Application of Pharmacogenomics on Drug Discovery and Development

CONTINUING PROFESSIONAL CONTINUINGDEVELOPMENT MEDICAL EDUCATION

Akreditasi PP IAI–2 SKP Application of Pharmacogenomics on Drug Discovery and Development

Ratih Dewi Yudhani Pharmacology Departement, Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia

ABSTRACT Individual variations in the response to drugs and drug toxicity occur commonly in the clinical setting and in drug development research protocols. Cumulative evidence strongly suggests that genetic polymorphisms in drug metabolizing enzymes, transporters, receptors and other drug targets are contributing to inter-individual diff erences in the effi cacy and toxicity of drugs. Pharmacogenomics refers to the application of genome-wide approaches in order to understand genetic infl uence on drug response and to develop novel drugs. This application of pharmacogenomics has implications in predicting a patient’s response to medications, reducing adverse events and improving rationality of drug development. Pharmacogenomics profoundly change the way clinical drug trials are conducted, as well as infl uencing drug development process. This review provides an overview of the pharmacogenomics application on drug discovery and development.

Key words: Pharmacogenomics, drug, discovery, development

ABSTRAK Variasi respons individual dan toksisitas terhadap obat sering ditemui di klinik dan selama proses penelitian dan pengembangan obat baru. Beberapa bukti jelas mengindikasikan bahwa polimorfi sme genetik pada gen-gen yang meregulasi ekspresi enzim yang terkait dengan metabolisme obat, transporter, reseptor, dan target obat yang lain, berperan dalam menentukan perbedaan efi kasi dan toksisitassuatu obat di antara individu. Farmakogenomik mengacu pada aplikasi genomik untuk memahami pengaruh genetik pada respons obat dan aplikasinya dalam proses penelitian dan pengembangan obat baru. Farmakogenomik dapat diaplikasikan untuk memprediksi respons individu terhadap pengobatan, mengurangi kejadian yang tidak diinginkan terkait dengan pemberian obat dan meningkatkan rasionalitas dalam proses pengembangan obat. Karena itu, farmakogenomik menyebabkan pergeseran paradigma terkait penelitian dalam rangka penemuan obat baru di tahap preklinik dan bagaimana perancangan uji klinis obat. Tinjauan ini memberi gambaran aplikasi farmakogenomik pada proses penelitian dalam rangka penemuan dan pengembangan obat baru. Ratih Dewi Yudhani. Aplikasi Farmakogenomik dalam Penemuan dan Pengembangan Obat.

Kata kunci: Farmakogenomik, obat, penemuan, pengembangan

INTRODUCTION Although ‘pharmacogenomics’ and the older drug discovery research and the development Pharmacogenomics is a science of determining term ‘pharmacogenetics’ are often used process, and are improving the strategies how genetic variability infl uences physiological interchangeably, pharmacogenomics is of medical care. The Human Genome and responses to drugs, from absorption and broader in scope, and refers to the complex International HapMap project has opened metabolism to pharmacologic action and interactions of genes across the genome. the chance for new generation of diagnostics therapeutic eff ects.1 Pharmacogenomics Pharmacogenomics includes identifying tools aimed at identifi ying and characterizing refers to the application of genome-wide candidate genes and polymorphisms, human diversity. In particular, they have approaches in order to understanding genetic correlating these polymorphisms with possible provided a large resources of SNPs that infl uences on drug response and to developing therapies, predicting drug response and explain much of variation between diff erent novel drugs. Historically, pharmacogenetics clinical outcomes, reducing adverse events individuals and diff erent ethnic groups. studies were developed initially to and selecting dosing of therapeutic drugs on The diff erences in response to medications understand individual diff erences in drug the basis of genotype.3 are often greater amongst members of a pharmacokinetics and metabolism, and were population than they are within the same often focused on single gene polymorphisms In the 21st century, emerging genome science person or between monozygotic twins. The (SNPs), especially in drug metabolism genes.2 and technologies are shifting the paradigm of existence of large population diff erences with

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small intra-patient variability is consistent with the idea of genetic inheritance as a determinant of drug response.4

The source of individual variation in response to drugs may be SNPs or mutations.5 SNPs are abundant in the human genome and may aff ect the pharmacokinetics and pharmacodynamics of a drug.6 Cumulative evidence strongly suggests that genetics polymorphisms in drug metabolizing enzymes, transporters, receptors and other drug targets are contributing to inter individual diff erences in the effi cacy and toxicity of drugs.4 Individuals respond diff erently to drugs and sometimes the eff ects are unpredictable. The use of pharmacogenomics is to identify genetic polymorphisms that predispose patients to adverse drug eff ects, although Figure 1 Pharmacogenomics involment in the drug discovery and development process they may occur in only a small subset of the Abbreviation people treated with a new drug. Given the FTIH : First in Human GCP : Good Clinical Practice potential value of knowing all the possible POC : Proof of Concept GPMSP : Good Post-Marketing Surveillance Practice factors that infl uence the eff ects of new Reg : Regulatory assessment PK : Pharmacokinetics agents, it is likely that pharmacogenomics will LCM : Life CycleManagement have an increasingly important role in drug discovery and development.7 This paper is during clinical trials. In current times, the in a vital pathway, a receptor, a transporter, a addressing the pharmacogenomics and its scenario has changed and with the availability protein in signal transduction or any protein application in the process of drug discovery of sophisticated pharmacogenetic tools, the produced in a pathological condition. After and development. attrition rate can be signifi cantly reduced. sequencing of the human genome, the This will be translated into reduction in loss number of drug target was estimated to be DISCUSSION of fi nancial resources for drug development. around 8000 and 4990 out of which could The process of drug development includes With in vitro methods, it can be identifi ed be actually acted on.12 These targets are pathway identifi cation and target selection, during preclinical studies, whether the drug known to exhibit variations owing to genetic screening of chemical compounds, drug is metabolized by polymorphic enzymes, and polymorphisms, and drugs which are based development, preclinical and clinical studies, a decision regarding continuation of the trial on targets showing wide polymorphisms and also drug marketing.8 The promise of can be made. This information can also help can have variations in their eff ect13. This can pharmacogenomics is that it will solve two in selecting appropriate patients with normal lead to inconsistent results in the preclinical major problems in healthcare, the diminishing metabolizing enzymes in phase I clinical trial, and clinical studies. Thus, the targets can be productivity of the drug development process it can also help prevent adverse events.10,11 characterised based on pharmacogenetic and the unacceptably high proportion of studies and suitable drug compounds selected patients who receive either no benefi ts The implementation of pharmacogenomics for further investment at an early stage.8 from drugs or experience adverse events. Its in effi cacy and safety studies has impacted proponents suggest that pharmacogenomics a broad spectrum of drug discovery and In most cases, variation in drug response will be part of a fundamental transformation in development activities. Figure 1 shows in a disease is attributed to many genes the drug discovery and development process, a framework for the application of the rather than a single gene mutation. In while current clinical trials are designed to pharmacogenomics process at various stages such cases, it would be appropriate to do a observe eff ects in populations rather than to throughout drug discovery including target pharmacogenomic study comparing SNPs give information on inter individual variation and candidate selection, clinical development, maps and gene expression between normal in drug response.9 drug approval and life cycle management and aff ected individuals to identify the genetic (LCM).4 factors associated with the disease, and thus The two most important concerns for new provide newer targets of drug development. drug development are effi cacy and safety. 1. Pharmacogenomics and Drug Target Potential future drug targets can be called Before the advent of pharmacogenetic tools, Selection as “tractable” or “drugable” targets.14 Novel the predictability of both these factors was very The process of drug discovery starts with the approaches for high throughout experiments low. This will be translated into heavy fi nancial identifi cation of a potential target at which to discern associations between disease and loss due to attrition of the drug compound the drug can act. The target can be an enzyme disease traits with large numbers of tractable

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Table 1 Phases of clinical development by pharmacogenetic studies.8 Table 2 depicts

Phase I studies • These comprise the fi rst exposure of humans to a putative medicine, focused on safety some possibilities for incorporating genotyping • Up to 100 individuals may take part in a series of studies into diff erent phases of a clinical trial.16 • Designed to provide information about pharmacokinetics and pharmacodynamics • Not always randomized • Useful in identifying minimal and maximal dosages At present, in most of the trials reported in Phase II studies • Conducted in patients and look to establish an initial indication that the compound is eff ective the literature, pharmacogenomic profi ling is • Involve up to 1000 individuals applied prospectively mainly during Phase • Focus on drug effi cacy, safety and determining appropriate range of drug doses in patients with I trials. Research subjects are enrolled into a disease or condition of interest • Can be randomized the trial on the basis of genotypes that Phase III studies • These large trials, costing tens or even hundreds of millions of pounds, provide the most predict metabolic capacity to respond to convincing evidence of effi cacy and safety to support a regulatory submission the drugs of interest, or genotypes that • Usually a comparison of new therapeutic intervention with standard treatment or placebo could prevent adverse events through • Generally a randomized and blinded study • Often the fi nal stage of testing before new drug approval can be granted particular pathways.18 At the Phase II level, Phase IV studies • Large-scale, long-term post-marketing studies the candidate-gene approach can be used • Focused on identifying morbidity,mortality and adverse events in conjunction with genotyping to correlate • Might identify new indications particular polymorphisms with phenotypic Table 2 Genotyping at diff erent stages of clinical trials diff erences in effi cacy. In later Phase III

Phase I trials • Genotyping might be carried out to try and identify and correlate polymorphisms with phenotypic trials, pharmacogenomic profi ling can be elements (such as pharmacokinetic/pharmacodynamic properties, excretion and serum levels) used to distinguish responders from non- • Certain research subjects with particular genotypes might be excluded from the trial responders.16 • Certain research subjects with particular genotypes might be enrolled preferentially Phase II trials • Genotyping might be used for genotype–phenotype correlations • Genotyping could be used to attempt to associate specifi c polymorphisms with diff erences in 3. Pharmacogenomics for Predicting effi cacy using the candidate-gene approach Effi cacy and Safety of Drug Phase III trials • Use results from Phase I and II trials to design an optimal large-scale Phase III study In addition to its direct clinical impact on • Test candidate genes for effi cacy and metabolism patients and healthcare systems, variable • Might be useful to conduct large-scale genotyping to discover new pharmacogenomic markers • Identify which sub-populations show more adverse events to certain drugs effi cacy is also an important issue for drug • Identify responders versus non-responders to certain drugs development. Failure to show effi cacy in Phase IV trials Studies to assess the following: phase II studies is the most common reason for • Rare adverse events and the relationship of such events to specifi c sub-populations 14 • Marketing considerations; that is, whether a diagnostic test might be capable of distinguishing terminating the development of medicines. the drug of interest from competitors, and whether the market for a given drug would justify the In contrast to the conventional methods where development of diagnostic testing preclinical and clinical studies are done with the purpose of determining effi cacy, drugs drug targets are now available.15 Selection of The most common reason for termination of which have designed with pharmacogenomic the right target for development of a drug is a clinical trial is lack of effi cacy, followed by support have a predetermined effi cacy status. vital and pharmacogenomics can play a vital safety concerns.10 This occurs mostly in phase The chance of a drug failing in preclinical and role in it.8 II and phase III. The phase III study, done on clinical studies due to the absence of effi cacy a larger study population, utilises a very is minimized.2,19 The effi cacy of a drug, is 2. Pharmacogenomics and Clinical large resources. If a trial is terminated, the determined by appropriate target selection, Trials loss incurred fi nancially as well as in terms which can be guided by pharmacogenomic The decision as to which molecules should of time is unacceptable for a pharmaceutical methods.19,20 For some drugs, measurement progress from preclinical development into fi r .m 8 Currently, the failure rate of potential of expression of an obvious molecular drug studies in humans is a pivotal point in the products in development is more than target will provide a reasonably accurate pharmaceutical development process that 90%. There is a burgeoning recognition basis for pharmacogenomic selection of has tremendous implications in terms of that novel approaches and tools such as patients.21 For example, the drug Herceptin fi nancial costs, time and eff ort. This fi rstly pharmacogenomics may enable exploration (trastuzumab), an anti-HER2 monoclonal necessitates a series of experiments, mostly of the pathophysiological mechanisms antibody against metastatic breast cancer, with animal to accumulate suffi cient evidence underlying diff erences in drug response and was found to be eff ective only in women who of therapeutic eff ect and safety, called reduce attrition.17 were over expressing the HER2 protein during preclinical phase, followed by clinical trials early clinical trials. In the subsequent trials, in healthy and unhealthy human volunteers Before the advent of pharmacogenetic studies were done only on women found designed to determine the effi cacy and safety studies and proteomics, effi cacy and safety to be over expressing the HER2 protein.19,20 of the medicine.14 The clinical testing prior concerns were poorly predictable in a clinical The availability of a test for a subgroup with to registration of a medicine is divided into trial. Currently, the predictability of safety and a higher probability of positive response diff erent stages as experience of the molecule effi cacy of a drug has increased to a signifi cant to treatment with Herceptin allowed this is gained during development (see table level, as both are infl uenced by the genetic drug to progress through further studies to 1).14,16 status of the individual, which can be assessed approval.14

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A major challenge in pharmacogenomics Tabel 3 Eff ects of CYP variants on therapeutic effi cacy

application for predicting effi cacy is that the Metabolizer Active drug Prodrug effi cacy phenotype is likely to be multigenic phenotype (inactivated by metabolism) (needs metabolism to produce active metabolite)

and potentially confounded by environmental Drug Enzyme Inactive Metabolite Prodrug Enzyme Active Metabolite factors, thus require more research to be fully Poor Increased effi cacy, active metabolite may Decreased effi cacy; prodrug may accumulate; may clinically applicable. Nonetheless, prediction accumulate, usually require lower dose to avoid require lower dose to avoid toxic accumulation, or for effi cacy is a hugely promising area for toxic accumulation may require alternate drug pharmacogenomics. By using genetic and Ultra-rapid Decreased effi cacy, active metabolite rapidly Increased effi cacy, rapid onset of eff ect, may require inactivated, usually require higher dose to off set lower dose to prevent excessive accumulation of other biomarkers to identify appropriately inactivation active metabolite responding subgroups in phase II studies, compounds that are eff ective in patient certain drugs and is based on the number fully mature and pharmacogenomics was subgroups may be developed further, and type of functional alleles of certain genes integrated into drug development processes signifi cantly speeding the delivery of new that a patient carries. These genes most and incorporated into clinical practice: medicines to meet patient needs and commonly encode the CYP enzymes. The • The rate of delivery a new medicines increasing the productivity of pharmaceutical metabolizer phenotype can range from “poor,” through pharmaceutical research and research and development.14 used to describe patients with little or no development will increase, utilizing a greater functional activity of a selected CYP enzyme, understanding of safety issues and defi ning The second major concern in a clinical trial to “ultra-rapid,” used to describe patients with genetically-defi ned patient groups in which a is drug safety profi le. During a clinical trial, substantially increased activity of a selected compound is eff ective. the occurrence of a serious adverse drug CYP enzyme. Poor metabolizers are unable to • Pharmaceutical companies will be able to reactions (ADRs) could jeopardize the drug metabolize certain drugs effi ciently, resulting create drugs based on the proteins, enzymes, status. Usually, such an event would culminate in a potentially toxic build-up of an active drug and RNA molecules associated with genes and in the termination of the trial.8 There are or the lack of conversion of a prodrug into an diseases. This will facilitate drug discovery and two important places in the development active metabolite. In contrast, in ultra-rapid allow drug makers to produce a therapy more pipeline where pharmacogenomics studies metabolizers, an active drug is inactivated targeted to specifi c diseases. This accuracy not can contribute toward safety. The fi rst occurs quickly, leading to a subtherapeutic response, only will maximize therapeutic eff ects but also during early clinical trials in which indication of while a prodrug is quickly metabolized, leading decrease damage to nearby healthy cells.14,24 adverse events (AEs) can present considerable to rapid onset of therapeutic eff ect. Table 3 • Pharmaceutical companies will be able to risk to a development program; however this summarizes the eff ects of CYP variation on discover potential therapies more easily using risk can be eff ectively manage during clinical therapeutic effi cacy.22 genome targets.The cost and risk of clinical trials to allow decisions to be made in timely trials will be reduced by targeting only those manner, cutting the lag time between steps 4. The Promise of Pharmacogenomics persons capable of responding to a drug. in the progression of a drug through the in drug discovery and development • Decreases in the number of adverse drug pipeline. The overall safety of medicine in the The promise of pharmacogenomics is that it reactions, the number of failed drug trials, clinical trials would increase considerably, and will solve two major problems in healthcare: the time it takes to get a drug approved abrupt and abandonment of drugs at later the diminishing productivity of the drug and a wider range of possible drug targets stages of development could be avoided4. The development process and the unacceptably will promote a net decrease in the cost of second application of pharmacogenomics on high proportion of patients who receive healthcare.14,24 drug safety is expected in phase IV when AEs either no benefi ts from drugs or experience to be observed only after tens of thousands adverse events.9 Pharmacogenomics not only CONCLUSIONS of patient have had exposure to the drug. can provide insights into safety signals that The variations in drug response can be This is the most critical time for new safety may become apparent at phase II but also better studied with wider application of concerns to arise and high cost-burden for underscore the role of pharmacogenomics pharmacogenomic methods. This integrated drug developer if serious adverse events lead in providing information to help research approach will enhance our comprehension to a product withdrawal. This implies to an and development decision making. This use on how drug metabolism genes are regulated improved post marketing surveillance system of pharmacogenomics data will be critical in and how this knowledge can be better applied in which DNA from AEs patient is available, facilitating the rational development of new to provide value-added data in drug discovery enabling rapid clarifi cation of a diagnostic medicine.14 and development process. The potential profi le or test of extremely high sensitivity and for widespread use of pharmacogenomics high specifi city.4 The ultimate promise of pharmacogenomics in the drug development process merits is the possibility that knowledge of a patient’s an examination of its fundamental impact Drug toxicity occurs mainly due to increased DNA sequence might be used to enhance on clinical-trial design and practice. This plasma drug levels, which may be the result of drug therapy to maximize effi cacy, to target application of pharmacogenomics has poor metabolizing capacity owing to genetic drugs only for patients that are likely to implications for predicting a patient’s polymorphisms.8 The metabolizer phenotype respond and to avoid adverse drug reactions.23 response to drugs, reducing adverse events describes the patient’s ability to metabolize It would expected when the technology is and improving rational drug development.

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