12May

New Hope for Patients with Inborn Errors of Metabolism and Rare Diseases

May 12, 2020 Metabolon

Sometimes, there is no playbook. That’s often the case with inborn errors of metabolism (IEM), defined as rare genetic disorders that cause alterations or deficiencies in enzymes involved in metabolism, and other rare diseases. A patient may exhibit clinical signs that don’t map to specific disorders, or a screening panel may come back with no clues. In these frustrating situations, clinical researchers – and patients – need more places to turn for answers.

Applying metabolomics to clinical samples can help screening efforts by vastly expanding the information available to clinical researchers. When used in a clinical setting, metabolomics can measure small molecules in large volumes to identify potential biological pathways that are disturbed in diseased patients. While whole-exome sequencing has provided a valuable systems-based approach in the clinical laboratory, a recently published paper describes a clinical metabolomics approach to drive precision medicine forward, as a method for the screening of metabolic diseases through the analysis of a multi-pronged mass spectrometry platform. In the paper, authored by a team of 11 Metabolon scientists featured in the March 2020 issue of The Journal of Applied Laboratory Medicine, the authors assert that by simultaneously measuring hundreds of metabolites in a single sample, clinical metabolomics offers a comprehensive approach to identify metabolic perturbations across multiple biochemical pathways.

To arrive at their conclusions, the authors performed a single- and multi-day precision study on hundreds of metabolites in human plasma on four, multi-arm, high-throughput metabolomics platforms. This resulted in the reproducibility of the method for the measurement of key IEM metabolites in patient samples across multiple analytical batches, proving the method to be robust and reproducible for the screening of patients with previously undiagnosed inborn errors of metabolism.

Clinical metabolomics has the potential to make precision medicine a reality delivering transformational medicine. Traditional clinical testing of patient samples involves analyzing and measuring individual analytes or biomarkers. In the case of IEM’s, the screening method typically includes three panels, which measure in the range of 50-60 small molecules. Metabolon’s application of clinical metabolomics extends the number of biomarkers that can be measured significantly. Instead of 50-60, we can identify more than 500 small molecules, giving researchers a broader range of biomarkers to mine for insights.

The application of metabolomics is exceptionally significant for IEM and rare disease detection. There are hundreds of IEM diseases, and often the clinical manifestations of those diseases are vague, or the metabolic pathway that is disturbed is not immediately apparent. Applying global, or untargeted, analytical approaches, where prior knowledge of the affected metabolic pathway is not required, provides advantages over targeted analytical approaches and can extend the diagnostic potential of IEM screens beyond the 34-58 disorders that are currently evaluated in newborn screening programs, especially in complex cases. That makes throwing out this wide net to measure as many biomarkers as possible invaluable in a clinical setting.

When evaluating large quantities of information, it is paramount to make data quality a top priority. A critical step in drawing insights from untargeted metabolomics is accurate metabolite identification. Metabolon’s Precision Metabolomics™ workflow delivers Tier 1-2 identifications for detected metabolites and uniquely provides high confidence in the identification of compounds. By contrast, most metabolomic practitioners operate primarily with annotations that only meet the standards of Tiers 3-5, where some unique features are identified. Still, there is low confidence in confirming the metabolite. Data quality is extremely important to Metabolon, with exceptionally high standards applied to our work in clinical metabolomics. From start to finish, we emphasize quality control measures and checks and balances.

Metabolon’s method of clinical metabolomics is validated by Clinical Laboratory Improvement Amendments (CLIA), a regulatory standard for all testing of patient samples. 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. Additionally, Metabolon has a New York State Department of Health Clinical Laboratory permit to perform Quantose IR and IGT testing for the identification of insulin resistance and impaired glucose tolerance under the categories of Clinical Chemistry and Endocrinology.

In addition to the validation work we do to demonstrate the properties of the method, such as precision and accuracy, we also run the method under very specific quality control guidelines, which are even stricter than our research guidelines, including running batch controls for each of the analytic batches. We start by setting up the assays following policies that dictate how to establish a reference population, how you qualify the normalizing matrix, and so on. The typical regulatory requirements for review of the results is exceeded, with an additional analytical and lab director review in addition to our typical sub-level review. All of these steps ensure data quality and accurate insights.

Applying our expertise to clinical metabolomics is just one example of how Metabolon reveals biological insights otherwise unseen through other technologies by leveraging our proprietary discovery platform and one of the world’s richest and most diverse patient data sets. We are unique in our ability to receive samples, process them under a clinically validated metabolomics platform that’s controlled for clinical testing, and provide impactful results. Expanding the capabilities of metabolomics to the clinical setting has enormous potential for researchers and patients alike.

Curious about how metabolomics could enrich your study? Contact us today at hello@metabolon.com to learn more.

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04May

Stool Sample Collection: A Bottleneck to Gut Microbiome Research

May 4, 2020 Metabolon

Our gut microbiota is rich with biological insights, which can help clinical investigators better understand factors that influence both sickness and health. But despite its huge importance, this area of research is plagued by challenges. Stool samples from a diverse patient set are needed for researchers to gather valuable insights. Yet, collection, storage, and shipping issues constrain the quantity and quality of testable material. A new approach is needed to help researchers more fully explore the clues that live in the intestinal microbiota.

To appreciate the challenges – and opportunities – associated with gut microbiome research, we sat down with our internal expert Dr. Lisa Freinkman, R&D Staff Scientist, as well as Scott Rabuka, Senior Director, Molecular Products at DNA Genotek Inc., an experienced leader in molecular collection solutions for microbiome applications, to address some key questions.

Why is studying the gut microbiome so important?

Dr. Freinkman: The gut microbiome is composed of the microbes, primarily bacteria, that live in our digestive tract. These tiny organisms not only help break down our food, but also play an important role in other areas of our health, especially the development and regulation of the immune system. Therefore, it’s no surprise that gut dysbiosis contributes to metabolic disorders, including obesity, diabetes, as well as to diseases that involve unhealthy immune responses centered on the gut, such as Crohn’s disease and inflammatory bowel disease. Perhaps less obvious is the emerging association between the gut microbiome and neurological disorders, including autism, epilepsy and Parkinson’s disease, through the gut-brain axis. The list of diseases and conditions linked to specific gut flora continues to expand, with new scientific discoveries emerging nearly every week. But in most cases, we are missing key information about how gut microbiota exert their effects on the host to promote either health or disease. Direct analysis of gut microbiota composition in the fecal metabolome is critical in order to decipher this functional information, and that’s where microbiome research presents some special challenges.

To learn more about the importance of the gut microbiome, check out our recent interview with Dr. Sean Gibbons from the Institute for Systems Biology.

What are some of the challenges with feces sample collection?

Mr. Rabuka: The biggest challenge most researchers face when collecting fecal samples is the cold-chain requirement associated with the transport and storage of the samples. They must get the samples from the donor to the lab while maintaining temperature-controlled shipping conditions. This forces researchers to request that donors collect their samples on-site in the lab or in a clinical setting. Alternatively, home collection requires expensive packaging, ice-packs, and costly, temperature-controlled courier services in addition to the inconvenience of donors having to store collected sample(s) in their home freezers. What’s worse, from our years of experience in the gut microbiome space, we know that these cold-chain transport methods are often still inadequate at providing the temperature stability required to ensure the integrity of the sample between the time of collection and the time of sample processing in the lab. A lack of temperature stability means that the microbial profile analysis from these samples will include inherent biases, negatively affecting the accuracy of the metabolomic signature.

Traditionally, fecal samples are collected either in plastic specimen containers using a wooden stick, in a tube including an integrated spoon attached to the lid, or through a very basic plastic ice-cream type container. None of these offer any homogenization of the sample at the time of collection and make the subsequent sample extraction step laborious. The lack of homogenization also introduces biases through improper distribution and lack of uniform surface contact between the sample and the stabilizer, if present. This can lead to inadequate stabilization action of the chemistry, leaving portions of the fecal sample prone to microbiome profile changes associated with post-collection microbial growth and/or decay during transport and storage.

We also have to think about the individuals asked to provide the samples. It is extremely difficult, if not impossible, to collect these samples on demand. Most donors are incapable of producing a sample if asked to do so within a short amount of time. Fecal sample collection does not compare to any other human sample type: blood, saliva, or urine. Because of this, allowing donors to collect samples from the privacy of their own homes is crucial for successful studies.

Although snap-freezing (e.g., use of dry ice or liquid nitrogen to freeze the sample) is the “gold standard” for fecal metabolomics analysis, this method may limit the cohort enrollment to participants who will be able to collect and bring samples to the lab or clinic within a very restricted timeframe (usually a few hours) or alternatively will have to come on-site to collect and provide their samples. This restricts the number of potential participants, especially when trying to collect from individuals who have health conditions or mobility impairments.

What can we learn from the intestinal microbiome through metabolomics?

Dr. Freinkman: Metabolomics is the systematic measurement of hundreds to thousands of small molecules, or metabolites, in biological samples. In every cell and organism, metabolites serve as the currency of energy harvesting and storage, as well as the building blocks of DNA and protein, among many critical functions. But, within the context of the gut microbiome, another key property of metabolites is their ability to work as chemical signals, especially among microbial cells and between microbes and their hosts. From a gut microbe’s point of view, metabolites are great signaling molecules because, compared to protein and nucleic acids, small molecules are less energetically costly to produce, easier to export out of the cell, typically more stable in the extracellular environment, and less likely to trigger a host immune response. That explains why so many of the gut microbiome’s known effects on our health are mediated by metabolites. Therefore, from the researcher’s standpoint, metabolomics can provide the key causal link between the composition of the gut microbiome – usually derived from metagenomic sequencing – and the phenotype of interest. This mechanistic understanding can form the basis for rationally designed treatments to support a healthy gut, such as supplementing a patient’s diet with a beneficial small molecule or inhibiting a microbial enzyme to prevent the formation of harmful metabolites. Knowing which metabolites are behind the microbiome’s role in a particular disorder can also provide a way to monitor the effectiveness of any treatment. For all these reasons, metabolomics provides a much more complete and actionable understanding of the gut microbiome than metagenomic analysis alone.

Mr. Rabuka: Many investigators studying the human gut microbiome have generated fantastic amounts of data on the microorganisms that may be present in people’s gastrointestinal tract and the impact that these microbial communities can have on their health status. Nonetheless, knowing which microorganisms are present is often insufficient in allowing us to truly understand what biological and biochemical pathways are active and what chemical product they are releasing into their environment. If we want to regulate or modify effects caused by or modulated by the gut microbiota, we need additional information regarding these said pathways.

For example, many studies in the fecal microbiota transplant space have shown that inactivated gut bacteria present in a fecal sample, when transplanted into another individual via fecal material transfer (FMT), can cause a significant and clinically relevant change in their state of health. This clearly suggests that not only the microorganisms but also the accompanying compounds, substrates, by-products, etc. influence a body’s response to the transplant. Unless we can understand how each component present in the fecal matter is produced and how they can directly interact with the host’s biological processes, we can only see one part of the equation. Metabolomics provides us with an additional layer of insights crucial to a broader, more accurate interpretation and understanding of the microbiome.

Ready to see what new insights metabolomics can help your research reveal? Contact us today at hello@metabolon.com to learn more.

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28Apr

Delivering Clinical Insights with Targeted Biomarker Assays

April 28, 2020 Metabolon

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 hello@metabolon.com to get started.

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16Dec

Metabolon reveals a new ally for drug research and development programs: Picking program winners and demonstrating their value

December 16, 2019 Metabolon

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[1] 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 [Image 1]. 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].

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. [Image3].

Image 3:

Metabolon reveals a new ally for drug research and development programs: Picking program winners and demonstrating their value

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 [REF 2 and 3].

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 [Ref 4 and 5].

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 or contact us today to get started.

References:

[1] 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

[2] 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.

[3] 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.

[4] 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.

[5] 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

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