The State of Obesity-Related Clinical Research: Q&A with Simon Bruce, Vice President, Internal Medicine, Drug Development Solutions, ICON

Simon Bruce
Vice president of internal
medicine and drug
development solutions
ICON

In early 2024, ICON surveyed over 100 professionals working in obesity-related clinical research to get their opinions on the current state and future of obesity R&D. Simon Bruce, vice president of internal medicine and drug development solutions at ICON spoke with Pharmaceutical Executive about the survey and what it suggests about the state of the obesity-related pipeline.

Pharmaceutical Executive: What is driving the confidence in the obesity-related pipeline?
Simon Bruce: With an estimated 2.8 million people dying every year as a result of obesity, there is a clear need for the development of effective interventions. Recent developments, such as the approval of the GLP-1 receptor agonist semaglutide to treat obesity, have proven far superior to older weight-loss drugs, and have boosted confidence in the effectiveness of and the demand for pharmaceutical approaches to treating obesity.

Importantly, these recent advancements have been propelled by an improved understanding of the underlying pathophysiology that obesity shares with a constellation of other conditions, including type 2 diabetes, cardiovascular disease and non-alcoholic fatty liver disease. GLP-1, for example, is a gut-derived hormone released after food that helps mediate the function of many organs and systems – including the liver, the pancreas, the heart and the brain. GLP-1 agonists, which are approved to treat obesity and type 2 diabetes, have previously demonstrated improvements in overall mortality and specific outcomes related to atherosclerosis, cardiac failure and kidney failure in diabetics. Recently this class of medication demonstrated a reduction in major adverse cardiovascular events in non-diabetic obese patients and improvement of heart failure symptoms in this population.

Armed with the knowledge that obesity is a highly heterogeneous condition with many potential avenues for therapeutic intervention, researchers are now exploring many interdisciplinary approaches to obesity treatment, including the development of single treatments for multiple indications and combination interventions. The many differentiated treatments needed to address the global obesity epidemic have likely contributed to the confidence survey respondents reported in their obesity-related pipelines, with 66 percent confident that their pipeline would be successful in the current market.

PE: Why do most respondents believe that a combination of interventions is better to treat obesity?
Bruce: While high confidence in the success of their obesity-related pipeline was likely buoyed by the success of semaglutide, few respondents (17 percent) believed that a single therapy would be the path forward in the future of obesity treatment. Instead, the majority (64 percent) favored combination therapies to treat obesity and comorbidities.

The anticipated focus on combination treatments is best understood by the success of past combination therapies that lacked the safety profile and weight loss efficacy of the current generation of incretin hormones but which worked by addressing both energy intake and energy expenditure. And while weight loss alone can mitigate a variety of risks for chronic disease, different individuals may have different balances of lipid handling, insulin resistance, pancreatic reserve or degrees of inflammation, which will stimulate more precision medicine approaches based on obesity “phenotypes”. Drug combinations, therefore, have the potential to optimize a more personalized treatment approach depending on the type and number of obesity-related co-morbidities impacting that patient.

For example, GLP-1 receptor agonists alone may pose risks to older patients with sarcopenia, because they result in loss of both fat and lean mass. For these patients, the addition of medications that preserve muscle mass may not only improve the quality of weight loss but also enhance fat loss given the role of skeletal muscle in energy expenditure. Medications targeting new molecular pathways will provide additional opportunities to explore multidrug synergies.

Combination interventions, including those that combine behavioral and pharmaceutical interventions, may also help improve patient adherence, by displaying synergies of symptomatic relief. For example, diet can improve gastrointestinal health and relieve discomfort, exercise can improve metabolic and endocrine health, and weight loss improves joint, endocrine, cardiac and inflammation status.

The interdisciplinary approach to obesity-related pipelines seen today was reflected by the survey respondents, of whom only 37 percent reported studying obesity alone. The indications most commonly included in obesity-related research were reported to be diabetes (55 percent), metabolic disease (48 percent), mental health (39 percent) and cardiovascular disease (38 percent).

PE: What are the challenges to running clinical trials for anti-obesity therapies?
Bruce: Many survey respondents cited challenges with running clinical trials for anti-obesity therapies, and it was identified in the survey as the most challenging stage of obesity-related drug or device development (31 percent), with phase 2 trials identified as especially difficult. Phase 2 trials are commonly the most important value-inflection point particularly for newer agents where often the dose range is not fully known, the need for titration for tolerance may require additional duration of exposure, and where the magnitude of weight loss at 3-6 months must be used as a proxy or estimate of potential Phase 3 efficacy. The importance of looking at interim and surrogate metabolic, cardiac and inflammatory markers as well as patient reported outcomes may all be highly relevant in these initial proof-of-concept studies. Respondents identified that the biggest challenges in obesity-related clinical studies were a lack of obesity-appropriate trial designs (39 percent), a lack of long-term follow-up studies (44 percent) and difficulty recruiting diverse patient populations (38 percent).

Long-term obesity studies are needed to determine treatment effects on clinical events linked to obesity-related comorbidities, but conducting these trials is very costly and challenging, with only 22 percent of respondents reporting that their studies followed patients beyond five years. Improving the efficiency and reducing the cost of long-term studies requires high levels of retention and compliance. This can be driven by easing patient burden with decentralized and hybrid approaches to follow-up. In addition, implementing tokenization, which allows consented subjects’ anonymized prospective medical record data to be tracked for longer term outcomes, can protect against loss of endpoint data and allow for continued data collection after a trial is completed.

Diversity in obesity-related clinical trials has become another area of growing concern. Underrepresentation across racial and ethnic minorities is a frequent difficulty in obesity-related 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 therapy trials. Successfully enrolling a representative population for obesity-related clinical trials requires a concentrated effort, such as the use of targeted messaging and digital tools.

Respondents also noted a lack of obesity-appropriate trial designs. Although regulatory guidances exist that outline requirements to support filing for an obesity indication, newer mechanisms of action and importance of safety data will require sponsors to think carefully and creatively about study design on a case-case basis. This may be attributed, in part, to the significant portion of obesity drug research that involves multiple indications, or treatments that originated in another indication. One example of alternative clinical trial design is the potential use of master protocols to facilitate screening and to efficiently test new agents for efficacy across different potential obesity-related indications. Additionally, increasing the use of decentralized trial elements may facilitate broader patient/subject engagement, participation and representation while reducing participant burden.

PE: What are the barriers preventing the general population from accessing these treatments?
Bruce: Cost of treatment emerged as the primary barrier to reducing obesity in the general population cited by survey respondents, with 41 percent of respondents identifying cost as the biggest barrier. Access to treatments was identified as a key barrier by 30 percent of respondents. Ultimately, the existing and future therapies must demonstrate cost-effectiveness and need to be available to underserved populations globally. Efficient drug development strategies are needed to facilitate the achievement of these goals.