A 2025 survey highlights growing momentum for multi-indication drug development, with opportunities in innovative trial design, targeted patient selection, and real-world evidence to speed label expansion.
A 2025 survey of cardiometabolic drug developers found strong interest in multi-indication strategies, yet limited adoption of master protocols, precise patient stratification, and non-traditional endpoints. Early planning, innovative trial designs, and greater use of real-world evidence could improve efficiency, support broader label expansion, and enhance clinical and commercial outcomes.
Drug developers have started deploying multi-indication development strategies in the metabolic space, moving beyond the traditional stepwise model of sequential label expansion. A
Multi-indication drug development has gained traction in recent years due to a better understanding of glucose metabolism and its link to various diseases. Glucose metabolism plays a critical role in regulating cellular energy and maintaining blood sugar levels, even as nutrient intake is irregular in timing and quantity. While metabolic dysfunction is known to cause diverse diseases, many specific mechanisms remain unclear. Therefore, compounds that modulate glucose metabolism hold significant promise as therapies and research tools.2
Nutrient-stimulated hormones (NUSH), like Glucagon-Like Peptide-1 (GLP-1) and the gastric inhibitory polypeptide (GIP), are key upstream modulators of glucose metabolism. Released from the small intestine after nutrient intake, these hormones bind to receptors in the pancreas and brain (hypothalamus, and hindbrain). In the pancreas, NUSH receptor activation promotes insulin release. In turn, insulin promotes the uptake of glucose by cells, lowering blood sugar. In the brain, GLP-1 receptor activation reduces feelings of hunger and increases satiety.3
Despite their central role in glucose metabolism, native GLP-1 and GIP make poor drug targets due to their short-lived effects and the need for injection-based delivery of peptide compounds. However, the development of longer-acting and more potent NUSH receptor agonists, like semaglutide (a GLP-1 receptor agonist), has helped overcome these barriers and clarify the link between aberrant glucose metabolism and a range of diseases. Mounting evidence of the wide-ranging clinical benefits of NUSH receptor agonistshas prompted a shift from single-indication to multi-indication metabolic therapies.4
Novo Nordisk’s GLP-1 RA, semaglutide, was initially approved as Ozempic in 2017 for type 2 diabetes, based on its ability to continually lower blood glucose. Since then, GLP-1 RAs and multi-receptor agonists have demonstrated wider therapeutic effects. An accumulation of real-world evidence supported semaglutide’s label expansions to obesity in 2021 and cardiovascular disease in 2024. Beyond these indications, GLP-1 RAs and dual GLP-1, GIP RAs have been shown to reduce addictive behaviors, impact memory, and provide long-term efficacy in obesity-related comorbidities, including cardiac, renal, and liver diseases.5
Semaglutide’s development followed a sequential multi-indication strategy, with real-world evidence of therapeutic effects beyond its initial indication informing subsequent label expansion. The drug was used as an off-label obesity treatment for years before gaining approval for weight loss in 2021 under the name Wegovy. In 2024, Wegovy was further approved for reducing cardiovascular death, heart attack, and stroke in patients with or without diabetes. This label expansion was catalyzed by findings from cardiovascular outcome trials required by regulators to establish the drug’s long-term safety.6
Today, developers are moving beyond this stepwise model, hoping to accelerate label expansion through more proactive multi-indication development strategies and trial designs. This shift is reflected in
The ICON survey indicates that despite understanding the value of multi-indication development most developers have yet to implement specific development strategies adapted to multi-indication compounds.4 Acceleration of these multi-indication pipelines requires developers to proactively improve the resource efficiency of their programs by shifting from single-drug, single-indication trials to trial designs better suited for evaluating multi-indication assets.
For instance, master protocols can streamline multi-indication development by allowing researchers to test a drug across several conditions within a single study, saving time and resources compared to conventional single-indication trial formats. However, only 12% of survey respondents reported using these designs in their multi-indication pipelines. Hesitation to adopt master protocols often stems from uncertainty about regulatory expectations and operational feasibility, concerns that can be addressed through early strategic consultation with partners experienced in multi-indication development.
Another barrier to multi-indication development, traditional patient screening methods, are implemented by about 80% of ICON survey respondents. These methods can limit the relevance of trial findings for multi-indications. For example, screening criteria can be overly broad (e.g.: body mass index (BMI)) and fail to account for the diverse underlying causes of disease, varying risk profiles, and differences in treatment responses among individuals. A more precise approach to patient screening, using stratification by comorbidities and related factors, can identify subpopulations most likely to benefit, ultimately enhancing both clinical outcomes and commercial success.
Developers of multi-indication assets may also benefit from incorporating non-traditional endpoints, which only 15% of survey respondents reported using. While regulatory bodies often prioritize specific primary endpoints, these measures may not fully capture the broad range of benefits relevant to physicians and payers for multi-indication therapies. Incorporating additional biomarkers alongside primary endpoints provides a more comprehensive view of treatment effects and can support exploration of a wider range of outcomes, formulary selection and preferred pricing.
Finally, real world evidence (RWE) is becoming increasingly vital for medicines with broad indications, diverse patient populations, and uncharacterized long-term impacts. RWE can guide expansion strategies, support regulatory decisions, and bridge knowledge gaps left by clinical trials. The ICON survey’s finding of underutilization of long-term follow-up and RWE may be explained, in part, by persistent challenges related to real world data generation and study designs suited for long-term follow-up.
As the market for multi-indication therapies becomes more dynamic, developers must adopt strategies that prioritize early cross-functional planning, innovative trial architecture, and a dedication to evidence generation. These elements are key to unlocking the full value of emerging therapies, which continue to illuminate the intricate links between metabolic dysfunction and disease, paving the way for more diverse and targeted treatment options.
Alan Baldridge, MD, Senior Director, Gastroenterology and Hepatology, Drug Development Solutions, ICON
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