Rising levels of obesity have become a global health issue, with an estimated 2.8 million people dying each year as a result.1 In the face of this major medical crisis, the development of effective drugs and interventions for the treatment of obesity is clearly an important undertaking. And, with recent advances in the field — such as the use of glucagon-like peptide-1 (GLP-1) receptor agonists — the future of obesity drug development is experiencing dramatic shifts.
ICON recently conducted a survey of more than 100 professionals currently engaged in obesity drug and device research and development. Representing organisations that range from small biotechs to large pharmaceutical companies and academic institutions, these professionals are well positioned to provide insight into the current obesity drug and device research landscape, as well as where it is headed. Using these survey results within the greater context of obesity treatments, we can understand current trends and challenges in obesity research.
Putting obesity drugs in context
Historically, methods of treating obesity have been limited. Lifestyle modification – such as diet, exercise and behavioural therapy – rarely takes into account significant risk factors, including genetics, environment and other elements outside a patient’s control. And lifestyle modification, alone, has been found to be insufficient in achieving lasting weight loss. Case in point: Patients who lose weight through lifestyle changes typically regain 80 percent of weight lost within five years.2
Bariatric surgery has been considered a more effective approach. Yet, it is highly invasive and only recommended for a limited subset of patients. And past pharmacological therapies for obesity, such as the combination of phentermine and fenfluramine popular in the 1990s, have led to serious health concerns, including primary pulmonary hypertension and heart valve disease.
Recent years have seen significant strides in pharmacological therapies. Of particular note are the regulatory approvals of GLP-1 receptor
agonists as well as dual (GLP-1 and gastric inhibitory polypeptide) incretin receptor agonists, such as semaglutide and tirzepatide, to treat obesity. Considered among the most powerful anti-obesity agents currently available, this class of drugs stimulates insulin production and synthesis, and also reduces appetite and slows gastric emptying. Studies have also shown positive impacts on obesity comorbidities such as cardiovascular diseases and non-alcoholic fatty liver disease.
With pharmacotherapy research ongoing, these approved incretin receptor agonists are only the tip of the iceberg. New GLP-1 receptor agonists are being investigated – both individually and in combination with other mechanisms. Other researchers are exploring the potential of amylin receptor agonists or analogues, as well as the use of tocotrienols. Of the respondents to ICON’s survey, two thirds (66 percent) are confident in their organisation’s obesity-related pipeline success prospects, which speaks to a promising future for obesity treatment.
The multi-indication trend
Given the interconnected nature of obesity and its associated comorbidities, the importance of addressing these conditions alongside obesity has become apparent to those involved in obesity drug research and development. A key theme that underpinned a great deal of ICON’s survey was the inclination toward multi-indication and combination therapies. Despite the success of incretin agonists, just 17 percent of respondents felt the future of drug development lay in single therapies such as semaglutide, tirzepatide or retratrutide. Instead, 64 percent thought that combination therapies for the treatment of obesity and its related comorbidities would represent the future.
This was reflected in the research that was reported by survey respondents. Only 37 percent stated that they were investigating obesity alone. Meanwhile, for those who included other indications in their obesity research, a wide variety of therapeutic areas were represented, with diabetes (55 percent), metabolism (48 percent), mental health (39 percent) and cardiovascular diseases (38 percent) being the most commonly selected.
Facing the challenges of clinical trials
Despite promising developments in the field of obesity, and researchers’ confidence in their pipelines, there are still obstacles to overcome. Of the various challenges facing obesity drug and device developers, 31 percent of respondents considered issues associated with clinical trials as top on their list. Specifically, of the elements that go into a clinical trial, the three ranked most challenging were: lack of obesity-appropriate trial design (39 percent); lack of long-term follow up (44 percent); and difficulty recruiting diverse patient populations (38 percent). Nevertheless, these challenges are not insurmountable.
Clinical trial design
Traditional clinical trial design may not always be the best choice for obesity studies. As reported in the survey, half (50 percent) of current obesity clinical studies include multi-indication components, creating challenges not seen when investigating a therapy for one indication at a time. Innovative trial designs provide a promising route for these studies, such as through master protocols, which are specifically constructed to test multiple hypotheses and may include parallel sub-studies, but have an overarching set of procedures to improve efficiency. For instance, under master protocols, a basket trial design is well suited to account for the interconnected therapeutic areas found within obesity-related comorbidities. This allows a single investigational drug or drug combination to be tested on multiple indications or subtypes of a single disease, which have a common molecular characteristic.
Long-term follow up
After initial approval is obtained based on weight loss, long-term studies are needed to address effects on the clinical events associated with obesity. This data is needed to compete against marketed products with an indication for event reduction. Novo Nordisk’s SELECT trial is an excellent example. Here, a five-year study provided clinical evidence showing that the company’s drug, Wegovy (semaglutide), reduced the occurrence of major adverse cardiovascular events, boosting Wegovy’s prospects clinically and financially.3
However, long term studies are expensive, highlighting the need to create efficiencies in execution. Effective compliance and retention improve efficiency and be achieved with patient centric trial designs including remote and hybrid study visits that ease patient burden. Traditional time-to-event analysis of clinical outcomes trials may not be as efficient as alternative statistical approaches that in some circumstances can reduce sample size.
After a clinical outcome trial has completed further follow-up can provide valuable insights into the potential for continued benefits. To help continue collecting patient data, clinical trial tokenisation enables the gathering of a participant’s health data on an ongoing basis through secondary sources such as electronic health records.
Diverse recruitment
Now more than ever, there is increasing pressure to ensure the recruitment of representative patient populations in clinical trials. In obesity clinical trials, the challenge is twofold: Despite similar levels of obesity across gender, women typically make up approximately three quarters of obesity clinical trial participants. At the same time, racial and ethnic minorities are typically underrepresented in these trials.
To improve diverse recruitment, targeted messaging, which includes demographic-specific language and imagery, can be useful. Additionally, the strategic use of technology, such as incorporating a smartphone element, can improve enrolment as well. Further, survey respondents believe that reducing patient burden (33 percent) and monetary incentives (30 percent) are the factors that could have the greatest impact in improving the diversity of the patient population during recruitment.
The future of obesity treatment
Looking to the future of human health, obesity levels are only expected to grow. In fact, the World Obesity Foundation estimates that by 2030, one billion people will be living with obesity globally. However, advances in research — including obesity treatment pipelines that instil confidence in more than half of researchers — and improving approaches to clinical trials are pointing to a very hopeful future.
Sources:
- Obesity. https://www.who.int/news-room/facts-in-pictures/detail/6-facts-on-obesity. Accessed 11 Aug. 2023.
- Hall, Kevin D., and Scott Kahan. “Maintenance of Lost Weight and Long-Term Management of Obesity.” The Medical Clinics of North America, vol. 102, no. 1, Jan. 2018, pp. 183–97, https://doi.org/10.1016/j.mcna.2017.08.012.
- “SELECT: Semaglutide Reduces Risk of MACE in Adults With Overweight or Obesity.” American College of Cardiology, https://www.acc.org/Latest-in-Cardiology/Articles/2023/08/10/14/29/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2fArticles%2f2023%2f08%2f10%2f14%2f29%2fSELECT-Semaglutide-Reduces-Risk-of-MACE-in-Adults-With-Overweight-or-Obesity. Accessed 22 Sept. 2023
