Best-in-Class Solutions Accelerate Development of GLP-1 Therapeutics

As biotech and pharmaceutical companies seek to expand GLP-1 agonists into new therapeutic areas, they need to overcome a range of clinical development challenges.

Last year, an American Heart Association presidential advisory for the first time formally identified the strong connections between cardiovascular disease (CVD), kidney disease, Type 2 diabetes and obesity as reason to define cardiovascular-kidney-metabolic (CKM) syndrome. Medical researchers and practitioners see in their own patients how these ailments interconnect and overlap, as do the pharmaceutical and biotech companies working to develop GLP-1 therapeutics. Initially approved for treatment of Type 2 diabetes — and later for obesity —studies in GLP-1 are now expanding in other indications such as obstructive sleep apnea (OSA), heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD). This expansion is creating opportunities for clinical trials related to a range of new therapy areas and their subpopulations.

A recent trial sponsored by Novo Nordisk, Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT), demonstrates where GLP-1 research is heading. When the study started, the industry already knew that semaglutide could reduce the risk of adverse cardiovascular events in overweight or obese patients with diabetes. The SELECT trial set out to understand whether the drug has similar effect on patients without diabetes. In a time-to-first-event analysis done at 40 months, the study found a 20% reduction in the incidence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes in this population.

Participant fatigue in GLP-1 clinical trials

The success of GLP-1 drugs in SELECT and other trials has biotech and biopharma companies racing to find which indications respond well to similar treatment. As of mid-2024, this includes at least 650 Phase I-IV trials, with about 430 of those already ongoing. These new studies benefit from important lessons learned during previous diabetes- and obesity-related trials, particularly as related to participation and retention.

To achieve the goal of a patient-centric trial, it’s important from the design phase onward to consider all potential causes of trial fatigue. This fatigue is usually a result of factors in the trial design that lead to a high patient burden, some of which may be specific to GLP-1 trials. These include:

1. Frequency and duration of study visits
2. Distance or travel time to the study site
3. Invasive or time-consuming study procedures such as mixed meal tolerance tests, MRIs or pharmacokinetic assessments
4. Requirement for frequent injectable investigational product administration
5. Complex and time-consuming patient diaries
6. Frequent self-monitoring of blood glucose readings or continuous glucose monitoring
7. Failure of therapy response, either from placebo or because the patient is non-responsive to the medication
8. High number of off-site visits
9. Following and maintaining and a new lifestyle, such as changes in food choices or exercise

The high study burden on the patient may lead to reduced compliance with visits, medications and procedures. It may also lead to decreased patient retention, which may result in significant delays to trial completion or loss of statistical power. Often, the remedy to these and other fatigue-causing factors starts with building solid interpersonal relationships and ongoing communication with the principal investigator (PI) and other trial facilitators. More than anyone else, the PI drives the patient relationship and can encourage continued participation and data collection, even when patients tire.

Whatever the reason behind a patient’s fatigue, education and encouragement are key to continued engagement. To that end, the PI can ensure patients understand the science of appetite and metabolic regulation, for example, to relieve some of the self-imposed expectations for instant weight loss or other quick signs of success. They can also discuss the range of expected reactions, including the fact that some people will respond quickly and others more slowly, and what side effects may arise. And, of course, they can support nonresponding patients by making sure they know the critical value of having end-to-end data from every participant, no matter the speed or strength of their response, in order to truly gain useful data that leads to accurate conclusions. The PI can help explain the “why” for participating and staying in the study.

Careful tracking of patient exercise and diet is a prime component of GLP-1 clinical trials, so these types of studies benefit greatly when a registered dietitian is involved in implementation. An experienced dietitian is able to guide site personnel, who can then advise and guide the patients throughout the life of the trial. Ideally, the dietitian and dietary information/tools are centralized to ensure all stakeholders — patients and site personnel alike — receive consistent counseling across all sites. This alleviates any concern that different levels of patient education or support could bias results. It is vitally important, however, that diet and exercise information be attuned to the cultural and economic makeup of patients. Patients must have access (through both cost and availability) to the foods they’re advised to eat, or your study is inviting the type of frustration and friction that leads participants to drop out.

Engaging a representative patient population

As with most clinical trials, GLP-1 studies are typically challenged to engage a pool of participants that reflects the diversity of the overall patient population. For example, the SELECT trial enrollment comprised just 28% of women participants and 12% Black participants. It is worth noting that trial ran from 2018 to 2021, before the U.S. Food and Drug Administration’s (FDA) diversity and inclusion in clinical trials mandate. However, it is representative of the average across most of today’s trials, where only 20–30% of participants are women.

When developing a plan to enroll a representative patient cohort, it’s important to look at whether your inclusion/exclusion criteria are inadvertently excluding large parts of the population. For example, studies should consider removing any blanket exclusions on patients with:

• Cognitive or physical disabilities
• Diagnoses of HIV or hepatitis
• Substance abuse disorder
• Other comorbidities that are generally considered exclusion criteria

This entails precisely addressing what can be excluded or included in a study and making the protocol as specific as possible so clear judgments can be made on an individual basis. Rosters can also be expanded, where appropriate, through inclusion of adolescence patients (ages 12 to 17) in adult studies that allow them as a separate cohort.

Expertise that accelerates your clinical development success

The PPD™ clinical research business of Thermo Fisher Scientific has significant experience in customized Phase I-IV metabolic clinical trials. We’re applying that expertise and commitment to every aspect of developing and running successful GLP-1 studies. This starts with our cardiovascular-kidney-metabolic (CKM) therapeutic area, which enables us to support drug developers across the spectrum of metabolic, renal and cardiovascular diseases with our cross-functional operational, medical and scientific expertise.

In the CKM therapeutic area, our multidisciplinary team is tapped into the end-to-end capabilities of Thermo Fisher Scientific and has connections and collaboration with experts in gastroenterology, hepatology, endocrinology, cardiology and nephrology. This connected approach enables a more holistic point of view, with key opinion leaders and medical staff working together in support of a standardized approach that address risks for all therapeutic areas. Our team has more than 25 years of GLP-1 experience, drawing upon deep knowledge to:

• Enhance and adapt study designs in accordance with the changing landscape of GLP-1 research
• Optimize patient recruitment and retention
• Consider appropriate endpoints and patient-reported outcomes
• Expand the depth of efficacy and safety assessments
• Increase the likelihood of trial success

We also have decades of experience ensuring diverse representation in clinical trials. Our teams consistently deliver a comprehensive diversity solution that includes proactive planning, proven study design strategies and solutions, unparalleled partnerships, and decentralized trial expertise. Our approach enables us to genuinely address where unconscious bias can influence whether patients are even offered a place in a trial. We acknowledge historic unethical clinical trial practices and make sure that informed consent forms are easily understood and available in the appropriate language.

In addition to our vast operational experience in CV, kidney and diabetes/metabolic trials, our global footprint enables access to diverse populations based on disease demographics and epidemiology. We’re also uniquely able to deliver a full suite of end-to-end offerings that include:

• Thermo Fisher Scientific manufacturing for production continuity from clinical trials to commercial scale. Thermo Fisher delivers everything needed for biologics, small molecule and viral vector manufacturing, all the way through validation and regulatory support.
• Early development services to identify areas of strength and potential weakness that could impact trial outcomes and develop an integrated, early-phase program that leverages our facilities, site network, operational expertise and development experience to execute successful trials.
• Real-world evidence (RWE) and real-world data (RWD) to empower truly meaningful decisions, both through Evidera, a preeminent provider of evidence-based solutions that demonstrate the real-world effectiveness, safety and value of biotech and biopharma products, and through CorEvitas, a leading provider of regulatory-grade RWE for approved medical treatments and therapies. Our researchers have experience with more than 100 data sources across more than 20 countries, collaborate with several data partners, and can extract deep insight from RWD.
• PPD™ Laboratory services Central Lab offers an integrated, flexible, one-stop solution for the collection, management and analysis of lab and study data in the clinical trial ecosystem.

In today’s active development landscape, GLP-1 studies face strong competition and potentially low retention rates. We are the right partner to enable you to successfully navigate these challenges from early development through post-approval. Our two-part webinar series offers a more in-depth look at the current state of GLP-1 research and how to overcome the many challenges to completing successful GLP-1 trials.

1. The Evolution of GLP-1s: Overcoming Clinical Development Challenges
2. The Impact of GLP-1s on Cardiovascular Clinical Development