Article | May 1, 2024

Trimming time: metabolomics insights to speed development of GLP-1 therapies

Multiple GLP-1-based therapies for type 2 diabetes and obesity have been approved in recent years, reflecting their strong clinical effectiveness in improving glycemic control. With the global prevalence of those metabolic diseases steadily rising, it is clear this class of drugs has immense potential to address the needs of large patient populations, and we are seeing a surge in development efforts among pharmaceutical players in the space.

While the market for GLP-1 therapy is opportunity-rich – not only for diabetes and obesity but also for other indications such as heart and kidney disease – it is also becoming increasingly saturated. For developers of GLP-1 agonists, success will hinge largely upon: 1) the ability to deliver clear efficacy and safety advantages over existing GLP-1 drugs; and 2) shortening time-to-market.

Biomarker-guided development has been proven to address both challenges, and nontargeted profiling of dynamic biomarkers can uncover novel biological insights that drive greater competitive advantages – from identifying new pathways to target to selecting patients most likely to respond a specific GLP-1 therapy. We discuss how below.

From metabolites to medicines: discovery metabolomics to drive GLP-1 therapy innovation

Discovery metabolomics offers a powerful tool to comprehensively explore metabolite and lipid profile changes induced by GLP-1 agonists. As a nontargeted approach, it allows for the discovery of both known and novel biomarkers that elucidate mechanisms underlying degraded GLP-1 effect and the metabolic pathways affected by therapy. This information can be used to design more potent and selective GLP-1 agonists and to identify new biomarkers for stratifying patient populations, predicting drug response, and monitoring treatment efficacy.

Now, with high throughput technologies available, the speed and scale at which these small molecule biomarkers can be identified and validated is unprecedented. Next-generation discovery metabolomics offers sponsors opportunity to rapidly uncover and apply new biological insights that can differentiate their GLP-1 agents and streamline their clinical trial sizes to accelerate development timelines.

Better measures? Exploring the broader metabolic landscape to advance GLP-1 agonists

Leveraging the properties of glucagon-like peptide-1 (GLP-1), which has glucose-lowering effects as well as an ability to slow gastric emptying and reduce feelings of hunger, GLP-1 agonists can revive insulin excretion and improve glycemic control in individuals deficient in the naturally occurring GLP-1 hormone.

Commonly used biomarkers in the development of GLP-1 agonists today include glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). Those with elevated baseline HbA1c or FPG levels are likely to have greater glycemic improvements with GLP-1 agonists, and decreases in these levels following treatment associate with therapeutic response. BMI is also commonly used to predict likelihood of response and for response monitoring.

It is important to note that HbA1c, FPG, and BMI are not specific to the GLP-1 signaling pathway, and therefore cannot capture the full spectrum of GLP-1 agonist effects on physiological processes like glucose metabolism and appetite regulation. HbA1c, for example, is influenced by factors other than glucose control, such as hemoglobin variants and erythrocyte turnover rates. FPG and BMI changes can be influenced by dietary intake and physical activity, making it difficult to attribute changes specifically to GLP-1 agonist treatment. And while they are indicative of short-term improvements in glycemic control and/or weight loss, they have less utility for predicting long-term clinical outcomes.

Applying discovery metabolomics, we can expand exploration of the GLP-1 metabolic landscape beyond the established measures, to discover and characterize additional biomarkers that may address these limitations and further accelerate GLP-1 agonist development for type 2 diabetes, obesity, and novel indications.

Sapient’s discovery metabolomics and the applications to accelerate GLP-1 agents to market

Sapient’s mass spectrometry-based discovery metabolomics workflow captures and measures >15,000 metabolites and lipids per biosample in a single run. With an analytical cycle time under one minute, our systems can process thousands of samples per day. Large-scale profiling leads us to the most biologically relevant signals, whether they are already known compounds or have yet to be characterized.

Metabolites and lipids are dynamic indicators of disease and therapeutic intervention, and can read out subtle changes related to both degradation in GLP-1 effect and GLP-1 agonist response – often well before changes in clinical symptoms are seen. They can denote early disease processes, detect early signs of drug response or adverse events, and be used to monitor for toxicity or resistance over time.

Such biomarkers that are discovered through a sponsor’s study can be cross-validated in Sapient’s Human Biology Database, which is a unique and powerful asset for population-level analysis. It is comprised of multi-omics data with paired phenotypic measures collected in over 100,000 human biosamples – including >10,000 individuals with type 2 diabetes and >15,000 people with obesity.

Our comprehensive approach significantly amplifies discovery potential and can reveal robust biomarkers that drive a competitive edge in GLP-1 agonist development efforts, including for:

Patient stratification in GLP-1 agonist clinical trials

The ability to subset patient populations drives smaller, faster, and more efficient clinical trials. If you consider a heterogeneous disease like type 2 diabetes, for example, there are multiple pathways by which an individual can go from a normal to a disease state – and each person’s distinct disease biology can affect how they will respond to treatment.

Our discovery metabolomics can broadly screen biosamples to identify distinct small molecule biomarkers or signatures associated with different disease subtypes. Patients can then be stratified into groups that, according to their disease biology, are more likely to respond favorably to a specific GLP-1 agonist. Similarly, we can assay samples pre- and post-treatment for biomarkers that associate with drug response, such as those reading out improvements in glycemic control and endothelial function. These biomarkers can be biologically validated in our Human Biology Database to determine if they are present in populations that represent a similar disease subtype and/or that have responded to other GLP-1 therapies.

Enriching a trial by enrolling only biomarker-positive patients can significantly lower the trial size while demonstrating maximum benefits for the treatment group.

Expansion of GLP-1 agonist indications

Sapient’s Human Biology Database can support the discovery of new therapeutic targets for GLP-1 therapies, including for efficacy-improving dual agonists for type 2 diabetes and obesity as well as for new disease indications. Strong evidence suggests that GLP-1 agonists have additional beneficial effects beyond glycemic regulation and weight loss, including cardiovascular risk reduction and anti-inflammation. As such, a number of GLP-1-based therapies for chronic kidney disease, cardiovascular disease, metabolic liver disease, and Alzheimer’s disease are now advancing in clinical development.

Our database contains a large representation of individuals with these diseases as well as diseases and conditions sharing similar profiles of metabolic dysregulation. We can mine the dataset for biomarkers associated with novel metabolic pathways and biochemical processes that could be modulated by GLP-1 therapy, delivering unique insight for indication expansion.

Safety profiling of GLP-1 therapy

Studies have found that GLP-1 agonists are associated with increased risk of gastrointestinal adverse events spanning from nausea and vomiting to pancreatitis and kidney dysfunction. Improving the safety profile of a GLP-1 agent can mitigate risk in clinical development phases and provide a competitive advantage when the therapy reaches market.

With discovery metabolomics, Sapient can screen for and identify early biomarkers of toxicity or adverse events associated with GLP-1 therapy. These biomarker changes can be read out well before clinical symptoms become evident, allowing for timely intervention to adjust or discontinue treatment. We can also leverage our Human Biology Database to validate whether the biomarker(s) behave similarly in other populations with the same disease that have experienced adverse events. Ultimately, this information can be used prospectively for patient selection in clinical trials, screening individuals for these safety biomarkers to identify and exclude those with high risk of adverse events.

Deepening GLP-1 mechanistic insights with discovery proteomics

In addition to metabolomics and lipidomics measures, Sapient offers discovery proteomics services that can be used to further profile the effects of GLP-1 and GLP-1 agonists. Capable of measuring >4,000 proteins and post-translational modifications (PTMs) in human plasma (and >10,000 in cells and tissue), our proteomics workflow can identify proteins affected by GLP-1 signaling, uncovering potential therapeutic targets and pathways for intervention. Our ability to deeply profile the proteome also enables characterization of even subtle protein changes associated with GLP-1 therapy, allowing for the monitoring of off-target effects, toxicity, and resistance over time.

By layering on and integrating proteomics data with metabolite and lipid biomarker discoveries, we can deliver multi-dimensional, multi-omics insight into the molecular mechanisms underlying GLP-1 to decipher the heterogeneity of GLP-1 biology and GLP-1 agonist responsiveness more fully.

As investment in and approvals for GLP-1 therapies accelerate, sponsors must ensure their development efforts can keep pace. Sapient’s next-generation discovery metabolomics and proteomics can provide an unprecedented view into metabolic and protein changes induced by GLP-1 agonists, offering invaluable insights that can speed development and differentiate the market positioning of a therapy. By leveraging our high throughput platform and expansive Human Biology Database, we can help sponsors rapidly identify and validate novel biomarkers to subset populations, optimize patient selection, and enhance the safety and efficacy profiles of GLP-1 agents – enabling smaller and more successful clinical trials.

Our comprehensive approach not only amplifies discovery potential but also facilitates the translation of these discoveries into actionable strategies that drive competitive differentiation and market success. If you’re interested in learning how Sapient’s workflow can be applied to speed development of your GLP-1 agonists, schedule a time to talk to our scientists here.