Beyond Appetite Suppression: A New Obesity Pill Targets Fat Burning Through Creatine Thermogenesis

Obesity is a complex, chronic disease affecting millions worldwide, contributing to a cascade of serious health issues including type 2 diabetes, heart disease, hypertension, and certain cancers. For decades, scientists and medical professionals have sought effective, safe, and accessible treatments to help individuals manage their weight and improve their health outcomes. While lifestyle interventions like diet and exercise remain foundational, pharmacological treatments have become increasingly important tools in the fight against obesity.

In recent years, a new class of drugs known as GLP-1 receptor agonists, such as Ozempic and Wegovy, have revolutionized the treatment landscape. These medications, originally developed for type 2 diabetes, have demonstrated remarkable efficacy in promoting significant weight loss. Their primary mechanism involves mimicking the action of glucagon-like peptide-1, a hormone that regulates blood sugar and appetite. By acting on receptors in the brain and gut, GLP-1 drugs increase feelings of fullness (satiety), slow gastric emptying, and ultimately reduce food intake. This reduction in caloric consumption is the main driver of weight loss observed with these therapies.

Despite their success, GLP-1 drugs are not without limitations. They are typically administered via injection, which can be a barrier for some patients. Common side effects include gastrointestinal issues like nausea, vomiting, and diarrhea. Furthermore, while effective at reducing fat mass, GLP-1s can also lead to a loss of lean muscle mass, which is undesirable for overall metabolic health. The high cost of these medications in many regions also presents a significant accessibility challenge. These factors highlight a persistent unmet clinical need for alternative or complementary obesity treatments that offer different mechanisms of action, potentially fewer side effects, better muscle preservation, and improved accessibility.

A Novel Approach: Targeting Energy Expenditure

Enter Eolo Pharma, a biotechnology company based in Montevideo, Uruguay, which is developing an investigational drug that operates on a fundamentally different principle. Instead of focusing solely on reducing food intake by suppressing appetite, their experimental pill, dubbed SANA, aims to increase the body's energy expenditure by stimulating fat burning. Early results from a small, preliminary human trial, described in scientific literature, suggest this novel approach holds significant promise for weight management.

The drug SANA is derived from salicylate, a compound historically known for its anti-inflammatory properties and used in the production of aspirin. Eolo's researchers initially explored salicylate derivatives for their potential in treating inflammation associated with metabolic diseases like obesity and type 2 diabetes. However, during preclinical testing in animal models, they made a compelling discovery: the compound not only improved markers of inflammation but also led to a significant reduction in body weight, even when the animals were maintained on a high-fat diet.

This unexpected weight loss effect prompted a deeper investigation into the drug's mechanism. Eolo scientists found that SANA activates a specific metabolic pathway known as creatine-dependent thermogenesis. This mechanism represents a distinct way to influence energy balance compared to the appetite-suppressing effects of GLP-1 drugs.

Understanding Thermogenesis and Creatine's Role

Thermogenesis is the process by which organisms generate heat. It's a crucial component of energy balance, influencing how many calories the body burns. There are different types of thermogenesis, including shivering thermogenesis (heat generated by muscle activity) and non-shivering thermogenesis (heat generated by metabolic processes, primarily in specialized tissues like brown adipose tissue).

Creatine is a molecule naturally found in the body, primarily in muscle cells, where it plays a vital role in rapid energy production (ATP regeneration). It is also a popular dietary supplement used by athletes to enhance performance and muscle growth. While creatine's role in muscle has been well-established, its involvement in energy metabolism in other tissues, particularly fat, has gained attention more recently.

Research dating back to the 1970s observed that animals exposed to cold environments utilized significant amounts of creatine. This hinted at a potential role for creatine beyond muscle function. More recent work, including studies conducted at Harvard a decade ago, pinpointed that creatine is actively used in fatty adipose tissue during cold exposure. In this context, the breakdown and cycling of creatine contribute to generating heat – a process now termed creatine-dependent thermogenesis.

Unlike brown adipose tissue, which is specialized for thermogenesis and contains a protein called UCP1 (uncoupling protein 1) that directly dissipates energy as heat, creatine-dependent thermogenesis involves a different pathway. It relies on the enzyme creatine kinase and the creatine pool within the cell to facilitate rapid energy turnover, which indirectly leads to heat production. This mechanism can occur in various tissues, including white adipose tissue, which is the primary site of energy storage and the main target for weight loss interventions.

Carlos Escande, cofounder and chief scientific officer of Eolo Pharma, explains, “It has been known for a long time that creatine has good effects on metabolism.” He adds, “What we have found is that our compound stimulates this creatine-dependent heat production pathway.” By activating this specific metabolic route, SANA encourages fat cells to burn energy and generate heat, effectively increasing caloric expenditure without necessarily reducing the amount of food consumed.

Early Clinical Evidence: The Phase I Trial

Eolo Pharma conducted a Phase I clinical trial to evaluate the safety, tolerability, and preliminary efficacy of SANA in humans. Phase I trials are typically the first step in testing a new drug in people, primarily focusing on safety and dosage, but they can also provide early insights into how the drug affects the body.

The trial was structured in two parts. The first part involved 17 healthy-weight individuals who received either a placebo or a single dose of SANA at varying low, medium, or high concentrations. The primary goal was to assess the drug's safety profile and how it is processed by the body (pharmacokinetics) in healthy volunteers. Encouragingly, SANA was found to be safe and well-tolerated across all tested doses, with no serious side effects reported.

The second part of the trial shifted focus to participants with obesity. A total of 24 volunteers with obesity were enrolled and randomly assigned to one of three groups: a placebo group or a group receiving a low, medium, or high dose of SANA twice daily for a period of 15 days. To ensure consistent conditions and monitor food intake, participants stayed at a clinical facility throughout the study, where they were provided with high-carbohydrate meals.

The results from this short-term study were promising. At the end of the two-week treatment period, participants receiving the highest dose of SANA demonstrated statistically significant weight loss, averaging around 3 percent of their initial body weight. This level of weight loss over such a short duration is notable and comparable to the initial weight loss rates observed in people starting treatment with GLP-1 drugs like Ozempic or Wegovy over a similar timeframe.

Crucially, participants in the SANA trial were asked to complete questionnaires assessing their appetite and satiety levels. None of the participants reported experiencing decreased appetite or increased feelings of fullness while taking the drug. This finding supports the proposed mechanism of action – that SANA promotes weight loss by increasing energy expenditure rather than by reducing food intake, offering a distinct advantage for patients who may not tolerate or respond well to appetite suppressants.

Preclinical Insights: Muscle Preservation

Beyond the human trial, preclinical studies in mice also provided encouraging data, particularly regarding body composition. When mice were treated with SANA while on a high-fat diet, they not only lost substantial fat mass but also appeared to preserve their lean muscle mass. MRI scans performed on these mice showed a greater percentage of lean body mass compared to control mice, despite significant overall weight reduction driven by fat loss. This is a critical point of differentiation from some other weight loss methods, including GLP-1 drugs, where preserving muscle mass can be a challenge.

Maintaining lean muscle mass is important for metabolic health, strength, and overall function. A weight loss therapy that preferentially targets fat while sparing muscle would represent a significant advancement, potentially leading to healthier body composition changes and better long-term outcomes for patients.

Comparing SANA to Existing Therapies

The emergence of SANA presents an exciting potential addition to the arsenal of obesity treatments. Its mechanism of action – stimulating energy expenditure through creatine-dependent thermogenesis – is fundamentally different from the primary appetite-suppressing mechanism of GLP-1 drugs.

Dr. Hans Schmidt, chief of bariatric surgery and co-director for the Center for Weight Loss and Metabolic Health at Hackensack University Medical Center, who was not involved in the Eolo study, commented on the novelty of SANA's approach. He noted that previous attempts to increase caloric output using stimulants, such as the controversial fenfluramine-phentermine combination (fen-phen) from the 1990s, often worked on overall metabolism in a less targeted way, leading to undesirable side effects like jitters or heart damage. “Those work on overall metabolism. They make you jittery, make you energized,” he said. In contrast, SANA “seems to work specifically at a cellular level on your fat cells,” suggesting a more targeted and potentially safer approach to boosting energy expenditure.

The oral formulation of SANA is another potential advantage. While injectable medications like GLP-1s are highly effective, many patients prefer the convenience and ease of taking a pill. An effective oral weight loss drug could significantly improve patient adherence and expand access to treatment for individuals who are hesitant about injections.

Furthermore, SANA's potential to preserve lean muscle mass, as suggested by preclinical data, could address one of the limitations of current GLP-1 therapies. A treatment that promotes fat loss while maintaining muscle could lead to more favorable changes in body composition and potentially better long-term metabolic health.

Addressing Unmet Needs and Future Potential

María Pía Garat, CEO of Eolo Pharma, emphasizes the ongoing need for diverse treatment options in the obesity field. “There's still an unmet clinical need, and that's where Eolo wants to help,” she states. While GLP-1 drugs have been transformative, they do not work for everyone, and some patients may not achieve their desired weight loss goals with these medications alone. Current GLP-1s can lead to up to 20 percent weight loss in clinical trials, which is substantial, but some patients may require further reduction to reach a healthy weight or manage co-morbidities effectively.

Dr. Angela Fitch, former president of the Obesity Medicine Association and cofounder of Knownwell, a primary care company specializing in obesity care, highlights the need for a variety of tools to tackle obesity. “Right now we are bringing a backhoe to the construction site when we need many more tools. We need more mechanisms like this that work on pathways other than appetite,” she explains. Fitch, who is not involved with Eolo, believes that “New medications present the opportunity to make an even greater impact.”

The distinct mechanism of SANA suggests it could potentially be used in several ways:

• As a stand-alone therapy: For patients who prefer an oral medication, do not tolerate GLP-1 side effects, or whose primary challenge is energy expenditure rather than appetite control.
• As an add-on therapy: In combination with GLP-1 drugs or other weight loss medications to achieve greater weight loss, potentially by targeting different pathways simultaneously (e.g., combining appetite suppression with increased energy expenditure). This could lead to synergistic effects and help patients reach more significant weight loss milestones.
• For specific patient populations: If future research reveals differential responses, SANA might be particularly effective in certain subgroups of patients with obesity.

The potential for SANA to be used in combination therapies is particularly exciting. By addressing both sides of the energy balance equation – reducing intake with GLP-1s and increasing expenditure with SANA – it might be possible to achieve more substantial and sustainable weight loss than with either drug alone. Furthermore, if SANA helps preserve muscle mass, combining it with GLP-1s could potentially mitigate the muscle loss sometimes associated with the latter.

The Road Ahead: From Phase I to Market

It is crucial to remember that the results reported by Eolo Pharma are from a small, early-stage Phase I trial. While the data is promising and supports the drug's novel mechanism, much more research is needed before SANA could potentially become available to patients. The drug development process is lengthy and rigorous, involving multiple phases of clinical testing.

The next step for Eolo Pharma is to conduct a larger Phase II trial. This trial is planned for later this year and is expected to enroll approximately 100 participants with obesity. The study will follow participants for a longer duration, likely 12 weeks, providing more robust data on the drug's efficacy and safety profile over a more extended period. Eolo hopes to conduct this trial in the United States, which would be a significant step towards potential regulatory approval in a major market.

Phase II trials are designed to gather more information about a drug's effectiveness, optimal dosage, and side effects in a larger group of people who have the condition the drug is intended to treat. Positive results from the Phase II trial would pave the way for large-scale Phase III trials, which compare the experimental drug to existing treatments or placebo in thousands of participants to confirm its efficacy, monitor side effects, and collect information that will allow the drug to be used safely.

The journey from a promising molecule in a lab to an approved medication available to patients typically takes many years and involves significant investment and overcoming numerous hurdles. The success rate for drugs entering clinical trials is relatively low, and many promising candidates fail in later stages due to lack of efficacy or unforeseen safety issues.

However, the early data for SANA provides a strong scientific rationale for continued investigation. The unique mechanism targeting energy expenditure, the potential for an oral formulation, and the preclinical data suggesting muscle preservation are all compelling reasons to watch this drug candidate closely.

The Broader Impact on Obesity Treatment

The potential success of SANA, or other drugs targeting similar energy expenditure pathways, could significantly broaden the options available for treating obesity. It reinforces the understanding that obesity is a multifaceted disease with various underlying biological drivers, and that a one-size-fits-all approach is insufficient.

Offering treatments that work through different mechanisms allows clinicians to personalize therapy based on an individual patient's specific needs, metabolic profile, and tolerance for side effects. For instance, a patient who experiences significant gastrointestinal distress with GLP-1s might benefit from a drug like SANA that doesn't impact appetite in the same way. Conversely, combining SANA with a GLP-1 could be an option for patients requiring more aggressive intervention.

Furthermore, the development of effective oral weight loss medications could improve access and adherence compared to injectables. While the cost of SANA remains to be seen, oral drugs are often less expensive to manufacture than complex injectable biologicals, potentially leading to lower prices and greater affordability, although market dynamics and pricing strategies are complex.

The focus on creatine-dependent thermogenesis also opens up new avenues for research into the fundamental biology of energy balance and fat metabolism. Understanding these pathways better could lead to the identification of other potential drug targets in the future.

Challenges and Future Outlook

Despite the excitement surrounding SANA, significant challenges lie ahead. The Phase II trial will be critical in confirming the weight loss efficacy seen in Phase I over a longer period and in a larger group. It will also provide more comprehensive data on safety and side effects. Demonstrating long-term safety and sustained weight loss in large Phase III trials will be necessary for regulatory approval.

The competitive landscape in obesity treatment is also rapidly evolving, with numerous companies developing new drugs, including next-generation GLP-1s and medications targeting other pathways. SANA will need to demonstrate a compelling profile in terms of efficacy, safety, tolerability, and potentially cost or administration route to carve out a significant place in the market.

Nevertheless, the initial data from Eolo Pharma's SANA is highly encouraging. It represents a departure from the dominant appetite-suppression paradigm and offers a glimpse into the potential of targeting energy expenditure as a viable strategy for weight loss. If successful in larger trials, SANA could provide a valuable new option for individuals struggling with obesity, either as a stand-alone treatment or in combination with existing therapies, contributing to a more personalized and effective approach to managing this chronic disease.

The journey of SANA from an anti-inflammatory research project to a promising obesity drug candidate highlights the serendipity and persistent investigation often required in drug discovery. As the Phase II trial gets underway, the scientific and medical communities, as well as individuals affected by obesity, will be watching closely to see if this novel pill can fulfill its potential and offer a new path towards healthier weight management.

The need for diverse and effective tools to combat the global obesity epidemic is undeniable. Medications like SANA, with their unique mechanisms, are essential for building a comprehensive approach that can address the varied biological underpinnings of obesity and provide tailored solutions for patients. The future of obesity treatment is likely to involve a combination of different strategies, and drugs that target energy expenditure, like SANA, could play a vital role in that future.

As research progresses, it will be important to understand not only the average weight loss achieved but also how SANA impacts various metabolic markers, cardiovascular risk factors, and overall quality of life. Long-term studies will be necessary to assess the durability of weight loss and the safety profile over years of treatment. The potential for SANA to preserve muscle mass will also need to be rigorously evaluated in human trials.

In conclusion, Eolo Pharma's investigational drug SANA represents a fascinating and potentially impactful development in the field of obesity treatment. By harnessing the power of creatine-dependent thermogenesis to increase fat burning without suppressing appetite, it offers a novel mechanism that could complement or provide an alternative to existing therapies. While still in early development, the promising Phase I results and the unique scientific approach make SANA a drug candidate worth following closely as it progresses through further clinical trials.