In one of the last significant pieces of business in 1998, Quintiles Transnational Corp. (Research Triangle Park, NC) and Variagenics, Inc. (Cambridge, MA) formed a strategic alliance for commercializing Variagenics' pharmacogenomics technologies in the clinical development of new pharmaceuticals. The agreement is designed to apply knowledge of genetic variations that influence drug action, safety and efficacy to improve the rate of success of drug development, and to assist the pharmaceutical industry in developing safer, more effective products.
Under the terms of this agreement, Quintiles will market Variagenics' genetic variance discovery and analysis capabilities to its broad customer base of pharmaceutical and biotechnology companies engaged in clinical trials. Variagenics will be a preferred provider of contract pharmacogenomics services to Quintiles' customers. Financial terms were not disclosed.
"Of the elements changing medicine, genetics provides insights so profound that it has the ability to change everything we know about medicine and how medicines are developed," said Ludo Reynders, chief executive officer of Quintiles Contract Research Organization services group. "We expect the alliance with Variagenics will allow Quintiles to better serve the pharmaceutical industry by providing pharmacogenomics capabilities seamlessly along with our other clinical development services to improve the efficiency and success of drug development."
"As the market leader in providing clinical trials services and in integrating innovative, value-added technologies into the development process, Quintiles is an ideal partner for our first major corporate alliance," said Fred D. Ledley, president and CEO of Variagenics. "Genetic factors contribute substantially to variable drug effects and constitute a critical element of a product's profile that must be considered in clinical trials. We believe this alliance with Quintiles will accelerate the integration of pharmacogenomics into clinical trials to streamline new drug development."
Pharmacogenomics is a rapidly emerging field focused on understanding the genetic factors underlying drug action and applying this information to improve the clinical use and development of pharmaceutical products. In clinical practice, the understanding of how genetic variation leads to variable drug effects can be used to prescribe drugs selectively to individuals in regimens and doses that are most likely to be safe and effective. In drug development, knowledge of genetic variation that may affect drug action can be used to reduce the cost and complexity of clinical trials, increase the success rate of achieving regulatory approval, and achieve approvals for new classes of diagnostic and therapeutic products.
Quintiles Transnational is the market leader in providing a full range of integrated product development and marketing services to the pharmaceutical, biotechnology and medical device industries. Quintiles also provides healthcare policy consulting and health information management services to healthcare and governmental organizations worldwide. With more than 14,000 employees worldwide and offices in 30 countries, Quintiles operates through specialized work groups dedicated to meeting customers' individual needs.
Variagenics, Inc. identifies clinically important variances in genes that affect drug action and applies this information to the discovery and development of new drugs. The company has established a broadly enabling, proprietary technology platform for rapidly discovering normal genetic variations and determining their structural and functional consequences (see below). Variagenics is a privately held, venture-backed company.
Most drugs elicit a safe response in only a fraction of individuals. Consequently, drugs are commonly administered to patients with no certainty that they will be safe and effective. Many important drugs are effective in only 30-40% of patients for whom the drug is prescribed, and virtually all drugs cause adverse events in some individuals. Evidence suggests that much of the variability in drug action may be due to genetic variation among patients.
Genetic effects on drug action underlie variable clinical responses. Every drug interacts with many different proteins on the pathway of drug action. Variagenics has demonstrated that up to half of all proteins exhibit common variances and are present in different forms in different individuals. Variances on the pathway of drug action may cause a subset of the population to have favorable or unfavorable responses to a drug. Understanding such genetic effects on drug action will enable the use of gene-based diagnostic tests to identify patients for whom a drug will be safe and effective. This focus on identifying variances on pathways of drug action should be distinguished from studies aimed at gene discovery or understanding the etiology of disease.
Variagenics' technologies enable the practical application of pharmacogenomics within the timeline, scope, and cost of conventional drug development programs. The Company's platform technology enables the rapid, economical discovery of sequence variances throughout the pathway of drug action. Variagenics then employs chemical biology and genetic methods to identify those variances that may have significant effects on drug action. This information can be applied in preclinical development for lead optimization and clinical trials can be designed to establish the association between specific variances and clinical outcomes. To date, Variagenics has studied variance in more than 6,000 genes potentially involved in drug action. The company began its first clinical trial to evaluate the pharmacological effects of certain proprietary genetic variances on the action of 5-fluorouracil for treating colon cancer at the Massachusetts General Hospital in May 1998.
Many experts today believe that pharmacogenomic studies should be performed on all compounds in clinical development, before clinical trials. Variagenics has developed models for the use of pharmacogenomics both to aid product approval and to increase market penetration, pricing and profitability of certain drugs. Variagenics' corporate philosophy is based on the importance of assessing potential genetic influences on dosing, efficacy or safety, which the company feels will be essential to ensure the most efficient path for clinical development and to maximize the commercial potential for pharmaceutical products.
Varigenics' Variance Imaging is a proprietary method for rapidly and effectively detecting genetic variation in gene sequences based on Enzymatic Mutation Detection (EMD). The method employs enzymes known as resolvases, such as the T4 endonuclease VII, which is naturally involved in recognizing DNA mismatches. This enzyme cleaves double-stranded DNA at sites where a "bubble" is formed in the helix by mispairing or an insertion/deletion of bases, and is normally responsible for recognizing and cleaving branched DNA intermediates that form during DNA replication and packaging. The fragments resulting from this cleavage can be easily imaged by conventional electrophoresis or on automated "sequencing" gels.
Variance Imaging (Figure 1) involves hybridizing DNA with a known sequence to a labeled test sample and exposing the resulting double-stranded DNA to resolvase. The enzyme scans along the double-stranded DNA, binding to single-stranded bubbles in the DNA that arise from the presence of a mismatch, and cleaving DNA immediately 3' to the mismatched base.
The fragments resulting from such cleavage can be separated and imaged by conventional gel-based electrophoresis (Figure 2), automatic gel-based sequencing devices (Figure 3), or newer methods including capillary electrophoresis. Significantly, this method reveals not only the existence of a sequence variance in the test sample, but also its location within the gene.
Variance Imaging has been validated on hundreds of variances in different genes and has been shown to detect all types of mismatches. Proof of principle studies have demonstrated a high degree of sensitivity and specificity (>98%) for known mutations in genes such as -globin, p53, CFTR, fibrillin, Rh, BRCA1, and MSH2/MLH1, as well as many variances that are candidates for Variagenic Targeting. Additional studies have demonstrated the utility of Variance Imaging for screening large numbers of genes for variances, and more than 20 genes of potential interest for pharmacogenetic studies have already been characterized.
Many different methods for mutation detection are used today. The earliest methods involved physical separation of single-stranded or double-stranded DNA containing different sequences based on their transit through various electrophoretic or chromatographic media. Genes can be repetitively sequenced using automatic methods or sequencing by hybridization. Variance Imaging is fundamentally different because it is specifically designed to recognize the variant base in double-stranded DNA.
Variance Imaging is a rapid, high-throughput method capable of achieving the extremely high levels of specificity and selectivity critical for pharmacogenetic studies. Variance Imaging is different because it not only reveals the presence of a sequence variance, but also allows imaging of its location within the gene. The Variance Imaging method provides a level of effectiveness, economy, and ease of implementation that is superior to any other current methods.
The use of resolvase for variance detection was invented by Richard Cotton and Rima Youil at the Murdoch Institute in Melbourne Australia, and by Borris Kemper at the University of Cologne. Cotton is a recognized leader in field of human genetics and is currently Head of the Mutation Research Center at St. Vincent's Hospital in Melbourne and Editor of the journal Human Mutation. Kemper is a leading expert on resolvase enzymes and is responsible for characterizing their structure and function.
For more information: Fred Ledley, president and CEO, Variagenics, Inc., 60 Hampshire Street, Cambridge, MA 02139. Tel: 617-588-5300. Fax: 617-588-5399.