INTRODUCTION

Adoption of multi-indication pipelines has extended to the cardiometabolic landscape and beyond. The successful label ex­pansion of GLP-1 receptor agonists (GLP-1 RAs), which mimic a metabolic hormone, established compelling evidence for the commercial value of multi-indication drug development beyond obesity.¹ The growing appetite for multi-indication drug develop­ment was reflected in a 2025 survey from ICON, questioning 155 biotech and pharmaceutical professionals across the US and Eu­rope whose research included cardiometabolic indications.² A strong majority of sponsors (92%) reported that at least one ther­apy in their pipeline had potential efficacy in more than one in­dication, and 83% reported actively developing a therapy in their pipeline for multiple indications.

To compete in today’s increasingly competitive cardiometa­bolic market, developers of therapies with multi-indication poten­tial must take a strategic approach that will accelerate cross-indication approvals and improve resource efficiency during development. This requires a proactive, strategic multi-indication development and commercialization strategy, which represents a paradigm shift from a historically reactive, serendipitous process.

Eli Lilly’s tirzepatide exemplifies a proactive multi-indication strategy. Initially approved for type two diabetes (Mounjaro) in May 2022, based on the Phase 3 SURPASS study, it was then ap­proved for chronic weight management as Zepbound 1.5 years later, in November 2023.^3,4 The rapid succession of approvals was enabled by early stage trials designed to support multiple in­dications, followed by parallel pivotal trials supporting individual indications.⁵ By contrast, Novo Nordisk’s GLP-1 RA received weight loss approval in June 2021 3.5 years after initial type two diabetes approval in December 2017, using a more sequential and less integrated development approach.^6,7

Unconventional clinical development strategies may be bet­ter adapted to multi-indication approaches than conventional ap­proaches developed with single-indication therapies in mind. However, the 2025 survey suggests that many sponsors are hes­itant to adopt these strategies, even as they recognize the value of multi-indication development. For instance, 1 in 10 developers said they used master protocols or other nontraditional study arms that enable multi-indication trials.2

Early consideration of unconventional trial formats, patient screening approaches, and endpoint selection in clinical trials may introduce efficiencies into the development of a single ther­apeutic for multiple indications. Similarly, cross-indication ap­provals can be supported by the implementation of more intentional long-term follow-up and real-world evidence (RWE) generation. In turn, more strategic multi-indication development strategies will accelerate cross-indication approvals for emerging cardiometabolic drugs going forward.

ADAPTIVE DESIGNS & MASTER PROTOCOLS

The survey reflected the persistent use of conventional trial formats, which were initially designed for single-indication ther­apies.⁸ However, nontraditional trial formats can be better suited to multi-indication development. For instance, master protocols can allow researchers to test a drug across several conditions in one study, saving resources needed to run separate studies in par­allel. Adaptive trial designs are another useful trial framework, which allow for data-based decision-making earlier in the clinical trial process, and can aid dose selection and early signal detec­tion across related pathways. Especially when trial populations overlap, implementing adaptive designs or master protocol trial formats can reduce timelines and costs during multi-indication development.

Frequently, hesitation to adopt adap­tive and master protocols stems from un­certainty around regulatory expectations and operational feasibility, rather than re­sistance. Scenario-based planning and early strategic consultation can help clarify the value and mitigate risks of adopting new or unfamiliar clinical trial models. For instance, partners can help sponsors select fit-for-purpose adaptive elements tailored to their therapeutic profile and pipeline, such as interim dose selection based on short-term weight loss, related biomarkers or tolerability signals. Rather than pushing a fixed model, experts in multi-indication development can help sponsors tailor in­novative trial designs to their specific risk profile, resource limits, and regulatory path — ensuring the design serves the program, not vice versa.

PATIENT SCREENING

In the ICON survey, four in five re­spondents reported using traditional pa­tient screening methods that often rely on broad inclusion criteria based on simple metrics such as body mass index (BMI) or waist circumference measurements.2 How­ever, this approach often fails to recognize that individuals may have different under­lying causes for disease, varying risk pro­files, and diverse treatment responses.

Sponsors can benefit from taking a precision approach to patient screening that enables stratification by relevant co­morbidities and related factors, such as in­sulin resistance, inflammatory markers, or psychological indicators. Stratified recruit­ment can enhance the clinical and com­mercial success of therapies with multi-indication potential by identifying subpopulations most likely to benefit from treatment, strengthening the evidence base for label expansions, and potentially improving payer and physician accept­ance of multi-indication approvals.⁹

ENDPOINT SELECTION

Effective patient recruitment, guided by precise inclusion criteria, must be com­plemented by a thoughtful selection of endpoints to ensure trial success. Endpoint choices directly influence regulatory ap­proval and the commercial viability of a drug. However, sponsors of multi-indica­tion therapies often face the challenge of reconciling regulatory mandates with clin­ically meaningful outcomes.

For instance, while regulatory bodies typically prioritize BMI change as a pri­mary endpoint for obesity trials, this metric may not fully encompass the broader health benefits relevant to physicians and payers. A singular focus on primary, regu­latory-accepted endpoints can, therefore, limit the commercial potential of obesity treatments that offer other significant im­provements in how patients feel, function and survive.

To address this, incorporating second­ary, surrogate and exploratory biomark­ers, alongside primary endpoints, can provide a more comprehensive under­standing of treatment effects. Exploratory endpoints, for instance, are invaluable for evaluating a therapy’s mechanism of ac­tion and identifying differential benefits across patient subgroups. Although not typically used for regulatory submissions, they can justify the investigation of a wider range of outcomes and generate new hy­potheses about a drug’s effects or mecha­nisms.

Despite their importance, nontradi­tional endpoints — such as exploratory measures — remain underutilized, with fewer than one in six sponsors reporting their use. Nevertheless, the significance of endpoint selection is widely recognized, with 43% of survey respondents identifying it as the most critical factor in successful multi-indication drug development.⁸

REAL-WORLD EVIDENCE

Real-world evidence (RWE) — clinical evidence derived from real-world data (RWD) on a patient’s health status and rou­tine healthcare — is increasingly vital for clinical developers. This is especially true for medicines with broad indications, di­verse patient populations and uncharac­terized long-term impacts. RWE studies can guide multi-indication expansion strategies by quantifying a therapy’s real-world impact on various conditions and comorbidities. In certain cases, RWE can even support regulatory decisions for new indications or post-market requirements. Furthermore, RWE bridges knowledge gaps from clinical trials, demonstrating a therapy’s value to payers and healthcare providers.

Despite its importance, generating high-quality RWE presents challenges due to limitations in RWD generation and the complexities of RWE study design. A 2025 ICON survey revealed that fewer than one in six respondents used RWE to inform multi-indication development, and only one in five integrated long-term follow-up strategies beyond 3 years into clinical de­velopment.8 Early guidance from experi­enced partners can help developers more effectively leverage RWE to demonstrate a therapy’s value, safety and effectiveness across multiple indications in diverse real-world settings.

EMBRACING MULTI-INDICATION DESIGNS

As developers increasingly embrace multi-indication development, the success of multi-indication therapies will stem not merely from pipeline adjustments, but also from development strategies designed with multi-indication objectives at their core. Companies that prioritize early cross-func­tional planning, innovative trial architec­ture and a dedication to evidence generation will be best positioned to un­lock the full value of their therapies.

REFERENCES

1. Zheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Tar­get Ther. 2024;9(1):1-29. doi:10.1038/s41392-024-01931-z.
2. Obesity and beyond: Embracing Multi-Indi­cation Potential during Clinical Develop­ment.; 2025. Accessed June 27, 2025. https://www.iconplc.com/insights/thera­peutics/obesity/obesity-and-beyond-em­bracing-multi-indication-potential-during-clinical.
3. Lilly. FDA Approves Lilly’s Mounjaro™ (Tirzepatide) Injection, the First and Only GIP and GLP-1 Receptor Agonist for the Treatment of Adults with Type 2 Diabetes | Eli Lilly and Company.; 2022. Accessed March 13, 2025. https://investor.lilly.com/news-releases/news-release-details/fda-ap­proves-lillys-mounjarotm-tirzepatide-injection-first-and.
4. FDA. FDA Approves New Medication for Chronic Weight Management. FDA. August 9, 2024. Accessed March 13, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-med­ication-chronic-weight-management
5. Melson E, Ashraf U, Papamargaritis D, Davies MJ. What is the pipeline for future medications for obesity? Int J Obes. Pub­lished online February 1, 2024. doi:10.1038/s41366-024-01473-y
6. FDA. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA; 2021. Accessed March 13, 2025. https://www.fda.gov/news-events/press-announcements/fda-ap­proves-new-drug-treatment-chronic-weight-management-first-2014
7. Novo Nordisk. Novo Nordisk Receives FDA Approval of OZEMPIC® (Semaglutide) In­jection For the Treatment of Adults with Type 2 Diabetes.; 2017. Accessed March 13, 2025. https://www.prnewswire.com/news-re­leases/novo-nordisk-receives-fda-ap­proval-of-ozempic-semaglutide-injection-for-the-treatment-of-adults-with-type-2-dia­betes-300567052.html
8. ICON plc. How Today’s Obesity Develop­ers Are Navigating a Multi-Indication Land­scape.; 2025. Accessed June 27, 2025. https://www.iconplc.com/insights/thera­peutics/obesity/survey-report-how-todays-obesity-developers-are-navigating
9. Tahrani AA, Panova-Noeva M, Schloot NC, et al. Stratification of obesity phenotypes to optimize future therapy (SOPHIA). Expert Rev Gastroenterol Hepatol. 2023;17(10):1031-1039. doi:10.1080/17474124.2023.2264783.

Dr. Simon Bruce is Vice President, Internal Medicine at ICON. He was trained in Internal Medicine with sub-specialization in Endocrinology at the National Institutes of Health. At NIH, he received training and conducted human patient-oriented clinical research. For the past 19 years, he has held positions of increasing responsibility in both large pharmaceutical and small to medium sized biotech companies. He has broad experience across all phases of clinical development and has been responsible for clinical development strategy and execution from pre-IND to first-in-human and phase 1/2 proof-of-concept trials through Phase 3 planning, execution and filing. Before joining ICON in 2021, he was a biopharma consultant leading clinical development of multiple compounds at Kinexum in the Metabolic and Diabetes therapeutic areas, including DPP4 and SGLT2 inhibitors, GLP-1 agonists, leptin and prandial insulins among others. Prior to Kinexum, he served as Chief Medical Officer with Adocia Inc (2014-2017), working on an ultra-rapid insulin in collaboration with Eli Lilly. His position at Kinexum was preceded by the role of Executive Medical Director, Endorcrinology at Halozyme Therapeutics (2012-2014) and Executive Director, Global Program Medical Director at Novartis (2010-2012).

Dr. Jack L. Martin is Senior Director, Cardiovascular Therapeutics, Drug Development Solutions at ICON. He is board certified in Cardiovascular Diseases and Interventional Cardiology. He has over 35 years of clinical practice and investigational experience. He is an experienced consultant for pharmaceutical and medical device companies. This includes all phases of product development including device design, trial design, FDA pre-sub and panel meetings. He has served as study chairman or the coordinating investigator for multiple multicenter international pharmaceutical and device trials. His previous roles included Assistant Professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Chief, Division of Cardiovascular Diseases and Chief of Interventional Cardiology, Health System.