Companion diagnostics and personalized medicine:
A review of molecular diagnostic applications

Mathew W. Moore1, Deepti Babu2, and Philip D. Cotter1,*

ResearchDx, Irvine, California, USA. 2Department of Medical Genetics, University of Alberta,

well established [1, 2]. The advantages of approaching medicine in this way are theoretically Personalized medicine is the customization of treatment based on a patient’s hereditary or clear; personalized medicine has the potential to somatic genetics and holds the promise of more efficiently, effectively, and safely direct revolutionizing healthcare. Companion diagnostics, health care than traditional non-targeted approaches. many of which are molecular genetics assays, are While the rate of progress has clearly increased, there are still significant technical and regulatory critical tools in the implementation of personalized medicine. Information derived from these tests hurdles to overcome. Several guidance documents provides for customizing specific therapies based from regulatory organizations worldwide have on the genetics of the disease. While the benefits attempted to address these challenges, and no are clear, the path to a successful companion doubt more will be presented in the near future diagnostic has required a forging of new alliances between drug and diagnostic developers, clinical Companion diagnostics are increasingly relied laboratories, physicians, pathologists, and healthcare upon to ensure the effective, safe development providers. Molecular genetic companion diagnostic and use of a personalized therapeutic. Multiple assays are becoming more relevant and important liaisons and partnerships between key stakeholders in an environment of increased regulatory guidance are needed in this complex, dynamic process. in their development and application. Here, we Many successful companion diagnostics are review key molecular genetics companion diagnostic genetic tests - particularly molecular diagnostics - tests and their applications in personalized medicine. and this speaks to their high impact and relevance KEYWORDS: personalized medicine, genetic,
Personalized medicine and the “new” genomics
“Personalized medicine” is a phrase first coined in INTRODUCTION
the 1990s, although the concept pre-dated this The concept of personalized medicine, whereby [4, 5]. Achieved successfully, personalized medicine disease diagnosis, treatment and prevention are harnesses power from innate biological information customized to one’s genetic composition, is now to direct appropriate therapies for appropriate patients - a goal that maximizes key components of effectiveness, efficiency, and safety. *Address correspondence to: Dr. Philip D. Cotter, ResearchDx, 13766 Alton Parkway, Suite 147, Independent of the Human Genome Project, personalized medicine efforts initially began with a consortium of the world’s largest pharmaceutical companies and scientists, created to identify Early strategic partnerships are necessary to create natural genetic differences between people [4]. personalized therapeutics. Few pharmaceutical The goal was to correlate informative genetic companies have depth of experience in the biomarkers with disease symptoms, or serious diagnostics arena. Partnerships can address side effects to certain medications. Drug experimental design, assay discovery, assay developers then hoped to develop more effective, validation, marketing and commercialization [3]. safer drugs to target these patient populations. However, some of these partnerships are not part of current pharmaceutical company outsourcing More recently, the interest in personalized practices. In addition, early alliances are difficult medicine has increased substantially; based on because the value of the drug and its diagnostic PubMed searches on the term ‘personalized are difficult to predict [3]. These and other factors medicine’, a 2011 publication found that the bring about several business challenges. number of scientific publications on the subject has shown an exponential growth in the period Commercially, there are several challenges for a from 1999 to 2010 [6]. Kongkaew et al. [7] companion diagnostic. The total market for the estimated that more than 5% of hospital therapeutic needs to be large enough to not only admissions are associated with adverse reactions justify the development cost of the therapeutic to prescribed drugs. Many of these are due to itself, but also now the cost of development for individual genetic differences that render one the associated companion diagnostic. In addition, hypersensitive to the drug, or unable to one has to market the value of both the therapeutic and the diagnostic. A companion diagnostic has the potential to reduce the market size for a Challenges in the drug development process
therapeutic by limiting the patient population. Responses from the larger pharmaceutical and Similarly, in an extreme case the companion biotechnology companies to create personalized diagnostic may leave the physician without a therapeutics have been lower than expected, based viable therapeutic treatment. These issues can on interest level. Success rates in bringing these make pharmaceutical companies less commercially drugs to market have also been low. A number of motivated to pursue a personalized therapeutic. scientific, strategic, commercial, and regulatory Regulatory factors can also bring challenges, factors have been attributed to this [9]. as there are inefficiencies in the current drug Jorgensen et al. [6] argued that the initial “one development process. The co-submission of a drug for one disease” model does not fit the therapeutic and diagnostic complicates the clinical reality of heterogeneous disease regulatory submission process and can lead to mechanisms at the molecular level. As a result, some diseases have not been as amenable to Historically, there were few regulatory guidance personalized medicine, as was initially postulated. Scientifically, it has also been more difficult to diagnostic co-development. More recently, identify and validate biomarkers in as timely a regulatory agencies have responded with guidance fashion than the industry initially expected. While documents, attempting to inform best practices, the drug development and regulatory process is and to provide clarity and consistency in assay well known and understood, the development of a successful biomarker requires an understanding of several success factors including biomarker Regulatory responses about companion
availability, robust technical assay validation, the diagnostics
importance of demonstrating clinical utility, and the ability to bring an investment-positive Regulatory agencies are quickly recognizing that commercial value proposition to the table [3]. companion diagnostics can be the key to a safe, This is extremely difficult to find without successful personalized therapeutic. In draft partnering with several organizations, introducing guidance from July 2011, the FDA indicated that, several logistical challenges to the process. “in most circumstances, if use of an in vitro Genetic tests as companion diagnostics 25 companion diagnostic device (IVD companion the colon, lung, breast and other sites [1]. These diagnostic device) is essential for the safe and companion diagnostics typically identify somatic effective use of a therapeutic product, (it and its) mutations identified in tumor cells, which help therapeutic product should be approved or cleared direct use of an appropriate therapeutic (Table 1). contemporaneously by FDA for the use indicated in the therapeutic product labeling” [10]. The Recent successful genetic companion diagnostic
guidance also stated that, “the results of the IVD tests in oncology
companion diagnostic device will be essential for Crizotinib and non-small cell lung cancer
the safe and effective use of the therapeutic Recently, rearrangements of the anaplastic product, and its use will be stipulated in the lymphoma kinase (ALK) gene were reported in labeling of the therapeutic product.” Because the non-small cell lung cancer (NSCLC) [16, 17]. IVD companion diagnostic was identified as Within three years, studies of ALK inhibition essential for this purpose, it was noted that, “with yielding dramatic response rates in patients with some exceptions FDA does not believe it may advanced NSCLC containing ALK rearrangements approve a novel therapeutic product or new were reported [16, 18, 19]. In pretreated patients therapeutic product indication for use with an IVD that generally have a 10% response rate to companion diagnostic if the IVD companion conventional chemotherapy, treatment with the diagnostic is not approved or cleared for that oral ALK inhibitor crizotinib (Xalkori®) yielded indication” [10]. Guidelines for the development an overall response rate of 55% and an estimated of IVDs also exist in the European Union (EU) six-month, progression-free survival rate of 72% Regulatory guidances put an increased focus and Significantly, the mechanism of resistance was relevance on the development of companion associated with ALK kinase domain mutations, diagnostics, many of which are genetic tests. substantiating that ALK was indeed the genetic Gene-based and molecular diagnostics testing is target of the personalized therapy [16]. This also growing at a 30-50% rate, and it has been reinforced that appropriate clinical application of estimated that as many as 1,500 genes and 5,000 ALK-targeted therapy was absolutely dependent proteins may be candidates for new molecular test upon a companion diagnostic to identify patients targets [12, 13]. It has also been recommended most likely to respond. The FDA has since that companion diagnostics be used at an early approved the drug, and requires use of its stage in the drug development process [9]. From companion diagnostic; this is indicated in product a financial perspective, molecular diagnostics within the USA alone was valued at approximately $2.7 billion in 2006, and was expected to reach Vemurafenib and metastatic malignant
$5 billion by 2010 (AGR 15%) [14]. Oncology melanoma
molecular diagnostics was the fastest growing The B-Raf proto-oncogene serine/threonine- sector at that time and was predicted to increase protein kinase (BRAF) gene is critical in the by 30% each year, tripling from its 2005 level of development of melanoma [20, 21]. Melanoma $315 million to more than $1.35 billion by 2010 tumor cells with BRAF mutations contain distinctive characteristics, such as unique morphological variants, an age at diagnosis often Personalized medicine in the oncology sector
before 55 years, and others [21]. A multi-centric There has been significant progress for study reported that the treatment of metastatic companion diagnostics and personalized medicine melanomas carrying the V600E mutation in in the oncology sector. For example, the use of BRAF with a selective small molecule inhibitor pre-symptomatic genetic testing and “targeted PLX4032 (vemurafenib) resulted in complete or therapies” tailored to genetic profiles of tumors is partial regression of disease in most patients part of a recommended evaluation for cancers of [20, 22]. From clinical trial studies, patients with Drug manufac
FDA approve
Required companion
Genetic biomarker
Genetic tests as companion diagnostics 27 BRAF V600E mutation-positive melanoma drug metabolism. Metabolism in the liver by receiving vemurafenib (Zelboraf™) showed cytochrome P450s represents the most common improved rates of overall and progression-free route of drug breakdown. Fast- and slow- survival, as compared to those receiving metabolizing variants due to mutations in these conventional therapy. This highlighted the enzymes can lead to under- and over-dosing of importance of a molecular disease model focusing drugs [8, 28]. The FDA approved Roche’s on specific biomarkers, identified by companion AmpliChip™ microarray-based assay to identify diagnostics, as bona fide targets that could benefit melanoma patients [21]. The FDA subsequently approved the drug and requires use of the Known to mediate the metabolism of almost 25% companion diagnostic prior to its administration; of drugs, adverse events with nearly 30 drugs are known to be related to drug accumulation in patients carrying variants in these two enzymes Key companion diagnostics outside the
oncology sector
Recently, findings were published on the prediction Genetic biomarkers identify risk for
of dose selection for warfarin after correlation life-threatening drug side effects
Companion diagnostics for hereditary mutations algorithm [8, 30]. Under- or over-dosing with are also becoming more widespread (Table 2). warfarin is the worldwide leading cause of Heterozygosity for the human leukocyte antigen hospitalization related to adverse events. Variants HLA-B*1502 allele, found almost exclusively in in CYP2D9 and VKORC1 are known to influence individuals from some parts of Asia, placed one the biologic breakdown of warfarin. Study results at increased risk of life-threatening reactions have shown that the prediction of dose selection to carbamazepine, a commonly prescribed anti- with a pharmacogenetic algorithm correlated well convulsant in those geographical regions [25]. with empirically determined maintenance doses. Once the risk for these serious reactions in those In fact, this outperformed clinical prediction and with the HLA-B*1502 allele became known, the standard dose estimates. This was particularly true FDA issued an alert, indicating that if an in the outlier population; patients with common individual tests positive for the allele … variants of the metabolizing enzymes fell within “carbamazepine should not be started unless the the range of standard dosing [8, 30]. The FDA has expected benefit clearly outweighs the increased been updating drug labels to include such genetic risk of serious skin reactions.” (http://www. information where compelling data exist [8]. New alliances are needed to ensure successful
rugSafety/PostmarketDrugSafetyInformationforPa companion diagnostics
tientsandProviders/ucm124718.html). The FDA then recommended an HLA-B*1502 companion diagnostic to be performed prior to prescribing diagnostic is complex, and is best achieved carbamazepine to those from at-risk populations. through a closely coordinated interaction between A 2011 letter to the New England Journal of diagnostic manufacturers, drug companies and Medicine augmented this warning by stating, “Given regulatory agencies [11]. More specifically, this the availability of other elective therapeutic requires alliances between drug and diagnostic choices, it may be prudent to advise HLA-B*1502 developers, clinical laboratories, physicians, carriers to avoid not only carbamazepine but also pathologists, healthcare providers, and others other structurally related anticonvulsants, such as phenytoin, oxcarbazepine, and possibly lamotrigine.” Although companion diagnostics have been developed and approved in some therapeutic Drug metabolism variances due to hereditary
areas, the regulatory process itself is still evolving. mutations
Each companion diagnostic case is unique and Other successful companion diagnostics are requires early interactions and planning to ensure associated with hereditary mutations that affect diagnostic
allele are at high risk for experiencing a (s) Companion
Drug Manufacturer
Genetic tests as companion diagnostics 29 Figure 1. Necessary alliances to develop a successful companion diagnostic.
The field of molecular diagnostics has advanced 1. Offit, K. 2011, Hum. Genet., 130, 3. rapidly since the first widespread introduction in the early 1980s, and has exhibited continual technological development. Thirty years into the age of molecular diagnostics, the stunning pace of advancement has shown no signs of abating, with the next generation of technologies rapidly Jorgensen, J. T. 2009, Oncologist, 14, 557. becoming the method of choice for drug 6. Jorgensen, J. T. 2011, Drug Discov Today, developers looking to include a companion diagnostic into their drug development cycle. Kongkaew, C., Noyce, P. R., and Ashcroft, While drug development companies are becoming D. M. 2008, Ann. Pharmacother, 42, 1017. increasingly receptive to adding a diagnostic to Bates, S. 2010, Drug Discov. Today, 15, 115. their drug development cycle, many large 9. Papadopoulos, N., Kinzler, K. W., and instructions are challenged by the implementation. Current development relies heavily on in-house technology, intellectual property, and expertise. 10. Services, U. S. D. o. H. a. H. 2011. Draft However, development of a companion diagnostic requires a complex and symbiotic collaboration Administration Staff - In Vitro Companion between public and private enterprise, research institutions, diagnostics, drug development, clinicians, patients and regulatory authorities. No in vitro companion diagnostic devices, one organization currently has the capabilities to combine all of the required pieces, and only such 11. Nikolcheva, T., Jager, S., Bush, T. A., and partnerships have the financial, scientific and Vargas, G. 2011, Expert Rev. Mol. Diagn., technical capabilities necessary to complete this 12. Ross, J. S. 2011, Biomark Med., 5, 277. 13. Ross, J. S. and Ginsburg, G. S. 2002, Drug 20. Smalley, K. S. 2010, Curr. Opin. Investig. 14. Sannes, L. 2007, Molecular Diagnostics: A 21. de Souza, C. F., Morais, A. S., and Rapidly Shifting Commercial and Technology 15. Administration, U. S. F. a. D. 2011, Table of 22. Flaherty, K. T., Puzanov, I., Kim, K. B., Pharmacogenomic Biomarkers in Drug Labels. Ribas, A., McArthur, G. A., Sosman, J. A., 16. Gerber, D. E. and Minna, J. D. 2010, Cancer O'Dwyer, P. J., Lee, R. J., Grippo, J. F., 17. Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Ishikawa, Y., Aburatani, H., Niki, T., 24. U. S. Food and Drug Administration 25. Chung, W. H., Hung, S. I., Hong, H. S., 18. Choi, Y. L., Soda, M., Yamashita, Y., Ueno, T., Takashima, J., Nakajima, T., Yatabe, Y., Wu, J. Y., and Chen, Y. T. 2004, Nature, Ishikawa, Y., Kimura, H., Mitsudomi, T., 26. Liao, W. P., Shi, Y. W., and Min, F. L. Tanio, Y., and Mano, H. 2010, N. Engl. J. 27. Phillips, E. J. and Mallal, S. A. 2011, N. 19. Kwak, E. L., Bang, Y. J., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, 28. Phillips, K. A., Veenstra, D. L., Oren, E., S. H., Dezube, B. J., Janne, P. A., Costa, D. B., Varella-Garcia, M., Kim, W. H., Lynch, T. J., Fidias, P., Stubbs, H., Engelman, J. A., 29. Jain, K. K. 2005, Mol. Diagn., 9, 119. Sequist, L. V., Tan, W., Gandhi, L., Mino- 30. Klein, T. E., Altman, R. B., Eriksson, N., Kenudson, M., Wei, G. C., Shreeve, S. M., Ratain, M. J., Settleman, J., Christensen, J. G., Haber, D. A., Wilner, K., Salgia, R., Shapiro, G. I., Clark, J. W., and Iafrate, A. J.


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