Targeting treatment

Progress towards more individualized treatment is gaining momentum, as our understanding of the associations between inherent differences in genetic and protein profiles and phenotypes of disease progression and drug response are elucidated. Nanogen, Inc., a leading provider of products for advanced diagnostics, is committed to helping drive these changes in healthcare. The company believes that diagnostics will be an increasingly important component of patient management, as molecular tests are used to provide physicians with information about the underlying pathology of each patient’s illness and the likely response to different therapies. Through product development and collaboration efforts, Nanogen is creating the tools needed to facilitate the development of diagnostic tests that will be used to personalize medicine.

Natural variations in an individual’s genes – in combination with environment, diet and other factors – affect his or her susceptibility to disease and response to therapeutics; these differences can be incorporated into treatment decisions. Likewise, variations in the biological basis of diseases can affect disease progression and outcome; these differences can be used to identify subpopulations of patients who may respond better to some therapies than others. Drug selection and dosing has historically been done on a trial-and-error basis, as the diagnostic tools available to physicians have been insufficient to enable personalization of treatment for many diseases. Advances in our understanding of the effects of a person’s genetic profile and biomarker status will guide therapeutic choices as we move away from one-size-fits-all drugs towards targeted therapies. By incorporating information about the patient’s proteomic and genomic profiles into health management, physicians will be better able to diagnose accurately, manage healthcare proactively and ensure that prescribed therapies will have the desired effect while mitigating risks of serious adverse reactions.

Pharmacogenetics, the correlation of specific genetic variants with response to drugs, is one component of personalized medicine. Variations may occur in genes encoding metabolizing enzymes, such as the cytochrome p450 gene family, or in genes encoding proteins involved in transport or excretion of drugs and breakdown products. Biomarker analysis is another component of personalized medicine that can be incorporated into various stages of drug development and patient care. Biomarkers are indicators of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention, and can be used to identify subpopulations of patients who might respond differently to a given therapeutic. Biomarkers can also aid in diagnosis by enabling physicians to distinguish between different physiological states with similar presentations and monitor disease remission or recurrence.

Personalized medicine will affect healthcare overall, and specifically the delivery of care to the patient, through impacts on drug development, on administration of therapeutics, and on early detection of disease risk. Nanogen is developing products to facilitate each stage in this process, enabling the realization of the benefits that molecular diagnostic technologies can bring to the healthcare market.

Impact on drug development

Drug development costs have soared, although the rate at which new therapies are being introduced has not increased concomitantly. Pharmaceutical companies are trying to mitigate rising costs of development by incorporating pharmacogenetic and pharmacogenomic testing into their drug development pathways. At the pre-clinical stage, analysis of genomic patterns is performed to evaluate potential toxicological effects. In early phase clinical trials, incorporation of pharmacogenetic testing can reduce the likelihood of unexpected adverse events in later trials by allowing drug safety and efficacy to be assessed in a variety of relevant populations or subpopulations. For drugs known to be metabolized by a specific enzyme, patients with variants in the gene encoding that enzyme could be proactively included in phase I studies. Later phase clinical trials could be enriched with patients most likely, based on genotyping or biomarker results, to show efficacy, thus enabling approval for drugs that are effective in a subset of patients.

Shifting failures from late to early clinical phases would result in significantly reduced drug development costs; by moving 10 percent of phase III failures to phase I, an estimated US$98 million in savings could be realized. Benefits from pharmacogenetic testing could also be realized after a drug has been introduced into the market. Genotyping individuals with unanticipated adverse reactions could allow particular genetic profiles to be correlated with the negative side effects and allow development of a test to identify patients at risk. This approach might reduce the number of patients who could receive the drug, but would allow the therapy to stay on the market rather than be recalled.

Nanogen products can meet the needs of pharmaceutical companies and clinical research organizations seeking to incorporate pharmacogenetic testing into their drug development process. Nanogen is the distributor for Jurilab’s DrugMEt microarray test for identifying variants in genes involved in drug metabolism. These glass-slide based arrays are well-suited for research efforts incorporating genetic testing into clinical product development, offering a simple and convenient method for analyzing mutations in seven drug metabolizing genes. For laboratories requiring more flexibility in test content, Nanogen’s electronic microarrays provide an open platform on which novel genotyping assays can be developed to analyze genetic variants known or suspected to be involved in the metabolism or mechanism of action of particular drug candidates.

Impact on patient care: treatment selection and dosing

Avoidable costs related to adverse drug reactions – including hospitalization costs and long-term care costs – have been estimated to exceed US$100 billion. Advances in diagnostic methodologies will enable physicians to select the most appropriate drug for a patient, and will guide dosing decisions to mitigate the risk of adverse events. Pharmacogenetic analysis of cytochrome p450 and other drug metabolizing genes can facilitate identification of those patients likely to metabolize drugs more slowly (‘poor metabolizers’) or more quickly (‘ultra-metabolizers’) than average. By identifying poor metabolizers and tailoring their prescriptions and dosing, the occurrence of adverse reactions can be reduced. Identification of ultra-metabolizers could aid in achieving effective therapeutic levels more rapidly.

Nanogen is developing reagents that clinical laboratories can use to develop assays to identify mutations in cytochrome p450 genes and other genes correlated with drug response. To meet the needs of the developing pharmacogenetic testing market, these reagents may be offered as ‘research use only’ (for markers with unproven clinical utility), ‘analyte specific reagents’ and/or ‘FDA-cleared devices’. For laboratories investigating their own genetic markers and seeking a flexible platform for assay development, the NanoChip400 electronic microarray system is an open, general-purpose detection system that can be used to create assays for known or novel allelic variants.

Impact on patient care: Better diagnosis and early intervention

Longer-term, genotypes and biomarkers will be used prognostically rather than just diagnostically to evaluate a person’s likelihood of developing disease. Patients can then take proactive steps, through dietary and lifestyle changes or prophylactic medication, to lower their risk or delay disease onset.

Jurilab, a Finnish company, has programs in hypertension, acute myocardial infarction and diabetes that take advantage of the uniquely homogeneous founder population in Eastern Finland. By combining genome-wide scanning with an assessment of patient healthcare records, Jurilab has identified unique markers that may serve as prognostic indicators of disease susceptibility. Assays based on these markers may, in the near future, provide additional tools for physicians to use in assessing a patient’s risk for developing disease. Nanogen and Jurilab are working together to further evaluate the clinical utility of these markers in other populations and develop products for those that provide value as prognostic indicators. Some of these markers may also offer new targets for development of novel therapeutics or provide value as biomarkers to aid in diagnosis or monitoring of therapeutic treatment.

Biomarkers are currently in use in the rapid care setting to aid in diagnosis; identification of novel biomarkers will significantly expand this market. These tests are particularly useful when similar symptoms are correlated with different physiological conditions. Nanogen offers Cardiac STATus products to detect elevation of cardiac markers associated with acute coronary syndrome (ACS); these FDA-cleared tests can aid in diagnosis of ACS and acute myocardial infarction.

Personalized medicine offers the promise of tailored healthcare, and assurance that a patient will be administered the most appropriate therapy and dose given their medical condition and ability to respond to the drug. The near-term challenge lies in bridging the gap between early-stage clinical research and actual clinical practice. Nanogen’s advanced diagnostic products provide the tools that will enable this transformation to occur.

 

DrugMEt microarray test
The DrugMEt microarray test enables pharmaceutical and biotech research laboratories and clinical research organizations to incorporate pharmacogenetic testing into their drug development efforts. 24 polymorphisms in seven drug metabolizing enzymes are analyzed; 16 samples can be genotyped on each glass slide array. The CYP2D6 deletion/duplication is analyzed via gel electrophoresis. The DrugMEt microarray test is available in the US as a RUO reagent.

NanoChip electronic microarrays
For laboratories seeking a flexible platform on which to develop ‘homebrew’ assays, Nanogen’s electronic microarrays offer significant advantages over other technologies. Because the NanoChip arrays are built by the user rather than containing predetermined content, the arrays offer unique flexibility in assay design. This feature is especially important in developing areas like pharmacogenetics.

Each site on the NanoChip microarray is an individually controllable microelectrode. Introduction of an electronic current enables rapid movement of nucleic acids in a sample to activated test sites, where target DNA can hybridize with complementary capture oligonucleotides. Allele-specific probes are used to detect the presence of genetic variants. The remaining array sites are unaffected and available for subsequent use. These active microarrays thus provide a tremendous amount of flexibility, enabling parallel analysis of different targets from multiple samples.

Cardiac STATus product lines
The Cardiac STATus products were developed to aid in the diagnosis of congestive heart failure and acute myocardial infarction. The Cardiac STATus line includes four FDA-cleared tests.

 

Pharma focus…

Recently, NGP had the chance to sit down with members of Nanogen’s senior management team and discuss their strategy for building an advanced diagnostics business. David Ludvigson, Nanogen’s President and Chief Operating Officer, Dr Walt Mahoney, Vice President of Research and Development and Carl Foster, Nanogen’s Vice President of Alliance Management, give their thoughts.

NGP. What strategies are behind Nanogen’s recent acquisitions?

DL. Acquisitions play an important role as growth accelerators. We specifically target companies with product lines that complement and add depth to our existing product portfolio, and that are or can be cash flow positive when integrated. In the past 15 months, we have acquired two companies and the business unit of a third. Epoch Biosciences, which we acquired in late 2004, brought us a very strong product line for real-time PCR for research and clinical diagnostic applications. We are leveraging the MGB technologies and proprietary nucleoside and dye chemistries developed by Epoch in our internal development efforts and also have an active out-licensing program to enable clinical laboratories and industry partners to incorporate these technologies into assays they are developing.

The acquisitions of SynX Pharma and the Cardiac STATus product line of Spectral Diagnostics have enabled Nanogen to enter the point-of-care market. Through these acquisitions, we will realize revenue in a new market area without incurring the significant capital expense required for organic growth. These companies fit the broader vision of Nanogen as an advanced diagnostics company focused on providing products for the full range of tests required to deliver truly personalized medicine – enabling laboratorians and healthcare providers to facilitate the transition of research discoveries into clinical laboratory tests and point-of-care tests for improved patient management.

Our investment in Jurilab is another example of our intent to build Nanogen’s breadth of capabilities through a variety of business relationships. Jurilab has leveraged a unique founder population in eastern Finland to identify genetic markers of susceptibility for several complex diseases. Through Jurilab, Nanogen has access to markers that may be the basis for novel diagnostic assays and, possibly, new drug targets.

NGP. Would you expand on the Jurilab investment and the value it brings to Nanogen?

DL. Jurilab is a Finnish company that is focused on three areas: sales and distribution of DrugMEt microarrays for pharmacogenetic testing; identification of novel molecular diagnostic markers; and identification of new drug targets. A significant strength of the company is its access to the North Savo Cohort, a highly homogeneous, isolated population of ~100,000 people. Jurilab has used its scientific expertise to identify genetic polymorphisms correlated to diseases in this population; the main areas of focus have been acute myocardial infarction, hypertension and type II diabetes.

As part of our continuing corporate development efforts, we made a strategic investment in July 2005 to purchase a partial equity interest in Jurilab. We saw multiple synergies between the companies. Jurilab’s DrugMEt microarray product, available in the US as RUO reagents, represented an opportunity to immediately enter the pharmacogenetics research market. Through our relationship, Nanogen has rights to the distribution of this product in the US and Europe. In addition, Jurilab’s discovery programs hold tremendous potential for identification of novel genetic markers that can be used as an aid in the early diagnosis of disease. These same programs offer an opportunity to create partnerships with pharmaceutical companies based on the potential of these genes as drug targets. Importantly for our vision of personalized medicine, these markers could also offer the opportunity to develop companion diagnostic tests in tandem with the development of novel therapeutics targeted to particular genes and genetic polymorphisms.

NGP. Tell us more about your interest in Jurilab’s type II diabetes project. What are the synergies with Nanogen’s current and future product lines?

WM. Type II diabetes is a debilitating disease that is growing at an alarming rate. The disease is associated with a wide spectrum of pathologies, including blindness, kidney failure, peripheral vascular disease and cardiovascular disease, which is the leading cause of death in patients with type II diabetes. Studies have shown that the average newly diagnosed patient has had diabetes for as long as seven years prior to diagnosis and already presents with macrovascular disease and diabetic retinopathy. An ability to detect at-risk patients earlier would have significant impact on healthcare costs and patient quality of life, perhaps leading to the reduction of type II diabetes in at-risk patients.

Jurilab has discovered novel genetic markers that could be used as an aid in the assessment of predisposition to type II diabetes. Such markers could also be the basis for pharmacogenetic tests that would predict the efficacy of various treatments. Our relationship with Jurilab therefore provides us with an unusual opportunity to develop high-value, proprietary diagnostic content for our molecular diagnostics business; create unique, more personalized solutions to evaluate and diagnose disease; and positively impact public health.

In addition to the diagnostic applications, Jurilab’s markers hold promise as novel targets for new therapies. Neither Jurilab nor Nanogen is focused on drug development, so we will work with Jurilab to identify partnership opportunities with pharmaceutical companies to enable realization of the full potential of these valuable discoveries.

NGP. Can you expand on Nanogen’s plans for partnering with pharmaceutical companies?

CF. As Walt mentioned, one primary focus of our activities in this area will be on Jurilab’s markers for type II diabetes. Current therapies primarily address glucose regulation and tolerance, and insulin production and excretion. Identification of genes and proteins involved in the early stages of insulin resistance could allow patients to delay onset of serious disease through lifestyle changes and, where necessary, early use of hypoglycemic agents. The novel markers identified by Jurilab could provide pharmaceutical companies with a greater understanding of the underlying disease process and valuable new targets for drug development efforts.

In addition to the markers identified by Jurilab, we are also talking to pharmaceutical companies about their current and projected use of pharmacogenetic testing in drug development.

Development of companion diagnostics for pipeline drugs may enable companies to reduce their clinical trial costs and timelines by identifying patients most likely to benefit from treatment. We believe that Nanogen’s broad capabilities as an advanced diagnostics company position us as the ideal partner for pharmaceutical companies seeking to incorporate genetic testing into their drug development efforts.