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Alere Developing Pair of NAT Platforms with Initial Assays Planned for HIV Viral Load, Flu

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Health management-services and diagnostics firm Alere is developing a pair of nucleic acid testing platforms, representing the company's first major move into the molecular diagnostics space, according to recent company presentations.

The first platform, called the Alere NAT Analyzer, will enable multiplexed nucleic acid measurements from whole blood samples, initially for HIV viral load monitoring but eventually for detecting or monitoring other infectious diseases, such as hepatitis C.

Alere expects to complete the requisite studies and registration process to obtain CE marking for the platform by the end of this year, and to begin clinical trials to support a premarket approval submission for the US market in 2013, according to recent company presentations.

The second platform, called the iNAT, will use isothermal amplification technologies from two companies Alere acquired in 2010 — TwistDx and Ionian Technologies. The system is expected to provide low-cost molecular testing capabilities in physicians' offices and, eventually, the home, according to the company.

Alere said that it has begun US clinical trials for its first test on the iNAT platform, an assay for influenza that likely won't near the market until the 2013 respiratory disease season. However, the company also said that it plans to develop additional infectious disease tests on the platform beginning next year.

Alere, formerly known as Inverness Medical Innovations until changing its name in May 2010, has been discussing development of its nucleic acid testing platforms in various investor conference calls since last year. The company has kept a relatively tight lid on details about the technology, and did not return multiple calls and e-mails for this story.

However, in a presentation in January at the JP Morgan Healthcare conference in San Francisco, Chairman and CEO Ron Zwanziger for the first time disclosed multiple details about the platforms.

According to Zwanziger's JP Morgan presentation, the NAT Analyzer is designed to measure viral load from small-volume, whole-blood samples. The rationale for developing the platform is based on a 2010 Journal of Clinical Microbiology paper published by scientists from Clondiag, a Jena, Germany-based biochip maker that was acquired by Inverness/Alere in February 2006 and is now part of Alere's German medical diagnostics arm Alere GmbH.

In that JCM paper, the Clondiag researchers demonstrated the feasibility of using small volumes of venous and finger-stick whole blood as samples for viral load testing, noting that the diagnostic sensitivities of a custom nucleic acid amplification assay of 1 mL of plasma and 10 µL of venous whole blood were comparable – a finding that the researchers wrote "provides the prerequisite to develop a point-of-care assay for HIV therapy monitoring and diagnosis, with the latter being particularly useful for infant diagnosis and for early detection of the acutely infected infants using only minute amounts of [whole blood.]"

Indeed, prior to its acquisition by Alere, Inverness' Clondiag group was already developing a point-of-care HIV viral load test that, according to various company presentations, could detect multiple HIV-1 and HIV-2 targets simultaneously using a real-time, microarray-based detection method called ArrayTube, which comprises custom biochips spotted with nucleic acid or protein probes in a standard laboratory microtube.

It is unclear whether the NAT Analyzer is integrating the Clondiag ArrayTube technology; however, in its JP Morgan presentation, Alere noted that the platform contains "internal process controls for nucleic acid purification, amplification, and detection;" and will use disposable cartridges requiring no sample preparation with a set-up time of less than 30 seconds and a test turnaround time of less than 30 minutes.

In Alere's most recent investor conference call to discuss the company's first-quarter 2012 financial results, Zwanziger noted that HIV viral load testing will be the first application for the NAT Analyzer, but that "other applications, including hepatitis C, are expected to follow."

Zwanziger also said that feedback from early-access partners "has been very positive, both on analytical performance and usability under point-of-care conditions, and we anticipate completing the technical file and studies to support CE mark before the end of this year."

Zwanziger did not address US commercialization plans in the Q1 conference call, but he did remark at JP Morgan that the company expects to begin clinical trials this year to support regulatory clearance of the NAT Analyzer in Africa; and expects to begin trials next year to support a premarket approval submission for US Food and Drug Administration clearance.

iNAT

Alere's second platform in development, the iNAT, is a point-of-care platform that will be able to detect any DNA or RNA sequence from raw, unpurified samples with full multiplexing capabilities in less than 15 minutes, according to Alere's JP Morgan presentation.

This platform will integrate a pair of isothermal amplification technologies that Alere brought on board with its 2010 acquisitions of TwistDx and Ionian Technologies.

Specifically, Alere acquired Cambridge, Mass.-based TwistDx in March 2010 for an aggregate purchase price of $70.8 million consisting of an initial cash payment of $35.2 million and a contingent consideration obligation of up to $125 million, according to Alere's Feb. 29 10K filing with the US Securities and Exchange Commission.

TwistDx developed the recombinase polymerase amplification, or RPA, method, which uses recombinase enzymes to pair oligonucleotide primers with homologous sequences in duplex DNA. According to the company's website, this method directs DNA synthesis to defined points in sample DNA and, if the target sequence is present, DNA amplification is initiated without thermal cycling or chemical melting.

The method works optimally at around 37° C and can specifically amplify DNA to detectable levels from just a few target copies within five to 10 minutes.

PCR Insider reported in August that Seattle's PATH institute is using the RPA method to develop a minimally instrumented, point-of-care nucleic acid amplification test to diagnose HIV-1 in infants in resource-poor areas of the world (PCR Insider, 8/25/2011). In addition, a University of Chicago team developing a multivolume digital PCR method and microfluidic "SlipChip" for HIV or hepatitis C viral load monitoring combined their platform with the RPA method in a study detailed in an April 2011 Analytical Chemistry paper (PCR Insider, 10/20/2011).

Meantime, Alere acquired San Diego's Ionian Technologies in July 2010, with terms of the acquisition requiring Alere to make payments based on the successful completion of multiple product-development milestones until 2015 with a maximum payment amount of $57.5 million, according to the Alere 10K.

Alere acquired Ionian Technologies primarily for its nicking enzyme amplification reaction, or NEAR, technology. This isothermal method was first described in 2003 by Ionian founder David Galas. The NEAR technology is based on the very rapid detection of any small DNA or RNA fragments generated directly from the target nucleic acid, according to the company's website. Importantly, it notes, no separate cDNA synthesis step is necessary for the detection of RNA targets. The NEAR amplification products can be detected by a variety of methods, including LC-MS, real-time fluorescence, and capillary electrophoresis.

In November 2009, Ionian Technologies and Roche Diagnostics inked an agreement giving Roche exclusive manufacturing rights for certain applications of the NEAR technology in exchange for Roche's help in identifying new applications and customers for the technology (PCR Insider, 11/12/2009). The current status of that agreement is unknown. Roche officials were not immediately available for comment.

Also in November 2009, Ionian said that it was developing a NEAR-based molecular diagnostics platform for the developing world under a two-year, $3 million grant from the Bill & Melinda Gates Foundation.

Alere noted in its JP Morgan presentation that the iNAT platform will not only use the RPA and NEAR technologies, but also Alere's patented lateral flow detection technology, and will "address the limitations related to the sensitivity of existing lateral flow tests."

The company also believes the test will provide low-cost molecular testing in physicians' offices; provide a tool for government organizations in pandemic preparation programs; be ideal for deployment in both the developed world and resource-poor settings; and, ultimately, "will drive infectious disease diagnostics into low-tech and home environments."

Zwanziger said during the Q1 conference call that the first iNAT test will be a flu assay, and that US clinical trials for the diagnostic are underway. "However, based on a lack of available flu samples due to low respiratory activity in the US in Q1, the launch of this platform into the US and EU hospital markets may not occur until 2013 respiratory season," Zwanziger said.

He added that "it’s important to note that this platform is more than a molecular flu test;" and that the "small-footprint device will be capable of fully multiplexing raw, unpurified samples within 15 minutes from sample input to results, using a cost-effective, cartridge-based system. Once the flu cartridge has been introduced, additional infectious disease applications should follow closely behind."

Alere said that possible follow-on iNAT tests targets may include Streptococcus A, respiratory syncytial virus, Clostridium difficile, chlamydia, tuberculosis, and methicllin-resistant Staphylococcus aureus.

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