Bile acid quantification provides insight into the mechanism of action for the treatment of NASH
Metabolomics Drives Identification of Rare Disease Signatures and Diagnoses
New Hope for Rare Disease Treatments
Specific Metabolic Pathways Underlie Noncommunicable Disease Multimorbidity
Can Sebum be Used as a Diagnostic Biofluid for Parkinson’s Disease?
Delivering Clinical Insights with Targeted Biomarker Assays
Metabolomics reveals biological insights otherwise unseen, making it a crucial component of drug development. For a successful metabolomics study, both small molecule discovery and the ability to dig deeper into specific biomarkers of interest are needed to uncover actionable insights that propel new therapeutic developments. A specific combination of technology and expertise is required to identify these biomarkers of interest and develop assays that are sensitive enough to explore them fully.
Metabolomics reveals biological insights otherwise unseen, making it a crucial component of drug development. For a successful metabolomics study, both small molecule discovery and the ability to dig deeper into specific biomarkers of interest are needed to uncover actionable insights that propel new therapeutic developments. A specific combination of technology and expertise is required to identify these biomarkers of interest and develop assays that are sensitive enough to explore them fully.
At Metabolon, we understand the crucial role targeted small molecule assays play in drug development, and we’ve established best-in-class expertise. Metabolon has developed quantitative assays for more than 900 biochemicals in over 20 different matrices, including more than 150 qualified and/or validated targeted biochemical assays for pharmaceutical and biotechnology research and development. These assays focus on specific metabolites or metabolic pathways and can be used to track biomarkers and enhance biological understanding across preclinical and clinical research.
Our approach speaks directly to the questions biopharma research directors are seeking to answer, such as understanding their therapeutic’s mechanism of action, establishing pharmacodynamics, gauging safety and efficacy, defining patient segmentation, and conducting post-market surveillance. Once the critical biomarkers that are most important to researchers are identified through discovery, a more precise and accurate quantitation of the biomarkers is sought. Metabolon’s strategic services offer biopharma clients global discovery followed with a direct targeted approach to dig deeper into promising and relvant biomarkers.
Metabolon’s targeted assay program is uniquely situated to fit into this workflow.
Targeted biomarker assay development is a natural progression following discovery using Metabolon’s first-in-class metabolomics platform. Metabolon’s discovery platform uses statistical approaches to assess the relative quantity of thousands of biomarkers. Our targeted assay program picks up from there, taking the discovery work and developing a more precise, accurate measurement of those few molecules that are of most interest. We apply LC-MS/MS based methods to determine absolute quantities of important biomarkers, using labeled internal standards as well as calibrators.
Our expertise in the measurement of endogenous biomarkers is unique and second to none. Most bioanalytical services offer expertise in exogenous biomarker measurements, such as the drug of interest or compounds that are exogenously introduced into a system. Metabolon targeted assays measure endogenous biomarkers naturally found at various levels within biological systems. Since endogenous biomarkers are sometimes present at the lower limits of analytical detection, the sensitivity of the assay becomes paramount. Furthermore, modest changes in biomarker levels may have biological relevance; Metabolon’s highly accurate targeted assays are required to tease out even modest changes in analyte levels. Our team of Ph.D. level method development scientists have a degree of experience in endogenous biomarker assay development that few places, if any, in the world can match. Our scientists are highly efficient and experienced in endogenous small molecule analysis, bringing additional data and actionable insights to drug development and clinical trials. No other bioanalytical company can translate metabolomic data and biomarker discovery into valuable biological insight using targeted LC-MS/MS analysis in the way that we can.
Finally, Metabolon’s capability is unique because we can operate under a research or clinical setting. In addition to our targeted work meeting specific client study demands, we also develop assays specifically used in clinical testing. Some of the pre-developed targeted assays offered by Metabolon include:
- Fatty acid metabolism panel
- Short-chain fatty acid panel
- Bile acid panel
- Cholesterol metabolism panel
- Stratum corneum panel
- Sebum lipid panel
- accuGFR™ panel (to estimate glomerular filtration rate)
- 7 alpha-hydroxy-4-cholesten-3-one (C4) panel
- Metal ion panel
LC-MS/MS-based assays can be customized based on client needs and developed under the quality system for research use only (RUO) or validated under Good Clinical Practice (GCP) and Clinical Laboratory Improvement Amendments (CLIA). Metabolon is ISO 9001: 2015 certified for analytical and diagnostic testing of biological specimens and accredited by the College of American Pathologists for diagnostic testing on human specimens.
Nowhere else will you find a laboratory like Metabolon’s that combines a world-class metabolomics discovery platform with a highly sophisticated analytical chemistry laboratory doing targeted analysis the way we do it. We have spent nearly 20 years building the best metabolomics competency in world to enable, accelerate and support drug development through biomarker discovery, understanding mechanism of action, patient stratification and more.
We proudly cover the whole breadth of the biopharma pipeline, from discovery to targeted analysis to clinical trial support, because your success is our goal.
Is your study yielding all the insights it could be? Download our free infographic to learn more about the five risks of drug development and how you can avoid them with metabolomics, and contact us today at [email protected] to get started.
Front lines of COVID-19
Metabolon scientists are collaborating with researchers on world-leading programs to use multi-omic deep phenotyping technologies, including metabolomics, to advance human health. A primary focus right now is on improving our collective understanding of the SARS-CoV-2 virus and the COVID-19 disease during this unprecedented pandemic.
Metabolon scientists are collaborating with researchers on world-leading programs to use multi-omic deep phenotyping technologies, including metabolomics, to advance human health. A primary focus right now is improving our collective understanding of the SARS-CoV-2 virus and the COVID-19 disease during this unprecedented pandemic. Metabolon has a strong history of working closely with scientists at the Institute for Systems Biology (ISB) like Dr. James R. Heath, Dr. Leroy Hood, Dr. Andrew Magis, Dr. Nathan Price, Dr. John Earls and Dr. Sean Gibbons.
Now, we are teaming up with ISB again to understand and treat coronavirus. Longitudinal blood samples are being collected from patients with varying COVID-19 disease severity to track their health over time. One goal for the project is to understand better which patients are at the highest risk of severe infection so that we can most effectively deploy medical resources. The work will also help to develop a deeper understanding of effective immune and organ system responses during the onset and recovery of affected patients.
The findings will be vital in helping to treat patients effectively and design optimal vaccines and therapies in response to viral outbreaks in the future. Similar to the SARs outbreak in 2003, this important work will also help us understand if there are any long-term health implications for those that recover from COVID-19.
Previous studies of viral infections suggest that patients’ metabolic profiles become altered during disease progression. These metabolic changes influence how a patient responds both through the degree of immune response and clearance of the virus from the lungs and other organs. Even in the early stages of the most recent COVID-19 pandemic, it was clear that pre-existing conditions such as coronary heart disease, diabetes, asthma, and hypertension have an impact on outcomes. As the virus has spread globally, no clear patterns of effects with age, gender and these pre-existing conditions have emerged. Given that therapeutic options are limited, and vaccine development remains in progress, there remain gaps in our understanding of the mechanisms of the virus to host interactions and the trajectory of the infection cycle that metabolomics studies looking across bodily systems will help reveal.
Metabolon is the industry leader in the ability to reveal metabolic perturbations across all biochemical pathways including amino acids, carbohydrates, lipids, nucleotides, microbiota metabolism, energy, cofactors and vitamins, xenobiotics, and novel metabolites. Given that metabolism represents the integration of genetic and non-genetic factors such as microbiome and lifestyle, it is a uniquely poised modality to assess health outcomes and severity of the disease, particularly relevant to understanding the trajectory of COVID-19 infection. Within this context, Metabolon has been given special dispensation by the state of North Carolina to continue all laboratory activity during this crisis due to our capacity to analyze human samples under both clinical and research environments. We are focused on maintaining our high levels of service while protecting our staff and maintaining the physical distancing protocols. We are committed to fast track mission-critical projects linked to COVID-19 research to support this vital work.
Our dedicated team of Study Directors, including experts with years of deep, infectious disease and drug development experience, are available now to address your questions, lead metabolomics study design and draft final biological interpretation reports. Please contact us today via metabolon.com/contact-us to learn how our experts may be able to support expediting your COVID-19 research.
References:
Wang, T et al. Comorbidities and multi-organ injuries in the treatment of COVID-19. The Lancet. 2020;395(10228): e52.
Wu et al. Altered lipid metabolism in recovered SARS patients twelve years after infection. Scientific Reports. 2017:7(9110).
Metabolon reveals a new ally for drug research and development programs: Picking program winners and demonstrating their value
Today’s biopharma companies are faced with extreme competition to secure support from investors, approval from regulators, and buy-in from payers. How can a company and its new molecule shine above the noise to overcome these challenges? Enter metabolomics, the study of metabolites, the small-molecule end products of metabolism collectively known as the metabolome.
Metabolon’s superior methodology and vast metabolite library allow for the capture of a complete story about your molecule at every stage, providing valuable input that builds a robust story about your data to shape a comprehensive Global Value Dossier, or what we call a Program Development Dossier.
Obstacles to clinical success
The barriers to program success for biopharma, whether success comes in the form of an asset sale or an approved therapy, are immense. The cost of securing approval for a new drug is now estimated at $2.6 billion, which has increased 145 percent over the last 10 years due in large part to an extremely high failure rate. But what is at the heart of the failure rate? When scientists and biopharma leaders reflect on the source of high drug attrition rates, they cite many factors including: failure of preclinical development models to predict treatment efficacy, safety issues or difficulty differentiating between responder and non-responder patients. A commonality to all these issues and their associated risks is that critical pieces of information are lacking or unclear, leading to a foggy decision-making landscape.
How can clarity emerge from the fog?
Are there better ways to clarify decisions along the R&D continuum to increase the probability that a molecule directed against a target will have efficacy in humans without compromising safety? Typically, this information is sought through two extremes:
- Profiling approaches (e.g. RNASeq, proteomics, etc.) which create overwhelming amounts of data.
- Assays that were selected based on the putative mechanism and target biology.
The former is difficult to wade-through to discern meaningful information and the latter relies on picking the right markers in advance, which frequently does not occur. Therefore, data that occupies a middle ground between these extremes is needed – something that is comprehensive, meaningful and readily interpreted. Metabolomics data provides a view of these properties and helps to enrich decision making from discovery through the clinic. Hence, small and large biopharmaceutical companies are constantly on the look-out for approaches that deliver this type of data.
Solutions, elixirs, promises
Biopharma companies are routinely bombarded by technologies that promise “the next great thing” that will “revolutionize drug discovery.” Clearly some of these can help incrementally, some will have little utility and some will provide true promise. The question is, how can you discern the best options for your program? One rubric for this is to reflect on what we described above, selecting the method that will deliver clarity through the fog – data that is comprehensive, meaningful and readily interpreted, and data that dynamically assesses a living system and links it to physiological changes induced by disease and drug response. These qualities describe metabolomics data.
Metabolomics provides comprehensive and meaningful insight into each stage of the drug development process, allowing drug developers to attain signals for both safety and efficacy (as well as their associated biomarkers). This capability informs decision-making across the drug development continuum. Importantly, successes driven by these insights accumulate along the way and across programs, suggesting strong potential for metabolomics to aid in reducing drug attrition. In isolated programs, these insights help build confidence, discharge risk and illuminate the value of the program. Regardless to the challenge at hand for biopharma, the Program Development Dossier approach presents the missing link to deliver winning drug programs.
Metabolomic insights empower effective decision-making
Metabolomics enriches R&D decision-making because of the fundamental properties of what it surveys – the metabolome – all the small biochemicals (metabolites) that circulate in the body or in a cell. Metabolomics is particularly important in creating clarity for drug research and development because nearly all the influences that effect physiological processes (disease, target biology, off target activity) affect the metabolome . Hence, measuring with metabolomics provides a consensus report for molecule action in the context of the model being used. Finally, because the metabolome and metabolic pathways are so extensively mapped, this consensus report is readily interpretable.
Image 1:Of course, the fundamental strengths of metabolomics are not new. What is new is that many biopharmaceutical companies have embraced the broadening view that metabolomics is a first-line tool for drug development. This video features leaders sharing their experience with metabolomics and Metabolon.
Enter the Program Development Dossier
Staples of drug research and development are to gain clarity on the effects of the target-molecule combination and obtain biomarkers that can accompany the program into clinical development. The importance of these insights and biomarkers is escalated when pursuing novel molecules and targets or entering a highly competitive space. As described above, metabolomics provides a powerful synergy to the standard data for gaining these important staples.
As companies build their Program Development Dossier – a comprehensive data package that includes detailed scientific insight into the molecule’s mechanism of action (MoA) and relevant clinical biomarkers – layering in informative data and biomarkers from metabolomics will help to build the most robust story to secure funding and move one step closer to approval. Ideally, studies begin in efficacy models, continue through preclinical development, and continue into first in human studies. In this way, the most translatable markers and understanding of the target/molecule combination will occur .
Image 2:Dossier data revealed through Metabolon’s proprietary untargeted metabolomics solution provides the framework to make a stronger, more confident and more valuable case for a molecule in a shorter timeframe and can travel through the drug development process. This dossier is equipped with translatable biomarkers, clarity on how the molecule/target combination is unique. With this type of Program Development Dossier, both large and small biopharma can have access to credible, highly relevant data that clearly demonstrates the potential value of their development program. In addition, this data can help organizations build an infrastructure in the form of translatable biomarkers that can be leveraged for future programs.
Some common questions that are addressed in a Program Development Dossier fueled by metabolomics are:
- Which model is most translatable/relevant?
- Is there a clear pharmacodynamic (PD) and efficacy signal from my animal model?
- Do I have blood biomarkers for monitoring PD and efficacy, including in non-rodent models?
- Will the biomarkers translate to humans?
- Are there any obvious liabilities with the molecule?
- Do I have the data to support a clear, compelling MoA that translates from animal models to humans?
- Is the molecule likely to achieve commercial success based on the competitor landscape?
- Do the biomarkers have potential for selecting sub-groups for trials or identifying responders?
- What is the clearest path for the next development milestone?
Insights from the dossier
Project teams are increasingly using metabolomics to enrich their drug research and development programs to solidify stakeholder support. Importantly, this use is agnostic to the target class (e.g. GPCR, enzyme, nuclear receptor) as it is recognized that nearly all areas of target biology on route to efficacy will impact metabolic pathways. Below are several abstractions from various organizations’ metabolomics-driven Program Development Dossier initiatives. .
Image 3:
Case studies of the Program Development Dossier in action
Markers of acute renal toxicity enable screening less toxic chemotypes
While in early development of a molecule directed at a novel target for lowering cholesterol, metabolomics screening revealed markers associated with acute renal failure in mice. Conventional markers did not clearly signify the issue or explain it. The metabolomic biomarkers provided confidence that the effects were clearly off-target and these markers were used to screen other chemotypes to show that the toxicity was isolated to a particular chemotype. This insight provided a potential way forward for the program. This example highlights the peril of relying solely on established markers as they were ineffective in reflecting and explaining the toxicity. In contrast, metabolomic fingerprinting provided clarity and a way forward .
Simple blood biomarkers for assessing response add to the development toolbox in NASH
Endpoints for nonalcoholic steatohepatitis (NASH) trials have many disadvantages including reliability. Simple blood biomarkers are highly desired. The need is amplified since there are so many novel targets in the NASH pipeline – quickly knowing if the program is heading in the right direction (i.e. hitting the target, signs of efficacy) is critical. Leveraging metabolomics, investigators at Gilead bolstered the confidence that they were on the right track in their successful phase II trial of GS-0976 by discovering several metabolite markers of efficacy. These biomarkers can accompany future development for reading out the pharmacodynamic activity or response of GS-0976 .
Biomarkers of acute inflammatory organ condition in early phase clinical trial delineated by metabolomics
Using metabolomics in clinical development can be beneficial to subtype individuals who respond but also may indicate who will experience adverse events. Metabolomics data showed a clear association with subjects that exhibited severe abdominal pain and inflammation of a specific organ. Over a dozen metabolite markers from two different classes – one related to the primary organ dysfunction and the rest to the activity associated with the inflammation clearly distinguished the group experiencing the adverse event. These metabolites can be used to monitor subjects in subsequent studies for early signs of the adverse event.
Distinguishing mechanism to differentiate molecule in crowded space
One route to finding molecules with novel MoAs is through phenotypic screening. One sponsor had discovered a potent angiogenesis inhibitor with similar potency to an approved drug. Despite it successfully moving through development, the MoA was unknown and Pharmacodynamic biomarkers were lacking. Metabolomics showed that the underlying MoA was clearly distinct from the approved drug and unique to any angiogenesis inhibitor described on the market. This provided a powerful leg-up in distinguishing their molecule from the competitors and identifying PD biomarkers that could accompany it into development.
Summary of what it can do
These examples highlight the importance of adding metabolomics to drug discovery and development programs. The clarifying enrichment and translatable biomarkers provided are clear assets embedded within the Program Development Dossier. The Program Development Dossier is a new companion to ultimately help pick the winners, determine how best to advance them and to demonstrate the value of the program. To learn more about how this approach can help your program read our whitepaper or contact us today to get started.
References:
DiMasi, Joseph A., et al. “Innovation in the pharmaceutical industry: New estimates of R&D costs.” Journal of Health Economics Volume 47, (2016): 20-33. https://www.sciencedirect.com/science/article/abs/pii/S0167629616000291?via%3Dihub
Zgoda-Pols, Joanna R., et al. “Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: investigation of nicotinic acid receptor agonists.” Toxicology and applied pharmacology 255.1 (2011): 48-56.
Wang, Ganfeng, and Walter A. Korfmacher. “Development of a biomarker assay for 3‐indoxyl sulfate in mouse plasma and brain by liquid chromatography/tandem mass spectrometry.” Rapid Communications in Mass Spectrometry: An International Journal Devoted to the Rapid Dissemination of Up‐to‐the‐Minute Research in Mass Spectrometry 23.13 (2009): 2061-2069.
Loomba, Rohit, et al. “GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.” Gastroenterology 155.5 (2018): 1463-1473.
Charlton, Michael, et al. ” Serum Acylcarnitines Are Biomarkers of Magnetic Resonance Imaging‒Proton Density Fat Fraction Response in NASH Patients Treated With the ACC Inhibitor Firsocostat (GS-0976).” Presented at EASL: The International Liver Congress™ 2019, April 10–14, 2019, Vienna, Austria
Tier 1 Metabolite Identifications: A Compass to Rich Research Insights
Research is like a treasure hunt. Without the right navigation tools, precious time is spent on trial and error exploration to find the right path, increasing the cost as well as the risk of program failure. Metabolomics provides uniquely valuable guidance for navigating a biological system, but the signal-to-noise ratio from vast amounts of data can cloud your ability to see the actionable insight.
In untargeted metabolomics, the critical step to separating noise from insight is accurate metabolite identification (often also called annotation). As pointed out by Schrimpe-Rutledge et al, “metabolite annotation is the crucial link between acquired data and meaningful biological information.”Phrased another way, the biological insight from a study is only as good as the metabolite annotation – if you want the highest quality metabolomic insight you need the highest quality annotation. In recognition of this fact, Sumner et al proposed a schema for stratifying the quality of metabolomic annotations. Tiers, or levels, ranging from 1 to 5 are commonly used to convey metabolite identification confidence. Tiers refer to the level of detail for each metabolite, and thus the assigned confidence for accurate identification. Tier 5, the lowest level of identification, offers a unique feature in the metabolite, but lacks the information required for confirmation. Through increasing precision measurement, additional unique characteristics are discoverable enabling a definitive identification of the molecule to be made. It is not until the appropriate level of detail is reached in Tier 1 that definitive compound identification based on multiple orthogonal measurements and comparison to data from an authentic standard can be achieved. Therefore, Tier 1 identifications represent the highest level of confidence in the annotation. Tiers 2 through 5, on the other hand, represent decreasing levels of confidence based on less rigorous or more ambiguous criteria.
While most metabolomic practitioners operate primarily with annotations that only meet the standards of Tiers 3-5, Metabolon’s Precision Metabolomics™ workflow is uniquely designed to deliver Tier 1-2 identifications for detected metabolites. This unique level of confidence in the annotations is made possible by Metabolon’s use of a chemocentric approach to metabolomics that uniquely detects metabolite features and matches them against Metabolon’s vast in-house library. Metabolon built this library through the analysis of >5,000 authentic standards run in-house using our methods and instruments. This approach to untargeted metabolomics means that all metabolite annotations meet the stringent criteria required for a Tier 1 or 2 identification.
Our method stands in stark contrast to the more traditional metabolomics workflow in which the individual ion features, the instrument signal from a mass spectrometer, undergo statistical analysis. Only the most significant are subjected to an attempt at a high Tier identification. Metabolon’s approach leverages this vast library to ensure accurate annotation of not only the metabolites, which show statistically significant changes in a study, but also those which remain unchanged, and therefore add crucial insight into the underlying biology.
The field of untargeted metabolomics continues to expand due to its growing track record of providing a crucial understanding of biological processes including aging, disease, and the role of the microbiome in health. Metabolon sets the standard in delivering high-quality metabolomic data. By harnessing the power of our extensive library and delivering metabolite measurements with Tier 1 identifications, Metabolon leads the way to unlocking the information stored in the metabolome and revealing the contained biological story.
To learn more about how metabolomics can help you uncover actionable insights with our Precision Metabolomics platform, contact us at [email protected].
References: