and Lactobacillus probiotic bacteria into drug delivery vehicles. This technology can be applied to create genetically engineered bacteria which possess the ability to produce the GLP-1 protein once ingested orally.

Genetic Engineering Strategy

Employ well-documented probiotic bacterial vehicles, genetically engineering natural GLP-1 production and secretion functions, while optimizing bacterial dosage for enhanced yet localized (to the gut region) GLP-1 presence and optimal transient colonization.

Bacterial Strain Selection

Fleur utilizes GRAS (Generally Recognized As Safe) strains with established safety profiles:

• Lactobacillus reuteri
• Lactobacillus casei (LcS)
• Bifidobacterium longum
• Lactococcus lactis
• Escherichia coli Nissle 1917

By transforming these strains, we create engineered bacteria that, once mixed into yogurt for easy consumption and delivered to the gut, produce wild-type GLP-1 that acts as a molecular messenger, binding to GLP-1 receptors and stimulating insulin release while regulating appetite and energy balance.

Competitive Advantages

Fleur defines a new category and invents a new market by combining gut health benefits with GLP-1 boost for weight loss:

Fleur vs. Competitors

Feasibility Assessment

Scientific Feasibility

Our bacterial strains are commonly utilized in fermented dairy products and are known to survive passage through the upper GI tract. Fleur is scientifically feasible because:

• Local gut delivery mimics physiological secretion patterns
• Genetically engineered probiotics have already been demonstrated in laboratory models and small animal studies
• Established precedent exists with three peer-reviewed publications demonstrating successful GLP-1 production in probiotic bacteria

Economic Feasibility

Yogurt drinks are inexpensive and familiar consumer products that can be easily incorporated into existing food processing infrastructure. This approach provides:

• More cost-effective option than current injectable therapies ($30/month vs $886-$1,349/month)
• Integration into existing food product manufacturing with large volume margins
• Lower capital requirements compared to pharmaceutical development

Environmental Feasibility

Fleur enables lower production footprints through:

• Use of local, renewable agricultural resources
• Fermentation-based manufacturing process aligned with sustainable biotechnology practices
• Reduced waste compared to injectable delivery systems

Safety Considerations

Laboratory Safety Protocols

Adhering to the highest safety standards, all undergraduates are required to be supervised and wear appropriate personal protective equipment (PPE). Any experimentation is conducted to minimize risk to students. Although our usage of Lactobacillus species and standardized E. coli strains poses minimal safety risk, lab coats, goggles, and gloves are worn for added protection. Students with long hair are required to secure it, especially to maintain a sterile environment.

Biological Safety Assessment

Our choice of GRAS-status bacterial strains ensures that Fleur maintains an excellent safety profile. All strains selected have:

• Extensive histories of safe human consumption
• Presence in numerous commercial food products globally
• Well-documented safety profiles in scientific literature

A Force For Good

At Notre Dame, we are guided by the question: "What would you fight for?"

Through Fleur, we fight for a low-cost, sustainable obesity solution in the long-run.

Fleur's Mission

Stay Fit

Fleur provides a natural, sustainable solution to address metabolic conditions, improving the quality of life for individuals struggling with metabolic disorders. Unlike pharmaceutical interventions with significant side effects, Fleur works with the body's natural systems.

Gut Health

Fleur's science-backed formulation supports gut health, which plays a critical role in immunity, mental health, and digestion. The probiotic foundation delivers benefits beyond GLP-1 production, contributing to overall wellness.

Stronger Together

Fleur promotes collective well-being by creating a community of health-conscious individuals. Fleur inspires positive change and encourages people to support one another in their journey toward a healthier, happier future.

References

• Luo, J., Zhang, H., Lu, J., Ma, C., & Chen, T. (2021). Antidiabetic effect of an engineered bacterium Lactobacillus plantarum-pMG36e-GLP-1 in monkey model. Synthetic and Systems Biotechnology, 6(4), 272-282. https://doi.org/10.1016/j.synbio.2021.09.009
• Wang, L., Chen, T., Wang, H., Wu, X, Cao, Q., Wen, K., Deng, K. Y., & Xin, H. (2021). Engineered Bacteria of MG1363-pMG36e-GLP-1 Attenuated Obesity-Induced by High Fat Diet in Mice. Frontiers in Cellular and Infection Microbiology, 11, 595575. https://doi.org/10.3389/fcimb.2021.595575
• Duan, F. F., Liu, J. H., & March, J. C. (2015). Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes, 64(5), 1794-1803. https://doi.org/10.2337/db14-0635
• Centers for Disease Control and Prevention (CDC). (2023). National Diabetes Statistics Report. U.S. Department of Health and Human Services.
• Canadian Agency for Drugs and Technologies in Health (CADTH). Clinical Review Report: Semaglutide (Ozempic). Common Drug Review.
• Marketdata LLC (2023). U.S. Weight Loss Market: 2023 Status Report.
• ResearchAndMarkets (2024). U.S. Functional Foods and Beverages Market - Forecasts to 2030.
• Grand View Research (2023). Probiotic Supplements Market Size, Share & Trends Analysis Report By Region, And Segment Forecasts, 2023-2030.
• Allied Market Research (2023). U.S. Probiotic Drinks Market by Type and Distribution Channel: Opportunity Analysis and Industry Forecast, 2021-2030.
• GlobalData Healthcare (2023). Obesity Drug Market Dynamics and Forecasts.
• International Diabetes Federation (IDF). IDF Diabetes Atlas, 10th Edition. 2021.
• Morgan Stanley Research. (2023). The Weight Loss Drug Market: Sizing the Opportunity.
• Forbes. (2023). Survey on Public Acceptance of Injectable Weight Loss Drugs.
• McKinsey & Company (2023). The Future of Wellness: Opportunities in the Global Health Economy.