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Pharmacogenomics

Pharmacogenomics a new paradigm for

Pharmacogenomics offers the opportunity to adopt a new paradigm in drug development. The is faced with a number of challenges including relatively low productivity and success in bringing new drugs to market. Investors demand that pharmaceutical companies deliver several new drugs to the marketplace each year. Additional pressure in the form of price control comes from government, managed care and insurance reimbursement institutions. Pharmaceutical companies are rethinking the old drug development paradigm and many are investing in pharmacogenomics as a new approach to the discovery, development and marketing of new drugs.

harmacogenomics will increase the number for patients based on their individual genetic By Michael P. of new viable drug targets and decrease the make-up. Understanding the underlying genetics Murphy, MSc Prisks associated with development. behind a patient’s response to should Incorporating pharmacogenomics into drug devel- allow pharmaceutical companies to develop safer opment will eliminate the unpredictable response and more effective drugs. In addition, under- of drug treatment due to genetic polymorphisms standing how individuals are genetically predis- that affect , and tolerance. posed to risk of disease may result in new drug The of new drugs will become more pre- targets, thereby leading to new classes of drugs dictable as we correlate genetic changes in drug designed to delay or prevent disease onset. Many targets, receptors and transporters with associated in the pharmaceutical industry have made signifi- patient response. Ultimately, pharmacogenomics cant investments in pharmacogenomics with the promises to change how physicians choose drugs expectation that it will help eliminate the unpre- and the correct dose based on each individual’s dictable nature of drug development, bring new unique genetic profile. For now, this important products to market aimed at preventing common tool can impact the way pharmaceutical companies diseases and create premium pricing for their develop drugs provided they are willing to accept a products1. A new paradigm in drug development new paradigm that recognises that drugs rarely and healthcare has begun and some would argue work in all patients. that Pandora’s box has been opened, leaving pharmaceutical companies not with the decision The promises of pharmacogenomics of whether they will or will not participate, but Pharmaceutical companies, physicians and the how and when2-5. This article hopes to examine public are anticipating the promise of significant those factors that have brought pharmacoge- advancements in brought on by the nomics to the forefront of drug development. The ‘genomics revolution’. Pharmacogenomics, the opportunities and hurdles facing pharmaceutical study of heritable traits affecting patient response companies embracing the pharmacogenomics to drug treatment, holds its own promises (Figure paradigm are presented in the context of the 1); to forever change the way drugs are developed major business challenges facing the pharmaceu- and ultimately, the way in which drugs are chosen tical industry.

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Figure 1 The promises of pharmacogenomics

Evolution from pharmacogenetics ings from genomics and the project Pharmacogenomics has evolved from pharmacoge- will further expand the scope of useful genetic netics, focused primarily on genetic polymor- markers. How quickly will this evolution take phisms (mutations) responsible for interindividual place? Consider that despite our well-established differences in and disposition. knowledge of variants found in drug metabolism Genotype-phenotype correlation studies have vali- genes (some discovered more than 20 years ago) it dated that inherited mutations result in two or is still not routine practice to incorporate pharma- more distinct phenotypes causing very different cogenetic studies while drugs are developed. There responses following drug administration6. For are still not enough documented cases demonstrat- example, mutations in the gene ing the cost-benefit of this approach. CYP2D6, results in poor, intermediate, extensive, Pharmacogenomics companies working in partner- and ultra-rapid metabolisers7. Each of these phe- ship with the pharmaceutical industry will need to notypic subgroups experience different responses provide further evidence that pharmacogenomics to drugs extensively metabolised by the CYP2D6 can provide safer, more focused clinical studies that pathway ranging from severe to complete also save development time and expense. lack of efficacy. There are several examples where prospective Shifting to the new paradigm genotyping could be used to ensure that those with Most companies proactively conduct preclinical appropriate metabolism and efficacy phenotypes studies to determine the contribution that are targeted for therapy (Table 1)6,8,9,10. Using cytochrome P450s might have on metabolism and pharmacogenomic testing to choose the proper distribution given the well-established fact that drug and dose prior to therapy has been validated many of these genes exhibit genetic polymor- in case controlled studies6,11,12. These studies eval- phisms1. Including specific phenotypic subgroups uated patient’s predicted phenotype (ie, poor during Phase I studies ensures that toxicity and metabolisers) to determine their ability to safety issues are identified early in clinical develop- metabolise approved drugs. This approach has not ment. Indeed, drugs that appear to have less than yet taken hold for new drugs being developed. In desirable toxicity are discovered when companies fact, with the exception of Trastuzumab use pharmacogenomics to ensure the inclusion of (Herceptin®) no other compounds have been volunteers with the poor metaboliser phenotype in advanced through clinical trials and later approved Phase I clinical trials1. based on their linkage to pharmacogenomic traits. When a compound demonstrates efficacy or safe- Future pharmacogenomic studies will incorpo- ty in a subset of patients as demonstrated by phar- rate all of the genetic factors that affect patient macogenomic studies, companies must decide if outcome including metabolism, drug target, trans- there is a viable market to justify continued devel- porter and receptors. Bridging new find- opment. Continuing development of a compound

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Pharmacogenomics

Figure 2 Citation from FDA Guidance document outlining the importance of identifying genetic polymorphisms in order to allow the approval and use of drugs

that appears to demonstrate less than full efficacy in significantly increase the likelihood of developing the intended patient group carries uncertain risks drugs that benefit most patients without severe for companies. The drug may not be approved and adverse events in a relative few. if it is, it may be labelled with restrictions concern- ing marketing claims and use. Not considering Factors influencing pharmacogenomics pharmacogenomic studies can also carry risks. The adoption by pharmaceutical companies ultimate failure of the current development para- The pharmaceutical industry faces enormous chal- digm occurs when a drug is approved and market- lenges in the near term due to mounting pressures ed and later withdrawn from the market due to to produce high revenue generating ‘blockbuster’ unforeseen toxicity in a subpopulation of patients. drugs in the face of tighter regulation and controls Propulsid®, Rezulin®, Seldane® and Duract® serve over pricing. The many challenges the industry as examples of drugs pulled from the market faces include: because the companies did not appreciate the extent of adverse events that occurred in a subset of ‘Pharmaceutical companies need to patients. improve on the productivity and success These drugs were developed under the old devel- of bringing new products to market’ opment paradigm that largely ignores the fact that humans are genetically different, resulting in a G Tremendous pressure to get 3-4 new chemical enti- variable response to drugs. These companies ties (NCE) through the drug development pipeline assumed the ‘one dose fits all’ philosophy that pre- and approved each year in order to sustain the sumes that patients studied during clinical develop- expected double-digit growth. Investors have come ment had a common biological background with to expect this rate of growth from the pharmaceuti- respect to metabolism and efficacy. Genetic studies cal industry and hence the value of a company’s stock confirm that this is not the case, leaving the ques- depends in large part on their ability to bring several tion of why we would continue to develop drugs competitive new drugs to market each year. under the old paradigm. As early as 1997, the FDA advised pharmaceutical companies to consider a G A ‘crisis’ in the number of novel drugs entering new approach and incorporate the knowledge the development pipeline13. Despite new technolo- regarding genetic polymorphisms into drug devel- gy in high throughput screening and combinatorial opment (Figure 2). Importantly, the FDA recog- chemistry, there is a significant decrease in the nised that identifying genetic polymorphisms number of novel lead compounds. The number of might allow for the safe dosing, marketing and new break through drugs approved has steadily approval of drugs that would otherwise not be declined since 199613. Many of these compounds approved. Companies incorporating pharmacoge- fail because they lack appropriate biological activ- nomic testing throughout drug development can ity (efficacy) and tolerance profiles (toxicity) to

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allow continued development. Mergers among but at preventing or delaying disease onset. large pharmaceutical companies witnessed of late Linking specific mutations to disease risk will how- are in part oriented towards accumulating promis- ever, require significant investment in both family ing leads to feed the development pipeline. In addi- linkage and population studies. Once these associ- tion, an increased number of companies are buying ations are made they will have to be validated by or licensing new compounds from smaller biotech- case-controlled studies. Pharmaceutical companies nology companies. willing to invest in these types of studies will have the opportunity to develop proprietary pharma- G Relatively poor percentage of lead compounds cogenomic markers thereby positioning their prod- that survive the process to approval. ucts apart from others still operating under the old Only about 10% of compounds that enter clinical drug development paradigm. development are ever approved as drugs. Given the There are several pharmacogenomic service investment required for clinical development there companies available to provide genetic testing for is an enormous waste of time and money spent to clinical development. Every clinical trial patient bring drugs to market. An improvement of even a can be tested prospectively for known genetic poly- few percent could have a dramatic effect on the morphisms, including those responsible for metab- costs associated with drug development. olism. Those who are ready to invest in the phar- macogenomics opportunity will extend their analy- ‘The pharmacogenomics solution’ ses to Phase II-IV clinical trials to stratify the Completing the sequencing of the human genome patient population and target responders based on and the discovery of mutations that are responsible linkage to efficacy markers. Retrospective analyses for human disease will bring new targets for inter- can be done at the conclusion of studies provided vention by pharmaceutical researchers. The proper informed consent is taken along with a increase in new drug targets will create the oppor- patient sample (typically 5-6 milliliters of whole tunity for new lead compounds with a significant blood). Pharmacogenomic service companies can impact on the drug development process. No help to identify possible unknown variants found longer will drugs be directed at disease symptoms in target or receptor genes by resequencing the

Ta bl e 1 Examples of genes that have well-established responder or non-responder genotypes and phenotypes

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References appropriate candidate genes. Several of these serv- demonstrating medical need and justify the cost in 1 Murphy, MP. (2000) Current ice companies are capable of providing clinical comparison to previously accepted treatment. pharmacogenomic approaches diagnostic testing so that physicians can refer to drug development. patients for testing prior to prescribing newly G An increased awareness of the morbidity and Pharmacogenomics 1(2), 115- 123. approved drugs linked to pharmacogenomic traits. mortality costs associated with Adverse Drug 2 Mancinelli, L, Cronin, M, & Pharmaceutical companies need to develop a Reactions (ADR) and the need to minimise toxici- Sadee, W. (2000) pharmacogenomic profile for those patients who ty and improve efficacy for new drugs. Most in the Pharmacogenomics: the respond to therapy. This knowledge can be used industry are aware of recent findings published in promise of personalized throughout clinical trials to decrease the total num- the Journal of the American Medical medicine. AAPS Pharmsci: 2(1), 15 article 4 ber of patients enrolled in trials by studying a Association that found that ADRs are between (http://www.pharmsci.org). homogeneous population without compromising the fourth and sixth leading cause of death in the 3 Lichter, JB, & Kurth, JH. the power of these studies. By focusing on the US. Regulatory agencies will increasingly require (1997) The impact of responder subgroup, companies can eliminate that companies establish any toxicity or safety pharmacogenetics on the much of the variability in drug development. The issues in those individuals who are genetically pre- future of healthcare. Curr Opin Biotechnol 8(6), 692-695. drug development period offers an ideal opportu- disposed to ADRs due to either deficiencies in 4 Bhandari, M, Garg, R, nity to identify and optimise treatment based on metabolism (clearance) or those individuals lack- Glassman, R, & Ma, P. (1999) inherited genetic traits. ing the appropriate phenotype to benefit from The pharmacogenomics treatment (efficacy). Examples of approved drugs challenge: the only option is ‘The development and marketing of new with genetic traits linked to response are shown in how and when you participate. In Vivo 17(3), 36-41. drugs requires a substantial investment on Table 1. If these drugs were being developed today 5 Spear, B. (1999) Viewpoint- the part of the pharmaceutical would it not benefit the pharmaceutical compa- pharmacogenomics: today, companies’ nies, physicians and their patients if treatment tomorrow, and beyond. Drug were in part based on pharmacogenomic testing? Benefit Trends 11(2), 53-54. G The relatively high cost of marketing and devel- These are just a few examples where genotyping 6 Evans, WE, & Relling, MV. (1999) Pharmacogenetics: oping new drugs. Spending on research and devel- patients prior to therapy can ensure safe and effec- translating functional genomics opment has tripled since 1990 to $26.4 billion. On tive treatment. into rational therapeutics. average, pharmaceutical companies spend more on Science 286, 487-491. marketing than on . ‘The pharmacogenomics solution’ 7 Sachse, C, Brockmöller, J, Companies spend more than $7bn per year on Companies that utilise pharmacogenomic profil- Bauer, S, & Roots, I. (1997) 13 Cytochrome P450 2D6 variant marketing and sales . Frustrated by the unsuc- ing during clinical trials to include only those pre- in a Caucasian population: cessful launch of new drugs these companies have dicted responder phenotypes should see consider- allele frequencies and shifted their focus from pharmaceutical research able cost savings by limiting clinical trial enroll- phenotypic consequences. Am. and development to drug marketing. Investment in ment. A recently published study in which poor J. Hum. Genet. 60, 284-295. development, marketing and sales requires a return metabolisers were excluded from enrollment 8 Ueda, S, Meredith, PA, Morton, JJ, et al. (1998) ACE of $300-$600 million for each new . allowed the sponsor to decrease the trial popula- (I/D) genotype as a predictor Obviously, companies can no longer afford to tion by 10% for a pivotal Phase IIIb study11. The of the magnitude and duration bring drugs to market only to discover that a sub- cost per patient for a Phase III trial for a central of the response to an ACE set of the population suffers from life threatening nervous system (CNS) product is estimated at inhibitor drug (enalaprilat) in adverse events. between $8,000 and $12,000 per patient. humans. Circulation 98, 2148- 2153. Therefore, eliminating 10% of the trial population 9 Smeraldi, E, Zanardi, R, G Pharmaceutical companies are facing pressures to of known non-responders in a trial involving more Benedetti, F, Di Bella, D, Perez, lower drug prices and competition from generic than 450 subjects, can save between $360,000 and J, & Catalano, M. (1998) branding following patent expiration. In the US, $540,000 for a single trial. Additionally, some Polymorphism within the states such as Maine have instituted price controls predict that the contribution of pharmacoge- promoter of the serotonin transporter gene and on drug prescriptions. The US congress and other nomics to medical outcome is expected to add antidepressant efficacy of states are considering similar legislation. Countries $500m in extra revenue per drug16. Obviously, fluvoxamine. Mol. Psychiat. 3, including Australia, the UK, Germany, France, Italy companies will not appreciate the financial impact 508-511. and Spain all have limitations on either reimburse- of pharmacogenomics in development or follow- ment to patients for drug prescription or out right ing approval until a careful pharmacoeconomic Continued on page 32 pricing limitations imposed on the pharmaceutical assessment is done to compare the current devel- industry14. Companies must now justify the cost- opment and marketing approaches with those benefit before their new drugs can be integrated incorporating this new paradigm. More studies into the national healthcare system in these coun- are needed to convince the industry that revising tries. Given the competitive landscape for today’s current business models and incorporating phar- pharmaceutical industry they must go beyond macogenomics (with a possible segmented market)

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Figure 3 Theoretical model demonstrating the impact of pharmacogenomic tests associated with newly marketed drugs Illustration courtesy of Ken Conway, Millenium Predictive Medicine

will be more than offset by the potential savings reluctant to continuing to try new drugs when a using this approach. subgroup of patients fail to respond and the rea- sons for lack of response are not clear. Patients ‘Challenges and obstacles affecting the who do not get better following therapy typically pharmaceutical industry’s adoption of become non-compliant and fail to use drugs at the pharmacogenomics’ appropriate dose or schedule.

G The linkage between a pharmacogenomic trait ‘The pharmacogenomics solution’ and response in a subset of the patient population Figure 3 illustrates the theoretical differences in the will fragment the market for new drugs and may stability of drug sales from the conventional para- result in labelling restrictions. The reality is that digm to one that incorporates pharmacogenomic most drugs do not work in all patients. By current testing as a crucial element of product launch. The estimates the percentage of patients who will react model accounts for the loss in market share when favourably to a specific drug range from 20% to drugs ultimately demonstrate either toxicity or 80%16. Drugs that have known adverse events in a lack of efficacy in a subgroup of patients (Figure 3, subset of the population such as those caused by Green Line). Additional loss of market potential deficiency in metabolism (potential liver toxicity) occurs when the drug ends up as second choice and have warnings regarding dosing and may require physicians choose competing products because of regular testing of liver function. Of course market- uncertainties regarding both toxicity and efficacy ing groups within the industry believe that market in drugs prescribed to patients. In theory, the mar- fragmentation will result in lost market share, ket share will be further eroded when competitor hence decreased revenues and possibly the end of compounds linked to pharmacogenomics enter the so-called ‘blockbuster’ drugs. The reality is that market (Figure 3, Red Line). The basis, in part, for drugs that benefit a majority of the patient popula- this theory is that physicians will initiate therapy tion and stand in the marketplace with little or no and continue patients on drugs based on person- competition still have the potential as block- alised medicine, that is, prescribing drugs based on busters. Over time the market share can be eroded previously established pharmacogenomic tests that in the absence of significant competition due to predict efficacy and lack of toxicity (Figure 3, Blue lack of efficacy or worse, toxicity. Physicians are Line). For now the industry is waiting for the first

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Continued from page 30 successful launch of a drug that requires genetic G Drugs targeted to life threatening disease. Cases testing prior to prescribing. Several companies are when the treatment involves drugs that are either 10 Shak, S. (2000) Case study: contemplating the co-development and approval of expensive or quite toxic will utilise those pharma- and the development of Herceptin. pharmacogenomic drugs and diagnostic tests, pri- cogenomic tests that clearly differentiate potential Second Annual marily for compounds that demonstrate very good responders. Examples include targeting Pharmacogenomics Event. efficacy in a patient subpopulation. The floodgates Herceptin® for Her2neu positive breast cancer European Centre for may be opened after the first successful demon- patients and fluorouracil for dihydropyrimidine Pharmaceutical Information, stration of this new approach. dehydrogenase (DPD) efficient metabolisers. London, England. 11 Murphy, MP, Beaman, ME, Pharmacogenomics has already made an impact Clark, LS, Cayouette, M, Future of pharmacogenomics-based on drug development. Pharmacogenetics is used in Benson, L, Morris, DM, & Polli, drug development preclinical and Phase I studies to identify impor- J. (2000) Prospective CYP2D6 The long-term future of pharmacogenomics-based tant drug metabolism genetic polymorphisms. The genotyping as an exclusion drug development looks something like: list of genetic traits linked to efficacy continues to criterion for enrollment of a phase III clinical trial. Lead compounds coming out of preclinical phar- grow and be used for selecting drug treatment. Pharmacogenetics 10(7), 1-8. macogenomic testing will ideally be chosen based Within the next five years, pharmacogenomics will 12 Chou, WH, Yan, FX, on the fact that they are metabolised and eliminat- evolve as an integral part of the drug development DeLeon, J, Barnhill, J, Rogers, T, ed by several alternative pathways. Phase I volun- process. In concert with this paradigm shift will be Cronin, M, Pho, M, Xiao, V, teers who might be at risk for toxicity due to meta- the development of new diagnostic tests designed Ryder, TB, Liu, WW, Teiling, C, & Wedlund, P. (2000) Extension bolic status for these same paths of elimination to assist physicians in selecting the right drug at the of a pilot study: impact from might be identified and studied for dose limiting right dose. Ultimately patients will be the real the cytochrome P450 2D6 tolerance. Genetic traits that predict efficacy (ie, benefactors of gene-based drug selection. polymorphism on outcome receptor status) will be a focus of pharmacogenom- Personalised medicine will enhance drug therapy and costs associated with ic studies during Phase II-IV clinical studies to opti- by minimising adverse reactions and increasing the severe mental illness. J. Clin. Psychopharm. 20(2), 246-251. mise the population of patients who will respond chances of successful treatment. DDW 13 Gardiner, H. (2000) Drug positively to treatment. Pharmacogenomic tests val- Firms, Stymied in The Lab, idated as positive markers of response will be devel- Become Marketing Machines. oped as molecular diagnostic tests. Pharmaceutical Wall Street Journal, July 6, companies will partner with pharmacogenomic and Michael Murphy received a Bachelor’s degree in 2000. 14 Witcher, SK. In the land diagnostic companies to develop panels of tests that Biology in 1978 and his Master’s degree in Cell down under, a model for will be submitted for regulatory approval in paral- Physiology in 1983 from San Diego State national drug insurance. Wall lel with the new drug applications. University. He received his training in Molecular Street Journal. August 31, 2000. In the near term, pharmaceutical companies are Biology at the University of California, San Diego, B1, B4. likely to use pharmacogenomics in drug develop- Cancer Center and The Salk Institute. Mr Murphy 15 Lazarou, J, Pomeranz, BH, & Corey, PN. (1998) Incidence of ment for the following applications: has both industrial and academic experience adverse drug reactions in including work at Syntex Pharmaceuticals and as a hospitalized patients. A meta- G Development rescue, rather than rescue old faculty member in the department analysis of prospective studies. drugs which have been long abandoned. and Lombardi Cancer Center at Georgetown JAMA 279, 1200-1205. Companies are more likely to use pharmacoge- University. He was the first Director for the 16 Rubenstein, A, (1999) Pharmacogenomic-impact on nomics to determine if a genetic element is involved ‘Laboratory of Drug Analysis and Molecular drug discovery. Advance Tech in the subpopulation of patients who either Genotyping’ at Georgetown which serves the ana- Monitor (Publishers), copyright demonstrate toxicity or lack of efficacy for an oth- lytical and pharmacogenetic testing needs of 1999. erwise promising . As outlined in Georgetown and its collaborators. Mr Murphy this review, they will either decide to terminate was founder of Intek Labs, Inc, the first interna- development or those companies embracing the tional pharmacogenomics service company. He new paradigm will develop the necessary tests to served as Executive Director, Pharmacogenetics isolate the responder phenotype using genetics and for Pharmaceutical Product Development, Inc fol- later co-market the appropriate diagnostic tests to lowing the merger of Intek Labs with PPD in allow approval of the drug. November 1997. Starting in February 1999, Mr Murphy served as Vice President, G Drugs targeted to those individuals with an Pharmacogenomics for PPGx, a joint venture underlying genetic component predictive of disease between PPD-Intek Labs and AxyS onset. Diseases such as cardiovascular disease Pharmaceuticals. He joined Clingenix, Inc as Vice (coronary heart disease and restenosis) with a clear President, Pharmacogenomics in April 2000, genetic component will be targeted to those indi- directing the overall business and scientific strategy viduals at predisposed risk. of the Pharmacogenomics group.

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