GLP-1 agonists are garnering tremendous attention in the pharmaceutical space, giving rise to extensive research and development of these and other modalities in obesity. Along with opportunities, particularly in addressing multiple indications / comorbidities, there are several challenges conducting clinical trials in this space, namely long-term follow up and trial design.
 
A class of medicines designed to help manage blood sugar in Type 2 diabetes, GLP-1 agonists (Glucagon-like peptide-1) are increasingly being developed to treat obesity. The U.S. FDA approved the first GLP-1 agonist exenatide (Byetta) in 2005. Since then, Dulaglutide (Trulicity), Liraglutide (Victoza), Lixisenatide (Adlyxin), Semaglutide injection (Ozempic), and Semaglutide tablets (Rybelsus) have joined the list.

A similar class of medicines are called dual GLP-1/GIP receptor agonists. Tirzepatide (Mounjaro) is one of these, and was approved by the FDA in November 2023 for chronic weight management in adults with obesity. GLP-1 agonists work by mimicking the naturally occurring GLP-1 hormone to trigger its effects, such as insulin release, blocking glucagon secretion, slowing stomach emptying, and satiety after eating.
 
ICON, a clinical research organization, recently conducted a survey of more than 100 global industry professionals involved in obesity-related clinical research to gauge opinions of current obesity R&D and its outlook. Adrienne Stoudenmire, Vice President of Global Project Delivery, ICON Biotech, and Alan Baldridge, Senior Director, Drug Development Services, ICON, discuss current obesity R&D trends, challenges associated with obesity-related clinical research, and opportunities in this sector. –KB 
 
Contract Pharma: What are some of the key findings from the survey?
 
Adrienne Stoudenmire: Consisting of responses from more than 100 individuals whose organizations — from pharmaceutical companies to biotechs to academic institutions — are currently involved in obesity research, the survey explored the state of obesity drug and device research, as well as what these professionals expect for the future of the field.
 
Among these respondents, two thirds (66 percent) are confident in their obesity-related pipeline success in the current market. However, few respondents (17 percent) believed that a single therapy, such as semaglutide, would be the path forward in the future of obesity treatment, with the majority (64 percent) instead favoring combination therapies to treat obesity and comorbidities. Additionally, the survey highlighted the challenges associated with obesity-related clinical trials: Receiving 31 percent of selections, more than twice as many as the next highest choice, clinical trials were considered the most difficult stage of obesity drug and device development.
 
Contract Pharma: What are some of the current obesity R&D trends?
 
Alan Baldridge: When asked which areas were included in their obesity-related research, respondents most commonly selected the following: clinical research; genetics and epigenetics; effects of diet on obesity and overall health; and pharmacologic and device therapies. 
 
Traditionally caloric restriction and physical exercise have been the mainstay in weight loss management despite showing only modest initial success, plateau in weight loss, and rebound weight gain. Surgery is the only intervention to have demonstrated long-term benefit, but it is associated with significant risks that may not outweigh the benefits. Recently, pharmacological treatment is recommended in conjunction with caloric restriction and physical exercise as treatment and maintenance of weight loss. One cannot mention pharmacologic therapies without also mentioning the past year’s notable success of GLP-1 receptor agonists, such as semaglutide. There is a great deal of interest in further developing this class of medicines, both individually and along with other mechanisms, such as GIP and glucagon agonists. Researchers are also exploring the potential of other hormones of interest, such as amylin. While these are only a sample of anti-obesity medications in development, the overall trend is in promoting appetite reduction and satiety, in particular by leveraging hormonal interactions. There remains controversy regarding the duration of integrin therapy and maintenance of weight loss following discontinuation of GLP-1 agonist treatment. 
 
It’s important to point out that half of the respondents asserted that their obesity-related clinical trials involved multiple indications. The most common indications being included in research are diabetes (55 percent), metabolism and metabolic disease (48 percent), mental health (39 percent) and cardiovascular disease (38 percent). Meanwhile, only 37 percent of respondents said that their research was focused on obesity alone.   
 
Contract Pharma: What are the challenges associated with obesity-related clinical research?
 
Alan Baldridge: As noted above, clinical trials are largely viewed as the most challenging of obesity-related research activities. Survey respondents identified three particular aspects of clinical trials as the most challenging:
 
Lack of long-term follow-up studies (44 percent). There are a number of compelling reasons to conduct long-term follow-up studies, such as determining the sustained efficacy of an obesity therapy or tracking a treatment’s impact on health over time. In the case of Wegovy (semaglutide), a five-year study demonstrated the reduction of major adverse cardiovascular events, and boosted Wegovy’s prospects clinically and financially. A recently published study by Epic Research found that two-thirds of patients are able to maintain weight loss following GLP-1 agonist therapy.¹ Other studies have found weight gain following discontinuation of integrin therapy suggesting long-term prospective studies may be needed to resolve this question.  However, maintaining a long-term study can be costly, and it can be difficult to retain sufficient patients for the duration of the study.
 
Lack of obesity-appropriate trial designs (39 percent). There are a number of factors that complicate the design of obesity-related clinical trials. For example, typical controlled trials often deal with patients in the placebo arm dropping out when they do not see the desired results, making it difficult to conduct appropriate statistical comparisons. Further, a significant portion of obesity drug research involves multiple indications, or treatments that originated in another indication. Alternative clinical trial designs, such as those that use master protocols or decentralized trial elements, may be better suited to obesity research.
 
Difficulty recruiting diverse patient populations (38 percent). Diversity in clinical trials has become a growing area of focus across therapeutic areas. Underrepresentation across racial and ethnic minorities is a frequent difficulty in obesity clinical trials. And, despite similar rates of obesity across gender, men are estimated to make up only about one quarter of participants in weight loss trials. To successfully enroll a representative population for obesity-related clinical trials requires a concentrated effort, such as the use of targeted messaging and the use of digital tools. 
 
Contract Pharma: Where do you see the greatest opportunities for the sector?
 
Adrienne Stoudenmire: Opportunities for obesity drug development will likely lie in multi-indicational efficacy. With a high proportion of respondents feeling that the future of obesity therapies will be in combination therapies to treat obesity and comorbidities – as well as the success of GLP-1 agonists in addressing comorbidities, such as cardiovascular health and metabolic-dysfunction associated steatotic liver disease (‘MASLD’) – it becomes clear that obesity’s connection to other health concerns cannot be overlooked when developing treatment.  Ensuring that clinical trial protocols do not exclude patients from concomitant use of GLP-1 agonists during their trial participation where possible should be encouraged to ensure their widespread usage will not be a barrier in further research in addressing comorbidities. 
 
Another direction that drug developers may wish to explore is finding long-term therapeutic solutions. Current therapies, including GLP-1 agonists, require the continual ongoing use of medication to maintain weight loss. There is ample room in the sector for researchers to investigate therapies based on mechanisms that manage weight regain.
 
1.  lt K, Mast C, Deckert J, Gracianette M, Joyce B. Many Patients Maintain Weight Loss a Year After Stopping Semaglutide and Liraglutide. Epic Research. https://epicresearch.org/articles/many-patients-maintain-weight-loss-a-year-after-stopping-semaglutide-and-liraglutide.