This article has been updated from a previous version to correct Curetis' planned timeline for US regulatory clearance of its platform.
Having established commercial sales of its Unyvero P50 highly multiplexed pneumonia molecular testing panel in Europe, German molecular diagnostics firm Curetis is now well underway in its efforts to enroll approximately 2,000 patients in the US for a prospective clinical trial to support a regulatory submission for a similar test to the US Food and Drug Administration.
If all goes according to plan, Curetis hopes to have the trial fully enrolled by the second quarter of next year and to receive FDA 510(k) clearance for the test cartridge and corresponding instrument system, the Unyvero platform, by the end of 2014, according to CEO Oliver Schacht.
In addition, Curetis expects to garner CE marking by the end of this year for a new Unyvero test cartridge for implant and tissue infection, and is seeking to develop at least one new test panel per year for conditions such as sepsis, gastrointestinal infections, central nervous system infections, multi-drug and extreme drug-resistant tuberculosis, and pediatric infections, Schacht said.
Curetis believes that the advantages of its platform — its ability to simultaneously test for dozens of analytes, fully integrated sample prep, and ease of use, in particular — enables it to occupy a relatively unique niche in the molecular diagnostics market.
"We are not competing against homebrew, single-analyte PCR tests," Schacht told PCR Insider in a recent interview. "We are not at all focusing on me-too single-analyte products like, for example, Cepheid. All of our products are focused on at least 25 analytes."
Founded in 2007 by former employees of a medical diagnostics group at Philips, Curetis combined know-how from Philips with well-vetted sample prep and molecular analysis technologies to develop its own intellectual property and commercialize its flagship Unyvero system — a benchtop, cartridge-based nucleic acid molecular testing platform that combines proprietary universal sample prep, PCR, and array-based detection in a touchscreen benchtop instrument with dedicated software.
Each test cartridge, about the size of an external computer hard drive, can simultaneously run eight molecular assays using independent thermal cycling profiles and other test conditions — "eight labs on eight chips in a brick," as Schacht put it.
Meantime, each independent on-cartridge "lab" assays for multiple analytes and/or controls, combining to create a test panel comprising anywhere from 25 targets to potentially more than a hundred targets. The company's first commercial European assay, the Unyvero P50 Pneumonia test, simultaneously analyzes 39 DNA targets (specifically, 16 bacteria, one fungus, and 22 antibiotic resistance markers); while the company's next planned test for implant and tissue infection may contain well over 100 targets, Schacht said.
Unyvero achieves its high level of multiplexing through the use of endpoint PCR and array-based detection — "we could do real-time PCR, but we wouldn't be able to achieve the same level of multiplexing," Schacht said.
Although the company considers the platform's multiplexing capabilities to be a big competitive advantage, Schacht noted that sample prep is the "real differentiator."
Unyvero can "lyse and homogenize anything — even biofilms off of inorganic materials; for instance, a piece of a catheter tube," Schacht said. This homogenization step is followed by lysis and DNA purification using a spin column of sorts that uses vacuum pressure instead of spinning.
Schacht noted that another advantage of the platform is its ease of use — a notion shared by at least one early-access user, Jane Weile, a project leader at the Institute for Laboratory and Transfusion Medicine at the Heart and Diabetes Center of Bad Oeynhausen, Germany.
Weile's group was part of the European clinical trial of Unyvero. "It's a very specialized hospital," Weile told PCR Insider. "We only have 500 beds but … 120 beds in intensive care. We use [the P50 Pneumonia panel] for our ICU and immunocompromised patients … for ambulance and hospital-acquired pneumonia … in really critically ill patients where time is a crucial point."
Weile said that the turnaround time for the P50 test, from sample to answer, is about four hours. In terms of ease of use, Weile noted that Unyvero has much in common with the Cepheid GeneXpert system. "It's basically the same — for one sample it's maybe five minutes of total hands-on time," he said. "There is a one- or two-hour training, and you could get someone off the street to do it. Besides the GeneXpert system, it's the only system that I know of on the market that is a truly walk-away system. The technicians that are handling the system are happy because it's really easy."
Curetis received CE marking for Unyvero and the P50 Pneumonia test in May 2012, allowing it to commercially launch the test in Germany and other countries recognizing the CE mark. Schacht said that Curetis currently sells the assay directly in Germany, Austria, and Switzerland, while distributors sell the product in all other territories including Benelux, Eastern Europe, Russia, and the Middle East (PCR Insider 5/17/2012).
"We are in a way following in the footsteps of Cepheid's distribution network, after Cepheid moved to direct sales," Schacht said.
In general, Schacht said, Curetis is not positioning Unyvero to compete head to head against other molecular testing products. Instead, he said, the company is hoping people will see that the platform "is adding valuable information at a much earlier point in time [compared] to traditional culture. We are positioning it as an add-on to culture-based methods."
At April's European Conference of Clinical Microbiology and Infectious Diseases in Berlin, Curetis presented data from a validation study of more than 1,000 patient samples demonstrating an overall sensitivity of 80.6 percent and specificity of 96 percent for Unyvero P50. Moreover, Unyvero detected 378 additional pathogens not listed in the microbiology results, and it demonstrated a predictive value of 86.6 percent for detecting beta-lactam antibiotic resistance markers compared to conventional methods and overall predictive values of between 40 percent and 86 percent for a number of other antibiotic-resistance markers.
In another study presented at September's Joint Annual Meeting of the German Society for Hygiene and Microbiology and the German Society for Infectious Diseases (DGHM/DGI) in Rostock, researchers from Curetis and University Hospital Basel similarly compared Unyvero P50 Pneumonia with standard culture and antimicrobial susceptibility testing using clinical specimens from the lower respiratory tract of suspected pneumonia patients.
In 104 cases, Unyvero detected 76 percent of the pathogens that were both detected by culture and included in the Unyvero panel. In addition, Unyvero detected 68 microorganisms that were not listed in the culture report. In 82 percent of cases, Unyvero predicted the phenotypic antimicrobial susceptibility.
Weile said that Unyvero is most useful currently as a screening modality ahead of additional downstream testing. "The benefit is clear," Weile said. "But it's probably not so much for … detecting [particular] organisms. Very often we don't find the organism that is causing the infection. The patient has pneumonia, and if we don't find anything using the panel, then we know we have to look for something a little stranger. But we can rule out a lot of organisms … [and] that's quite a big benefit."
US and beyond
Curetis is now working to bring this benefit to the US. The company is currently enrolling patients in a clinical trial designed to support a 510(k) submission to the FDA for the Unyvero LRT (lower respiratory tract) assay, which is essentially the same assay as the P50 Pneumonia test.
The trial will commence at four sites — North Shore-LIJ Health System, Johns Hopkins Medicine, the University of Rochester Medical Center, and Northwestern Memorial Hospital — with the goal of assessing Unyvero prospectively on a cohort of about 2,000 patients.
Due to the fact that Unyvero is unique in its ability to test for multiple analytes, FDA has allowed the company to forego having to enroll prospective clinical trial data for each and every analyte — a task that would have required "something like 40,000 to 50,000 patients in order to test 50 patients per analyte, something that one is not going to be able to do," Schacht said.
As an alternative, Curetis has had to develop composite molecular comparator PCR assays to compare against the Unyvero assay when culture results are negative, an undertaking that has delayed the company's US regulatory ambitions.
Nevertheless, "we think this will set a precedent" for how highly multiplexed analyte tests are evaluated by FDA," Schacht said.
At last month's Interscience Conference on Antimicrobial Agents and Chemotherapy in Denver, clinical researchers from Northwestern Memorial Hospital and Curetis presented some early data from an evaluation of Unyvero LRT on 26 clinical respiratory specimens collected at the hospital.
In this relatively small cohort, Unyvero LRT achieved an overall sensitivity of 89 percent and overall specificity of 98 percent for pathogen identification, and detected an additional six pathogens not detected by routine culture. Meantime, resistance marker detection was 87 percent sensitive and 97 percent specific — "data that indicate that the system can significantly contribute to patient management by providing rapid pathogen identification and antimicrobial resistance profiling," the study's authors wrote.
As the US clinical trial for Unyvero LRT progresses, the company is setting its sights on its next test panels, with a panel for implant and tissue infections closest to market.
This assay, currently called Unyvero i60 ITI, is designed to detect pathogens and resistance markers known to cause infections that commonly occur after implantations such as prosthetic joint surgeries or after tissue trauma such as burns. The current test consists of 52 primer pairs specific for 27 pathogens and 25 resistance markers.
Curetis has partnered with technology group Heraeus Medical to develop this test cartridge (PCR Insider 9/20/2012). The companies will co-fund product development, Heraeus' customers will be given access to the Unyvero system, and Curetis will pay a sales commission for any customers that Heraeus refers to Curetis. Curetis will also retain full control over commercialization both directly in Germany, Austria, and Switzerland, as well as via its international distributor network. The resulting Unyvero cartridge and application will be a Curetis-labeled in vitro diagnostic.
At the DGHM/DGI meeting in Rostock last month, Curetis presented another poster with some of the first data from an evaluation of the i60 ITI panel. Specifically, company scientists demonstrated that the panel was able to detect pathogens in clinical sample types like synovial and sonication fluids, swabs, and tissue material in concordance with standard microbiological assays. The panel also detected additional organisms, including some that are part of the normal skin flora and some anaerobic bacteria that are known to be involved in biofilm formation on orthopedic materials but notoriously difficult to identify and therefore underdiagnosed.
Schacht said that Curetis expects CE marking by the end of this year for i60 ITI. Other potential disease areas that Curetis is eyeing for future tests include sepsis, gastrointestinal infections, CNS infections, multidrug and extreme drug-resistant TB, and pediatric infections. "Customers have inquired about a resistance marker-only panel … and it's possible we'll look at women's health," Schacht said. In general, he added, the company is looking to develop one new cartridge/panel per year. Curetis plans to announce the newest panel in its pipeline this fall.
One of the major remaining hurdles for Curetis — and indeed all developers of highly multiplexed molecular diagnostic tests — is the health insurance reimbursement landscape. In the US currently, test providers who are dependent upon CPT coding must provide codes describing the specific analytes being tested, as opposed to one code that describes a multiplexed test such as the Unyvero LRT assay, which could make it extremely difficult to obtain reimbursement for such an assay.
Curetis' strategy to navigate this morass — at least for the time being — is to target its platform only at in-patients with ICU-type infections, which means that the Unyvero tests would not need a CPT code, Schacht said.
He noted that currently in the US, approximately 20 percent of all patients discharged after receiving treatment for pneumonia get readmitted a few weeks later — a problem that Unyvero would theoretically curb.
"The hospital gets a lump sum from payors for ICU purchases, and it's their discretion as to what to spend it on," Schacht said. "We just need to convince the hospital to spend the $200 to $300 on the pneumonia cartridge because it will save them money in the long run."
Furthermore, Schacht added in an email following his initial interview with PCR Insider, "our health economics model and data suggests that a hospital with decent-sized ICUs and, say, 800 to 1,000 beds in total will be able to save several hundred thousand [dollars] each year by having better and earlier diagnosis of putative pathogens and their antibiotic-resistance marker profiles." This, he noted, translates to an estimated average savings per patient of at least $1,000 to $1,500.
It is possible that this strategy will work in the US, as long as Curetis is marketing only assays for ICU-related infections, or until the procedure for CPT coding multiplexed diagnostic assays becomes clearer. However, according to Weile, the clinical researcher from the Institute for Laboratory and Transfusion Medicine who was an early user of Unyvero, the picture may not be so simple in Europe, or at least in Germany.
"At the moment you can get reimbursement for singleplex PCR and so on, but it's not clear how this multiplex PCR or testing of 40 analytes [will work] — you won't get the same money as for 40 single tests," Weile said. "You wouldn't be able to afford it, because it would be a couple thousand euros for each test if you paid for each single analyte. At the moment, this makes it … at least in Germany … a little bit difficult for most clinics … they either have [Unyvero] as part of a trial at the moment or, like our hospital, are well-funded enough that they can afford it."
Schacht told PCR Insider that the current price for a pneumonia cartridge in Europe is €192 ($261), although he did not disclose the price of a Unyvero instrument platform. So far the company has placed about three dozen systems, and is on a pace of placing three new instruments per week.
Nevertheless, Weile added that, in his opinion, it is imperative that a test has some sort of reimbursement scheme in order to achieve greater market penetration, and it would likely behoove hospitals to conduct their own cost-benefit analyses of using the platform.
In fact, Curetis is now working to conduct such an analysis in Europe in the hopes of convincing potential customers of Unyvero's long-term cost savings. In July, the company said it had begun an additional, prospective, multicenter trial of Unyvero P50 Pneumonia to determine its clinical and health economic value (PCR Insider, 7/11/2013).
This new study aims to establish real-world data on the health economic impact of fast, near-patient molecular testing and subsequent therapy adjustments, Curetis said. It will be conducted in five European centers and will involve several hundred critically ill patients with pneumonia requiring mechanical ventilation.