Blog | 8/18/2025

Beyond GLP-1s: How can Companies Evolve Market Focus from Weight Loss to Improved Body Composition?

By Jordan Wang, Patrick Symmonds, PharmD, Sheela Hegde, MBA

Investors are Hungry for More and Better Weight Loss

Today, Novo Nordisk (semaglutide) and Eli Lilly (tirzepatide) lead the “weight loss race” with their incretin mimetics. In a head-to-head study, tirzepatide demonstrated 20% weight loss compared to semaglutide’s 14% after 72 weeks. Despite this, investors have demonstrated they are hungry for more.

Back in June 2023, Lilly’s stock hit a 52-week high following the release of Phase II data for retatrutide (triple hormone receptor agonist), which demonstrated an unprecedented 24% weight loss at just 48 weeks.

Conversely, in December 2024, Novo’s stock fell 20% after releasing that cagrisema (cagrilintide + semaglutide) missed its 25% weight loss target, having demonstrated 23% weight loss after 68 weeks.

Investors focus squarely on the percent of body weight loss as the key signal for the potential success of a new obesity asset. However, while most investors have their sights set on raising the upper limit of weight loss, some are beginning to bet on another horse – addressing the unmet needs with incretin mimetics.

A Critical Unmet Need: Superior Body Composition

With the current standard of care incretin mimetics, muscle accounts for about 25% of the weight lost. This is in line with traditional weight loss approaches such as a low-calorie diet or bariatric surgery and remains a significant concern for all patients undergoing weight loss treatments – especially those with low muscle mass or at risk for above average muscle loss.

Today, patients on or thinking about beginning incretin mimetics must face the potential for reduced strength, increased risk of falls and fractures, greater fatigue and weakness, slower and more difficult recovery from illness or surgery, as well as a slower overall metabolism, which may lead to faster regaining of weight if therapy is stopped. While incretin mimetics are being looked at as miracle drugs that allow people to lose weight and reduce the risk of obesity-related comorbidities, for some, it comes at the expense of quality of life and creates difficulties with stopping treatment.

These unmet needs have catalyzed new approaches that target energy storage and expenditure instead of food intake. These pathways involve greater specificity in the type of weight loss and intend to monitor visceral fat and lean body mass.

Novel Approaches to Obesity Treatments

While current and pipeline pharmacological therapies for obesity largely focus on food intake – representing ~60% of the US pipeline for weight loss drugs – emerging novel approaches, such as guiding energy storage and expenditure and directly targeting muscle growth and preservation, may help to address challenges with body composition.

Energy Storage: Insulin Sensitivity & Adipogenesis

Insulin sensitivity is directly tied to how energy is absorbed and stored. High insulin sensitivity allows the body to respond effectively to the presence of glucose, maintain healthy blood sugar levels, and reduce the likelihood of fat storage. Mechanisms targeting this pathway can help manage obesity by enhancing the body's ability to process and utilize glucose and may improve composition by biasing the insulin-mediated uptake of glucose toward muscle rather than adipose tissue.

Similarly, adipogenesis involves the formation of new fat cells. By blocking adipogenesis, or by promoting the formation of brown adipose tissue (which expends energy through thermogenesis) instead of white adipose tissue (which stores energy as triglycerides), therapies may target obesity by reducing fat storage and biasing energy storage toward muscle.

Energy Expenditure

Increasing the body's energy expenditure is another strategy in obesity treatment. By promoting thermogenesis in brown adipose tissue or inducing futile cycling, overall energy expenditure targeting fat stores can be increased.

Muscle Preservation

Muscle preservation sits at the intersection of energy storage and usage. Drugs targeting this pathway can preserve muscle by reducing muscle degradation, inhibiting proteins that limit muscle growth, and stimulating muscle protein synthesis.

While innovative and novel pathways continue to emerge, more research is necessary to understand and realize their potential in addressing the unmet needs of incretin mimetics.

Shifting focus to new mechanisms that address body composition comes with a set of challenges. The first is the lack of data which directly ties the impact of muscle mass to specific and measurable health outcomes. The second is the FDA's current approval process, which is heavily based on body weight rather than body composition. The third is current clinical practice patterns which focus on measuring weight and BMI rather than fat mass, muscle mass, and muscle function.

The Challenges Drug Developers Face

One of the primary challenges for developing weight loss drugs that prioritize body composition is the limited data available on how muscle mass impacts health outcomes. Low muscle mass, or sarcopenia, is associated with increased morbidity and mortality, higher surgical and post-operative complications, longer hospital stays, and reduced physical function; however, despite these known associations, there is a lack of comprehensive data on how low muscle mass progresses over time and its long-term effects on patients. This gap in knowledge makes it difficult to develop targeted interventions and to convince regulatory agencies and investors of the importance of muscle preservation in weight loss treatments.

To address this issue, more research is needed to study the natural history of low muscle mass, identify key risk factors and progression patterns, and assess the impact of low muscle mass on various health outcomes, including quality of life, physical function, and long-term healthcare costs. Greater understanding of this condition has the potential to bolster research into interventions aimed at preserving or increasing muscle mass, as well as improve how we evaluate their effectiveness in improving health outcomes. By filling these knowledge gaps, the industry can better advocate for the inclusion of muscle preservation as a critical endpoint in weight loss treatments and develop more effective and comprehensive therapies.

Another challenge is the need for drug developers to collaborate with investors and regulatory agencies and establish endpoints that go beyond traditional weight loss. Historically, the primary endpoint for weight loss treatments has been the reduction in total body weight; however, this approach overlooks critical aspects such as fat loss, lean mass preservation, and physical strength and function. To address this, drug developers must advocate for the inclusion of endpoints such as the reduction in fat mass to ensure that weight loss is not at the expense of muscle, preservation of muscle mass to maintain metabolic health and physical function, and changes in physical capabilities which indicate overall health and quality of life. These new endpoints require robust clinical trials and comprehensive data to demonstrate their significance and gain regulatory approval. This process involves significant collaboration and negotiation with the FDA, as well as securing buy-in from investors who are accustomed to traditional weight loss metrics.

The Market Decides What Matters

Back in January 2025, Veru Inc. released positive topline results for Phase II of enobosarm. Enobosarm, a muscle preserving therapy intended for use after stopping an incretin mimetics, had achieved its primary endpoint and demonstrated that…

• Patients would lose 71% less lean body mass when on enobosarm after semaglutide compared to those on semaglutide alone
• 55% fewer patients on enobosarm after semaglutide experienced a 10% or greater reduction in the ability to climb stairs compared to those on semaglutide alone

Improvement in both body composition and physical function was achieved, however, Veru’s stock plummeted following the announcement. Why? The amount of weight loss achieved was similar to semaglutide alone.

While one might expect that success at improving body composition would create a new frontier for weight loss, Veru suffered from a lack of stakeholder understanding. While Veru had set out to improve body composition and retain function, investors had decided that enobosarm had failed. The shift from weight loss to body composition remains in its infancy and presents significant challenges that require collaboration between drug developers, regulatory agencies, and investors.

In an interview in May 2025, Veru’s CEO, Mitchell Steiner, shared that they are working with the FDA to shift endpoints for enobosarm’s Phase III to reflect body composition endpoints rather than weight loss endpoints. He states “Again, what we are is not a weight loss drug. So, the weight loss guidance doesn't really apply. We're a body composition drug. The reason that's important is the endpoints in this case would be physical function, which ultimately predicts falls and fractures and mortality. It's a different game and we're going to have full clarity on that once we meet with the FDA.”

In June 2025, five to six months after Veru released Phase 2b data for enobosarm, other drug developers in the body composition space began sharing their Phase 2 results.

Regeneron released positive interim Phase 2 data for trevogrumab, which was able to spare about 50-80% of the lean mass loss due to semaglutide, as well as increase loss of fat mass.

Scholar Rock released positive Phase 2 data for apitegromab, which demonstrated ~55% lean mass preservation for patients on tirzepatide and greater fat loss.

Altimmune released Phase 2 data for its incretin mimetic candidate pemvidutide, a GLP-1/glucagon dual receptor agonist, which showed only ~22% of weight loss was attributable to lean mass.

Lastly, Lilly released Phase 2b data for bimagrumab, which showed ~93% of weight loss from fat mass when combined with semaglutide, and that, when used as a monotherapy, 100% of weight loss was attributed to fat mass and total lean mass increased 2.5%.

Despite these results, manufacturers either experienced modest increases (Regeneron, Scholar Rock, and Eli Lilly) or sharp decreases (Veru and Altimmune) to their stock price. While investors have already punished “poor” performers, they aren’t ready to reward these results.

Shifting Paradigms

Beyond greater research on patient outcomes and convincing regulatory bodies and investors, is the need to educate the field and change practice patterns. Clinician focus remains on weight loss and there is a significant lack of routinely measuring fat mass, muscle mass, or physical strength. Implementing monitoring practices, such as DEXA or MRI for body composition imaging and physical strength assessments such as stair climb power and grip strength, will be essential for accurately assessing composition and strength, and the efficacy of new therapies. While this shift may not require significant education or training it has the potential to significantly increase the amount of time dedicated to each patient visit, which could thwart widespread integration of these practices into routine care.

Outlook for Superior Body Composition Agents in Weight Loss

The next generation of weight loss treatments presents a significant opportunity for improving patient outcomes and advancing healthcare practices. Greater research and understanding of the positive effects of weight loss that prioritizes body composition will improve stakeholder buy-in and garner support for the development of these therapies. Working with regulatory bodies to shift endpoints and regulatory pathways to prioritize body composition alongside weight loss will be crucial for the approval and adoption of the next generation of weight loss therapies. By changing physician practices to include routine monitoring of fat mass, muscle mass, and physical strength, healthcare providers can offer more comprehensive care for patients undergoing weight loss treatments.

Upon crossing these bridges, the next generation of weight loss drugs has the potential to significantly improve quality of life, reduce health risks, and provide better options for patients; when they do, markets should finally recognize their potential and reward them.

 

For more information on ways manufacturers can differentiate their next-generation obesity therapies, please see our “Navigating to 2030" playbook series.