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MTM Laboratories Planning FDA Filings for Cervical Disease Tests

By Tony Fong

NEW YORK (GenomeWeb News) – Seeking to capitalize on what MTM Laboratories' CEO calls the "next-generation technology beyond HPV testing," the German diagnostics firm plans to file for regulatory approval in the US in the coming months for its assay for high-grade cervical disease.

In addition, MTM expects to launch a clinical trial sometime in the first half of this year in preparation for another regulatory submission for its lead product designed to take the company into the screening market for high-grade cervical disease. Eventually, the firm could be competing against some heavy hitters in the molecular diagnostics field for a piece of the HPV screening market, which is estimated to be an opportunity in the hundreds of millions of dollars.

During the first quarter, the company based in Heidelberg expects to file with the US Food and Drug Administration for its CINtec Histology assay used to detect the oncogenic activity of high-risk human papillomavirus, or HR-HPV, in frozen formalin, paraffin-embedded tissue, Bob Silverman, CEO of MTM, told GenomeWeb Daily News recently at the JP Morgan Healthcare Conference in San Francisco.

In addition, during the second quarter of 2011, the company plans to begin a clinical trial for its cytology test, CINtec Plus, in preparation of an FDA submission in the latter part of 2012. If approved, the test would move MTM into the cervical disease screening market.

According to Silverman, cervical cancer represents probably the largest cancer screening opportunity in the world for women, with about 150 million episodes every year. Of that, however, only about 1 percent of patients have cervical cancer.

While HR-HPV has been associated with cervical cancer, not all cases of high-risk HPV infection result in cervical cancer, and the vast majority of women with high-risk HPV don't get cervical cancer.

In the US, about 15 percent of women have high-risk HPV. "Obviously, they're not all getting cervical cancer. Most of the time it's a transient infection," Silverman said.

What is needed are markers that are specific for high-grade cervical disease that could become cancerous if undetected, and not just a risk factor. That's where MTM Laboratories and its technology comes in.

Both its CINtec Histology and CINtec Plus assays are based on the cellular protein p16 INK4a biomarker, which Silverman said is "very intimately involved in the need for the high-risk HPV infection to be there persistently and start its oncogenic transformation in the cells," Silverman said. "When that happens — because p16 is part of the normal cell cycle control mechanisms — [it] overexpresses and you get abundant levels of it in the cell."

The CINtec Plus assay includes the Ki-67 protein.

In terms of sensitivity, MTM's technology is close to that of HPV testing, according to Silverman, but in terms of specificity, the p16 test outperforms HPV tests.

In a general screening population from a 27,000-patient trial conducted in Europe, MTM found that for its CINtec Plus cytology product, 5.4 percent of the patients came back positive for high-grade cervical disease, compared to 11 percent for other high-risk HPV testing platforms, said Silverman, "so you find approximately the same amount of disease with half the rate of positivity."

As a triage for women with low-grade squamous intraepithelial lesions, CINtec Plus achieved a specificity of 68 percent versus 19 percent for high-risk HPV testing, he added.

Both the CINtec Histology and CINtec Plus are CE-marked and available in parts of Europe. The Histology assay also is available in the US as a Class I IVD test.

MTM's commercialization strategy moving forward is to first establish a customer base with its histology product — a market of about 4 million in the US and Europe — and then move into managing abnormalities with the CINtec Plus assay, which replaces an earlier product, the CINtec Cytology test, that is being phased out by MTM.

In November, MTM announced it had raised $9.8 million in a Series C round, largely to fund US regulatory clinical trials for the CINtec Plus platform in preparation of its FDA submission.

In the long term, MTM views CINtec Plus as a screening assay — and on that front, MTM has partnered with imaging analysis firm MetaSystems to incorporate computer-aided imaging to go along with the assay "and essentially have an imaging device" that would automate the screening process.

MetaSystems has a device that is used in about 1,000 laboratories in the US and Europe and is modifying software for that purpose, Silverman said. By the end of the year, the imaging device is anticipated to be validated and beta-tested, he added.

"As we bring more data to the table on the screening and we combine it with the imaging device, then we would go hard at the imaging," he said.

The company is tackling the high-grade cervical disease market with a bottoms-up approach with screening as its final target rather than its initial focus because of market opportunities and limited resources at MTM, Silverman said.

In histology, "there's absolutely nothing out there," except hematoxylin and eosin staining, which has issues with accuracy and difficulty of use, Silverman said. Targeting that market was a "no-brainer."

In cytology, if a woman has a low-grade cytology result, "she always gets a colposcopy," and if a woman has a high-risk HPV infection but nothing with a Pap smear, "there's really no solution," he said. From a competitive dynamic and clinical needs perspective, the market represented a "wide open" one.

Also, as a privately held firm with limited finances and financing options, MTM could not tackle the screening space. Silverman declined to disclose revenues for MTM, which has 75 employees across its five locations in the US and Europe.

Before joining MTM as president of its US subsidiary in Westborough, Mass., Silverman was vice president of international operations and vice president of marketing for medical device firm Cytyc, which was acquired by Hologic in 2007 for more than $6 billion. When it launched its ThinPrep Pap test as a primary screen, it turned out to be a "huge undertaking," Silverman said.

That approach was not possible for MTM.

"As much as I would like to say we can come out and do the big study on primary screening, there's too much inertia in the market to say, 'We're going to take Pap testing … and we're going to switch over to molecular markers,'" he said.

While MTM's technology is for detecting and managing high-grade cervical disease, if the company is successful in its plans to market CINtec Plus as a general screen, the technology would compete with molecular-based HPV tests, one of the hottest areas in molecular diagnostics. Companies that are developing such tests or have them already on the market include Qiagen, Hologic, Gen-Probe, and Roche.

In a recent research note, Dan Leonard of Wall Street investment firm Leerink Swann wrote that sales of HPV tests have nearly tripled between 2005 and 2009 from $120 million to $350 million with growth expected to remain at a double-digit pace for the next few years.

But in addition to competing with existing HPV tests, the CINtec technology could be used synergistically, Silverman said, because of sub-segments in the HPV market. For example, while HPV testing may be more meaningful for older women, in the context of screening for cervical cancer, results may be less revealing for younger women. Because younger women may be more sexually active, the rate of HPV infection is higher and a positive result may be less suggestive of high-grade cervical cancer than for older women, he said.

"One possible outcome is that older women are screened with HPV testing and if they're positive, they're managed with a product … like CINtec Plus," Silverman said, "and younger women would be screened with a product like CINtec Plus from the beginning."

In addition to cervical disease and cervical cancer, MTM is exploring p16's utility for other cancers, including melanoma, breast cancer, bladder cancer and head and neck cancer, he noted.