The Power and Promise of Pharmacogenomics

Sponsored by THE PROMISE AND POWER OF PHARMACOGENOMICS Page 3 Pharmacogenomics: Driving progress in precision medicine Page 4 Tools and technologies for pharmacogenomics Page 5 Bridging bench and bedside with pharmacogenomics Page 6 Pharmacogenomics: Scalable techniques and actionable insights © 2022–2024 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified. COL028293 0624 Learn more at thermofisher.com/here Guide clinical decision-making with pharmacogenomic molecular testing, enabling more effective patient outcomes Pharmacogenomics (PGx) can lead to better overall quality of care by making sure that medications are prescribed with the specific individual in mind, rather than guessing what may work best under the “standard of care” paradigm. PGx helps provide a better understanding of how variations in key areas of an individual’s genome may impact the efficacy of a medication, dosage considerations, and potential adverse drug reactions (ADRs). Thus, PGx can become a vital piece of the overall healthcare puzzle. Scan or click here to explore qPCR research solutions for PGx THE PROMISE AND POWER OF PHARMACOGENOMICS 3 PHARMACOGENOMICS: DRIVING PROGRESS IN PRECISION MEDICINE The push for more precision therapeutic discovery drives scientists to develop novel drugs tailored to patient-specific needs. Many factors influence interindividual therapeutic outcomes, including drug toxicity and efficacy, which vary between patients and disease states. Pharmacogenomics (PGx) is an ever-growing field in precision medicine, helping researchers optimize translational findings and define targeted success on a case-by-case basis.1 What is pharmacogenomics? PGx is a subset of precision medicine that focuses on the genetics behind pharmaceutical interactions, toxicities, and efficacies.2 In this field, researchers investigate how an individual’s genetic makeup modulates therapeutic response-related factors, such as drug metabolism and off-target effects.1 Interindividual response variability is a complex phenomenon related to age, environment, lifestyle, and genetics. This variability significantly challenges successful drug discovery and clinical translation. However, researchers may improve drug development success rates by incorporating genomic data into their workflows, such as selecting genetically supported targets, identifying disease driver mutations, or considering germline genetic variations that predict drug toxicity.1 PGx helps scientists predict effective drug doses, improve efficacy, prevent adverse drug reactions, and develop more targeted treatments.1 Addressing therapeutically relevant research questions Scientists estimate that efficacy rates vary broadly between different drugs, ranging from 25-80% effective, with some of the most used therapeutics failing more patients than they help.1 Additionally, variable adverse drug reactions are global healthcare burdens that contribute to costly drug toxicity and clinical development failures.1 PGx allows researchers to address these dilemmas with genetic explanations and solutions.2 Genetic variation influences drug metabolism. As a result, PGx can help scientists determine the personalized safe and effective dose of new or approved therapies. For example, polymorphisms in the gene CYP2C9 affect its encoded enzyme’s ability to metabolize the anticoagulant medication warfarin. This informs clinical decisions to administer lower warfarin doses for patients with these polymorphisms, avoiding overexposure and achieving therapeutic success.1 Researchers apply this concept to drug discovery and development across many disease states, including anticancer drugs, antidepressant and antipsychotic medications, and pro-drugs such as pain management and cardiovascular disease therapies.1,2 PGx research also goes hand in hand with other key aspects of drug pharmacodynamics and pharmacokinetics beyond metabolism, including drug absorption, distribution, and excretion.1,2 These are critical medicinal chemistry benchmarks for scientists developing and optimizing therapeutic candidates.1,2 Many in vitro and in vivo investigations have demonstrated that genetic factors play an important role in determining interindividual pharmacokinetics, such as monozygotic and dizygotic twin studies that revealed heritable pharmacokinetics for medications used to treat heart, renal, and liver disease.1 PGx testing may also provide opportunities for genetically informed early interventions related to lifestyle and environmental risk factors and disease susceptibilities, such as introducing diagnostics and treatments at the right time for the right person to maximize therapeutic benefit.3 A blossoming research field Although genetic factors do not account for all therapeutic response variability, PGx holds promise to help scientists move away from a one-size-fits-all mentality in drug development, enabling more personalized treatment choices and drug doses, and successful translational applications.1 The therapeutic utility of PGx stems in large part from scientific progress identifying molecular pathways associated with drug pharmacokinetics and pharmacodynamics, and evidence that interindividual genetic studies can yield controllable research questions and answers. PGx encourages researchers to continue exploring new drug discovery and development avenues.2 In addition to its growing relevance in academic research settings, PGx investigations may improve patient outcomes and enable more clinical implementation of genomics in future precision medicine. This can help reduce the economic burden of adverse drug reactions by helping the right medication reach the right patient at the right time, with less trial and error.1 See references on page 8 THE PROMISE AND POWER OF PHARMACOGENOMICS 4 TOOLS AND TECHNOLOGIES FOR PHARMACOGENOMICS Following the footsteps and findings of the Human Genome Project, scientists use and develop genetic technologies to optimize therapeutic response through pharmacogenomics (PGx).1 Technological advances, stateof-the-art testing platforms, optimized methods, and standardized laboratory practices help researchers make clinically relevant and genomically informed choices during targeted therapeutic development.2 History of PGx insights Over the past two decades, PGx research has driven successful precision medicine efforts, progressing the field into standard of care applications and paradigm shifting drug discovery. Early PGx studies established drug–gene variant pairs as fundamental units of precision medicine, centering pharmacokinetic, pharmacodynamic, and genetic mechanisms that provide insight into personalized drug dosing.2 These initial steps toward present-day PGx applications were largely taken by global experts in specific disease fields at academic medical centers. As a result, DNA testing lacked regulatory oversight and standardization and was not widely adopted across clinical and translational research laboratories.2 Alongside increased inclusion of genetic information on drug labels in the late 1990s and early 2000s, new technologies for genome-wide marker arrays, data management, and sequencing instigated more standardized and regulated PGx-guided drug development.2,3 These techniques ultimately replaced inefficient and manual laboratory practices for DNA extraction, Sanger sequencing, and variant determination, enabling technical scalability in the PGx field.2 Power in the present Scalable technologies and evidence-supported best practices for large scale genome-informed breakthroughs have emerged as key PGx tools. Advances in genotyping and sequencing enable standardized, regulated, and efficient data production.2 For example, high throughput techniques including real-time PCR, microarrays, and whole genome sequencing offer researchers speed and scalability and provide a foundation for automated variant detecting methods.2 Fully established PCR-based methods for PGx help achieve industrial genotyping efficiency. Real-time PCR technological advances contribute to scalable, off-the-shelf assays that detect genetic variation related to drug metabolizing enzymes, transporters, and receptors.2 For instance, in multicenter studies such as the INGENIOUS and PREPARE trials, scientists used PCRbased genotyping of known actionable alleles to investigate PGx predictors of adverse reactions for drug–gene pairs involved in pharmaceutical metabolism, enabling genotype-guided therapeutic dose considerations.2,4,5 Promise of the future Many commonly prescribed drugs and those in development pipelines lack efficacy or produce serious adverse reactions for subsets of patients. Globally, adverse reactions are substantial disease burdens that significantly contribute to healthcare costs. Factors such as dosage, administration frequency, and patient genotype influence the likelihood of a drug causing an adverse reaction, which may lead patients to switch or discontinue treatment.6 Advances in PGx technology may help remedy these costly drug development and prescription pitfalls for pharmaceutical, industry, and academic researchers alike.7 PGx is expected to continue providing personalized medicine solutions in drug development, helping scientists optimize doses, avoid toxicities, simplify clinical trials, and increase successful drug development rates. Researchers may also use PGx methods for biomarker discovery, turning to the latest technologies such as genotyping panels and next-generation sequencing to search for novel clinically relevant targets.1,2 Large scale research projects made possible by the new genetic technologies continue to innovate and inform PGx testing for precision medicine.2 Future opportunities to build best-practices in PGx research include tailoring and reporting allele variation frequencies across diverse population samples to broaden drug discovery and development horizons.2,8 Finally, the recent upsurge in pointof-care testing driven by the covid pandemic, such as PCR-based viral genotyping, underscores the unique potential and power of rapid and scalable molecular diagnostic platforms. Current technologies and future tools can be expected to provide quick, actionable results and routine PGx testing with fast turnaround for clinically relevant precision medicine applications.2 5 F or the first fourteen years of her career, Dr. Becky Winslow practiced as a clinical pharmacist and directed pharmacy operations. She became interested in pharmacogenomics (PGx) eleven years ago when she first worked as a clinical science liaison between a PGx laboratory and clinicians using their PGx test. Dr. Winslow was impressed by PGx’s potential to improve the negative medication outcomes she witnessed patients experience while practicing pharmacy. In the barriers holding PGx from helping more patients, she saw opportunities to repurpose her education, work experience, and skills to move PGx towards being a standard laboratory test prescribers use to manage medications. Finding success in PGx consulting, she rebranded her original clinical pharmacy consulting business to inGENEious RX. Since then, as a PGx Subject Matter Expert and Head Consultant at inGENEious RX and co-host of the Precision Health and PGx Podcast, Winslow has supported PGx stakeholders in various capacities, using her scientific and clinical education to bridge the gaps in PGx between the bench and the bedside. Q: Why is PGx important in the context of translational research? Translational research is a systematic effort to convert basic research knowledge into practical applications to enhance human health. PGx research is a type of translational research, and I would say PGx is the epitome of applying scientific discoveries made in the laboratory to real world medical practice. PGx is an interdisciplinary field, starting at the bench with researchers, and including clinicians, patients, policymakers, and payers. For example, laboratory research outcomes include published guidelines for how to use PGx in the clinical setting. Those guidelines started at somebody’s lab bench; we would not have them without scientists. Q: What types of tools enable PGx research? PGx research in a laboratory setting involves a variety of tools and technologies to analyze genetic variations and their effect on drug response. Sanger sequencing is a first generation DNA sequencing method. Researchers use this method to clinically test for single base pair changes or identify small insertions and deletions when they suspect variants in a known gene-linked disease. It is the gold standard for confirming genetic variants quickly in a cost effective manner for a low number of targets but would not likely be used for large sample numbers. Next generation sequencing (NGS) is massive parallel sequencing that revolutionized genomic research. It can identify more variants than traditional Sanger sequencing and provide information on the full genomic variation spectrum in a single experiment. It can also identify unknown and completely novel variants. NGS technologies enable researchers to sequence entire genomes or specific regions of interest in a quick and cost effective manner. Microarrays are another genotyping technology used to analyze large numbers of variants simultaneously. For example, microarrays are useful in large scale studies to identify genetic variants associated with drug response traits or adverse drug reactions. This method can detect single nucleotide polymorphisms, as well as copy number variations. Lastly, PCR is a genotyping technology that amplifies millions to billions of copies of a specific segment of DNA that contains genetic variants of interest, such as single nucleotide polymorphisms or insertion or deletion mutations. PCR products can also be used to determine the presence or absence of specific genetic variants. By quantifying gene expression levels, researchers can investigate how genetic variants influence gene expression profiles and subsequent drug response phenotypes. It is useful for detecting rare genetic variants and analyzing smaller sample volumes through target amplification. Q: What are the challenges and considerations that PGx researchers face? Study design and clinical implementation are challenges because of the complexity of genetic variation. Researchers must navigate that complexity to identify clinically relevant genetic markers associated with drug efficacy, safety, and toxicity. Drug response, for example, is multifactorial. It is important to control for nongenetic factors such as environmental and lifestyle factors that complicate the interpretation of PGx data. Another challenge is validation and reproducibility. Robust validation of pharmacogenetic associations is essential to ensure that study findings are reliable and reproducible. Large scale replication studies in diverse populations are needed to confirm the clinical utility of genetic markers. Researchers must also adapt to a constantly changing regulatory environment and develop infrastructure to store and translate research data. Q: What excites you about the future of PGx research? PGx research will continue to catalyze innovation in drug development, drug repurposing, and gene editing, fostering safe and effective medication invention and possibly eliminating the need for medication. A world in which toxic and nontherapeutic medication outcomes and their costs to healthcare stakeholders, patients specifically, are reduced or extinct is extremely exciting to me as my career goal has always been to improve others’ lives. This interview has been condensed and edited for clarity. THE PROMISE AND POWER OF PHARMACOGENOMICS BRIDGING BENCH AND BEDSIDE WITH PHARMACOGENOMICS An interview with Becky Winslow, PharmD Pharmacogenomics Subject Matter Expert, Head Consultant Above image: Becky Winslow, PharmD Courtesy of Luke Hastings, Video In Progress LLC Many factors affect how a patient responds to a drug. Pharmacogenomics (PGx) is a subset of precision medicine that focuses on the genetics behind different pharmaceutical interactions, toxicities, and efficacies. PGx improves drug discovery and development by helping scientists determine the right medication, dose, and lifestyle considerations for a given intervention. Many therapies in drug development pipelines miss the mark, producing serious adverse side effects or no therapeutic benefit for subsets of patients. PGx holds power and potential to help remedy costly drug development pitfalls for pharmaceutical, industry, and academic researchers and reduce the economic and healthcare burden of adverse drug reactions. Technological advances and high throughput techniques including real-time PCR, microarrays, and whole genome sequencing offer scientists speed and scalability in PGx research and create a solid foundation for future methods. This includes off-the-shelf assays that detect actionable drug– gene variation pairs and biomarkers involved in adverse reactions and therapeutic success. PHARMACOGENOMICS: Scalable techniques and actionable insights On-Demand Webinar Laboratories use the same laboratory equipment they invested in for COVID testing to perform PGx testing. With COVID testing reimbursement changing, many laboratorians are considering implementing PGx testing. PGx test panel design and test utilization that align with payers’ medical necessity definitions are key to pharmacogenomics laboratories’ financial viability and sustainability. Flyer: Medicines Impacted by Genetics Medicines can lead to a potential drug–gene interaction, but PGx can help reduce that risk. This resource is intended to help guide decision-making selecting pharmacogenomics (PGx) panels for the research of common medications. Whitepaper: Integrating pharmacogenomics into the standard of care Discover the benefits and strategies for integrating pharmacogenomics into standard care to optimize treatment decisions and improve patient outcomes. Infographic Get the facts on the importance of PGx testing and the impact PGx can have on medication management. Watch Now Download Now Download Now Download Now THE PROMISE AND POWER OF PHARMACOGENOMICS 8 Article 1: Pharmacogenomics: Driving progress in precision medicine 1 ) Pirmohamed M. Pharmacogenomics: Current status and future perspectives. Nat Rev Genet. 2023;24(6):350-362. 2 ) Jarvis JP, et al. Maturing pharmacogenomic factors deliver improvements and cost efficiencies. Camb Prism Precis Med 2022;1. 3 ) Aneesh TP, et al. Pharmacogenomics: The right drug to the right person. J Clin Med Res. Published online 2009. doi:10.4021/ jocmr.v0i4.207 Article 2: Tools and technologies for pharmacogenomics 1 ) Pirmohamed M. Pharmacogenomics: Current status and future perspectives. Nat Rev Genet. 2023;24(6):350-362. 2 ) Jarvis JP, et al. Maturing pharmacogenomic factors deliver improvements and cost efficiencies. Camb Prism Precis Med 2022;1. 3 ) Tutton R. Pharmacogenomic biomarkers in drug labels: what do they tell us? Pharmacogenomics. 2014;15(3):297-304. 4 ) Swen JJ, et al. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: An openlabel, multicentre, controlled, clusterrandomised crossover implementation study. Lancet. 2023;401(10374):347-356. 5 ) Eadon MT, et al. The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial. Pharmacogenomics J. 2023;23(6):169-177. 6 ) Sultana J, et al. Clinical and economic burden of adverse drug reactions. J Pharmacol Pharmacother. 2013;4(1_ suppl):S73-S77. 7 ) Harper A, Topol EJ. Pharmacogenomics in clinical practice and drug development. Nat Biotechnol. 2012;30(11):1117-1124. 8 ) Martin A, et al. An assessment of the impact of pharmacogenomics on health disparities: a systematic literature review. Pharmacogenomics. 2017;18(16):1541-1550. References © 2024 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified. COL028295 0624 Learn more at thermofisher.com/pgx The future of health care may include factoring genetic test results into treatment decisions. Applied Biosystems™ products help drive pharmacogenomics advancements, and we continue to participate in collaborations to make it accessible for laboratories, employers, and government agencies.