EMERGING IVD COMPANIES

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The Human Genome Project was a major step toward helping to achieve the goal of personalized medicine. By sequencing all of the genes in the human genome, scientists hoped to be able to identify genes causing or connected to disease more rapidly. On the downside, the study of so many genes is daunting, and technology has struggled to keep pace. It appears some companies are helping to end that struggle.

Today, using high-throughput, automated microarrays that hold thousands of bits of genetic information on a chip made of glass or silicon, scientists can study enormous numbers of genes rapidly. Then, via multiplexing, they can amplify and analyze multiple genetic loci simultaneously with the goal of identifying genetic diseases, creating diagnostic assays for them, and finding routes for prevention of their manifesta­tions, or a treatment or cure.

IVD Technology’s editorial advisory board and reader board members have identified three emerging IVD companies profiled below as having what it takes to set themselves apart in the increasingly crowded IVD market. Whether providing innovative technologies to enable efficient scanning of the genome for biomarkers or developing diagnostics for personal use, they are on the cutting edge of personalized medicine.

Illumina: From Discovery to Diagnostics

Illumina Inc. Location: San Diego, CA CEO: Jay T. Flatley Founded: 1998 Areas of emphasis: Microarray-based products and services for a range of genetic analysis applications, including SNP genotyping, gene expression, and protein analysis.

Founded in 1998, Illumina Inc. (San Diego) develops, manufactures, and markets products and services for a variety of genetic analysis applications including single nucleotide polymorphisms (SNP) genotyping, gene expression, and DNA sequencing powered by its BeadArray, VeraCode, and sequencing technologies. The company completed its first public offering in 2000 and has more than 1000 employees worldwide.

“Diseases are more complex than we initially thought, and because of this, researchers need technologies that enable the discovery of many genetic markers,” says Mickie Henshall, marketing manager of molecular diagnostics at Illumina. Microarrays have played an instrumental role in how the entire genome can be scanned to uncover such markers. With the BeadXpress platform, researchers can focus on markers that are clinically relevant.

The company touts its Bead­Array technology for whole-genome association studies in which scientists can look at from hundreds to millions of markers per sample. The VeraCode technology, powered by the BeadXpress system, enables researchers to conduct focused analysis, validation, and screening of the genome, ultimately letting users “bring it down to a smaller scale, both to control costs and to get more specific at a very competitive price,” Henshall says.

“The BeadArray technology was our core technology for our microarray-based applications until two-and-a-half years ago when we acquired the VeraCode technology,” Henshall explains.

Its newest VeraCode technology enables clinical researchers to validate multiplex panels for the creation of diagnostics, Henshall explains. This platform brings the level of detail down to a few hundred or even one SNP.

The company has developed VeraCode as its platform for going into molecular diagnostics to develop diagnostic assays. As an example, Illumina began working with Children’s Hospital in Eastern Ontario, CA, in early 2007 to develop screenings assays for hemoglobi­nopathies and spinal muscular atrophy (SMA) using the VeraCode technology. Henshall says, “Custom­ers draw upon our expertise and tools to develop customized assays.”

“Currently, the challenge in the marketplace is having a consolidated platform for running multiple assays that really cover the spectrum of tests that can be run. With VeraCode, we’re able to address genotyping, gene expression, and protein-based assays. These are all different things we can do with the system,” she says. “Under design control, we have built Bead Xpress in anticipation of entering the diagnostic market.”

The BeadXpress Reader system by Illumina is a high-throughput, dual color laser detection system that can scan a broad range of multiplexed assays developed using the VeraCode digital microbead technology.

With the three technologies together, Henshall says, “Illumina offers products that take customers from initial discovery down to molecular diagnostics.”

Illumina also participated in the National Center of Toxicological Research’s Micro Array Quality Control consortium, which arose to develop standards for the rapidly growing microarray arena. “This was a program that FDA set up to demonstrate that the results generated from microarray platforms were reproducible and reliable—to see if we could trust the gene assays that people had,” Henshall explained. “Our competitors participated, and we demonstrated that our platform is robust and consistent with FDA expectations.”

Henshall says the company’s greatest strength is its ability to cover the whole spectrum in a way that is user-friendly, easy to use, and sustainable.

Nanosphere: Creating the Gold Standard

Nanosphere Inc. Location: Northbrook, IL CEO: William Moffitt Founded: 2000 Areas of emphasis: Coupling gold nanoparticle chemistry and capabilities with multiplex array analysis, microfluidics, and human factors instrument engineering and software development.

“What they came up with is a way of attaching synthetic oligonucleo­tides to the surface of gold colloid reliably that allows it to remain stable for years in solution,” according to William Cork, chief technology officer at Nanosphere Inc. (Northbrook, IL). Using this technology, Nanosphere has created proprietary gold nanoparticle probes that have high multiplex capabilities and are highly sensitive and specific.

The goal is to be able to diagnose infectious and genetic diseases expediently. Aimed at diagnostic and molecular labs in community hospitals and elsewhere, learning about how silver and gold function at the nanoscale proved invaluable. “At the nanoscale, the properties of gold are different. On the macrosurface, silver won’t stick to gold, but at the nanoscale, gold actually acts like a seed for the silver so we can grow them together,” Cork explained.

One of the results is the Verigene system, a benchtop molecular diagnostics workstation. This system allows nucleic acid and protein detection on the same platform in a detection system that “is versatile, fully automated, offers rapid and accurate results, and requires minimal user intervention,” says Cork. Nanosphere designed this system, which uses a reader, a processor, and test cartridges, to be simple to use, convenient, and mobile, in addition to providing rapid multiplex target detection.

Because each cartridge is patient-based, results are available in hours rather than days or weeks. “We can avoid the batching requirement which is enabled by using random access,” Cork explains.

The Verigene system by Nanosphere.

“It relies on a microfluidic-device-controlled computer system which controls fluids, reagents, time, and so on in a single-use, disposable item,” Cork explains. Using bar coding technology, the reader reads a bar code that specifies the test and the patient ID. It processes the reagents within the cartridge to deliver an assay result, images the bound target material labeled with the gold nanoparticle, and measures the light intensity coming off the assay. These light measurements correlate to the assay results.

“One of Nanosphere’s key strengths is the ability to take optical, software, electrical, mechanical, and material properties and integrate and engineer them into a platform that provides a clinical diagnostic tool that is very simple and easy to use for the end-user,” Cork says. Although the technology itself is complex, the user interface is a simple sample-and-result system in which users put the sample in and read the results, since everything else happens inside the system.

Cork says what sets Nanosphere apart is the company’s ability to bring a nanotechnology to the clinical diagnostic market in a highly integrated and automated platform in a short time frame. Nevertheless, it does not do so by cutting corners. “The team is focused on doing everything right, all along the way,” Cork says. This diligence led to two consecutive FDA clearances in September 2007. “We were the first FDA-cleared assay for warfarin on the market. We’ve had a lot of firsts for a start-up company.”

The technology exists on a global platform, so the company hopes to expand into Japan and Europe. In addition, Nanosphere plans to add infectious diseases, expanded SNP capabilities, and protein assays to its platform.

“We are currently evaluating an assay for cardiac markers for troponin that might be an earlier detection system than what is available currently,” Cork concludes.

OraSure Technologies: Bringing Oral-Fluid Diagnostics to the Public

OraSure Technologies Inc. Location: Bethelem, PA CEO: Douglas A. Michels Founded: 2000 Areas of emphasis: Develops, manufactures and markets oral fluid specimen collection devices using proprietary oral fluid technologies, and other IVD products including immunoassays.

OraSure is one of the pioneer companies behind rapid HIV testing. Since 2002, it has provided rapid HIV tests that enable individuals to get results in 20 minutes. “Before that, most HIV testing in the public health sector was done using traditional blood tests, and tested individuals often never got their results,” said Douglas Michels, OraSure’s president and chief executive officer. Michels adds that the Centers for Disease Control and Prevention (CDC; Atlanta) estimate that up to one-third of tested individuals did not obtain results previously. Using the OraSure products, more than 99% of inividuals tested get their results. Testers can then connect those who test positive to care resources and provide on-the-spot counseling.

The OraQuick Advance test by OraSure Technologies Inc. is the first FDA-approved and CLIA-waived HIV-1/2 test that provides rapid and accurate results in 20 minutes using oral fluid, fingerstick, or venipuncture whole blood and plasma specimens.

The company uses the same oral technology for substance-abuse testing. “It is a very welcome alternative to urine testing,” Michels explains. “Collecting an oral sample is much more dignified, both for the collectors and the specimen donors.” There are hundreds of Web sites to help people beat a urine drug test; but with oral tests, the number of ways to outwit the tests is far fewer.

The technology saves time and money for employers who use drug testing in preemployment or cause testing. In parole and probation testing, oral testing eliminates problems such as gender mismatch, shy bladder problems, and other issues that arise when observed collection is mandatory.

OraSure also has some exciting developments in the pipeline. The company will start clinical studies for a rapid test for hepatitis C, also on the OraQuick platform, with a goal of expedient FDA submission. “We are very excited about it, especially since hepatitis C is about five times more prevalent than HIV worldwide, and half of those with it don’t know they are infected,” Michels says. Through an agreement with Schering-Plough, the company will be detailing the product into the physician office market.

OraSure is also working to gain FDA approval to sell the OraQuick HIV product over the counter in retail pharmacies and mass retail outlets, which will enable even-more-widespread testing. OraSure hopes to complete clinical studies soon and have the product on shelves this year.

Michels says strong and unique technology sets OraSure apart from other IVD companies, but also emphasizes that the company’s commitment to its strategic focus on infectious disease, substance abuse, and cryosurgery “enables us to understand the markets in which we participate and compete, who our customers are and what their needs are, and to anticipate their future needs.”

OraSure credits its success to its professional staff, including its scientists, operational staff, regulatory advisers, and sales and marketing force throughout the world. In fact, the company does business in 35 countries. While in 2­004 only 10% of the company’s business came from outside the United States, in 2007 that number had risen to 21% by the first half of the year.

In addition, the company is financially sound. Over the last several years, it has enjoyed a compounded annual growth rate of 21%. It has generated positive cash flow from operations for the last four years and has been profitable for the last two years.