This Summer, Medpace medical and operational experts attended the European Congress on Obesity and ENDO 2024 conferences. Learn more from Yulia Lurye, MD, Medical Department, Endocrine & Metabolic, as she recaps highlights from the conferences.
Focus on Novel Anti-Obesity Agents
The main conversation continues to revolve around novel anti-obesity agents, particularly incretin mimetics or nutrient-stimulated hormone-based therapies. Various combinations of GLP-1, GIP, and glucagon agonists or antagonists are currently under clinical development, including weekly or monthly injectable and oral formulations. While presentations of novel anti-obesity medications (AOMs) often start with their weight reduction effects, which may be prominent as almost a quarter of body weight loss within a year (in TRIUMPH-2 study Retatrutide in highest dose demonstrated weight reduction of 24.6% within 48 weeks)—additional focus has been placed on other direct and indirect beneficial effects, such as reducing cardiovascular risks, MASH scores, or pain scores associated with knee osteoarthritis. The principle of health gain alongside weight loss seems less theoretical and is supported by strong data from multiple clinical trials and post-hoc analyses of the STEP and SURMOUNT programs. Many questions have arisen regarding obesity treatment with GLP-1/GIP and reproductive health. So far, analyses of clinical data haven’t provided many insights, but interest is driven by practical observations of approved incretin mimetics use and improvements in reproductive health. It remains unclear whether these improvements are due to psychological factors related to weight loss or any physiological effects of GLP-1 and GIP on the reproductive system.
Combining Gut-Brain Nutrient-Sensing Signals
Data from phase 2 and 3 studies of dual and triple incretin mimetics indicate that the more gut-brain nutrient-sensing signals are combined in one chemical entity, the better the results: higher weight reduction with better tolerability. This is due to a familiar principle of targeting several receptors with lower “doses” of each component, which may explain the better tolerability and more potent cumulative effect. An interesting combination of incretin mimetics with sex hormones is being developed in the labs. If successful, it may address the specifics of obesity in postmenopausal and andropausal populations.
Lifelong Therapy and Legacy Effects
All clinical data support the definition of obesity as a chronic disease requiring lifelong therapy. In the extension phases of clinical trials across all programs (STEP, SURMOUNT, SYNCHRONIZE, TRIUMPH, ATTAIN, and other), discontinuation of the study drug was associated with weight regain. This has stimulated the search for novel AOMs with a “legacy effect,” allowing a longer “holiday period” once optimal weight is achieved. A potential candidate is MariTide, a monthly injectable GLP-1 agonist/GIP antagonist. In a phase 1 study, it demonstrated promising results (body weight reduction by 14.5% at 85 days). However, it’s too early to comment on its potential for long-term weight maintenance. Moreover, the initial hypothesis of GIP antagonism has been challenged by the efficacy of GIP agonists. It’s intriguing that GIP antagonism is returning to clinical research, which may help us better understand the pathophysiological components of obesity, such as impairments in nutrient-sensing gut signals and decreased sensitivity to them.
Advances in Oral Formulations
The well-known challenge of supplying injectable approved AOMs (Wegovy, Zepbound) creates a favorable background for developing AOMs in oral formulations. Orforglipron stands out in this context as a non-peptide-based incretin mimetic that doesn’t require special storage and can be taken independently of meals, unlike oral semaglutide Rybelsus. It has demonstrated good results in phase 2 trials: the mean change ranged from −9.4% to −14.7% at week 36, making it highly competitive with peptide-based AOMs.
Individualized Approach to Obesity Treatment
An important message worldwide continues to be “one size doesn’t fit all,” emphasizing the need for an individualized approach to treating obesity. Phenotyping and staging of obesity are recommended in decision-making algorithms for AOMs in individual cases. Analysis of gene polymorphism may provide an even more tailored approach. However, this type of testing is far from being implemented in clinical practice and is recognized as a perfect task for AI-based new technologies, which may help integrate gene expression, metabolomics, and microbiota.
Addressing Muscle Loss in Weight Loss Studies
Muscle loss accompanying weight loss in GLP-1/GIP studies has become another hot topic. While many practitioners are not convinced this is an issue, as any weight loss includes a reduction in lean mass, new agents aimed at preserving muscle mass are under clinical development. Initially tested in sarcopenic obesity, these agents may expand to broader groups of patients who could benefit from a combination of GLP-1/GIP with muscle-preserving agents.
The Role of Brain and Adipose Tissue in Obesity
On the scientific side, although the gastrointestinal tract as an endocrine organ takes a leading role, much attention has been paid to the roles of the brain and adipose tissue, as both are involved in or contribute to appetite/hunger dysregulation, impaired thermogenesis, and systemic and local inflammation (hypothalamic gliosis). This includes the disruption of the gonadotropin axis, with a new participant in this endocrine chain—kisspeptin, neurokinin B, and dynorphin (KNDy) neurons. However, there’s still much uncertainty about what comes first, what causes what, and what is a consequence. Research in animals and pre-clinical data of investigational products with anti-inflammatory mechanisms of action and central nervous system permeability support the hypothesis that such agents may benefit obesity treatment.
New Approach to Childhood Obesity Treatment
In practical medicine, a key change has occurred in the approach to treating childhood obesity. The main message is “stop watchful waiting.” The initiation of pharmacological AOMs, which are now approved for children over 12 years old (liraglutide and semaglutide), should start in parallel with lifestyle interventions.
Conclusion
Novel incretin mimetics or nutrient-sensing peptide-based therapies show promise not only in achieving substantial weight reduction but also in providing broader health benefits. The shift towards individualized treatment strategies, supported by phenotyping and genetic analysis, underscores the complexity of obesity as a chronic disease requiring tailored interventions. Moreover, the development of oral formulations and muscle-preserving agents offers new avenues for improving patient compliance and outcomes. Research continues to explore the interplay between gut signals, brain function, body composition, systemic and neuroinflammation, with a focus on both weight reduction and maintenance.
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With decades of phase I-IV metabolic experience and access to in-house and external data streams, Medpace supports the development and execution of rare to large global obesity trials. Medpace has medical, operations, and regulatory staff who understand the complexities of obesity trials from the perspective of the Sponsor, the patients, the clinical investigator, the scientific leader, and the reviewer at the regulatory agencies. Our matured relationships with global thought leaders, investigative sites, global ‘flagship’ metabolic site network, and patient advocacy groups, as well as knowledge of effective patient retention strategies, ensure efficient and quality patient enrollment which is key to the success of these programs.