NEW YORK – A long-standing development effort has come to fruition for Cepheid which this week debuted its 10-color molecular diagnostic testing technology in a new assay to help diagnose and profile extensively drug-resistant tuberculosis and select the best treatment.
Developed in collaboration with researchers at Rutgers University and with guidance and support from the Foundation for Innovative New Diagnostics, the test is now CE-IVD marked and the Danaher subsidiary said it expects to roll it out with assistance from FIND and the World Health Organization.
Cepheid is also developing other assays using the 10-color technology, and plans to incorporate it into the in-development portable Omni system, according to David Persing, the firm's chief medical and science officer.
Called Xpert MTB/XDR, the new 10-color real-time PCR test detects extensively drug-resistant Mycobacterium tuberculosis using recalibrated GeneXpert instruments.
As defined in a WHO report issued last year, multidrug-resistant TB (MDR-TB) is resistant to both rifampicin and isoniazid, the two most powerful anti-TB drugs, and requires treatment with a second-line regimen. Extensively drug-resistant TB (XDR-TB) is MDR-TB that also has resistance to at least one of the fluoroquinolone drugs and one of the injectable agents used in MDR-TB treatment regimens.
The WHO has estimated that approximately 6 percent of multi drug-resistant cases of TB are also extensively resistant. Globally, there were more than 13,000 XDR-TB cases in 2018, and these infections can be particularly dangerous because they are tough to treat, which makes contagion more challenging to control. Mortality for XDR-TB been reported to be as high as 41 percent in some cohorts.
Catharina Boehme, CEO of FIND, said in a statement that the Xpert MTB/XDR test will save lives. "Recent treatment advances are already making a huge impact, but for the best chances of survival patients need to be able to start on treatment as soon as possible — and the only way for that to happen is through rapid diagnosis," she said.
The Cepheid Xpert MTB/XDR test can indicate the presence of genetic markers that confer resistance to common pharmaceutical therapies for the bacterial infection, specifically isoniazid, ethionamide, fluoroquinolones, amikacin, kanamycin, and capreomycin.
Cepheid's Persing said that the 10-color technology expands the detection capabilities of the firm's GeneXpert platform through the use of four novel dyes developed at the firm's Bothell, Washington research facility.
"The 10-color system is the exact same GeneXpert module we use in all of our systems," Persing explained, "It is just calibrated for 10-color detection." The system essentially allows for multiplex detection of 10 independent targets in a single reaction, as opposed to splitting the sample to accomplish multiplexing, which Persing noted can impact sensitivity.
All of Cepheid's systems use the same core testing modules, Persing also said, and its GeneXpert family of instruments includes two-, 16-, 48-, and 80-module configurations. Although some instruments have special user interfaces that enable them to be CLIA waived, in general the workflows are similarly simple across the systems. The overall ease of use allows for rapid testing close to patients, for example at sexually-transmitted infection clinics in the UK, Florida, or a lab that recently opened in New York City — called the Quickie Lab at Chelsea Express — which Persing said uses two 80-module Infinity systems for high-throughput STI testing at the point of care.
The fact that the modules in the systems and the test cartridges themselves are identical across the different instruments means that the results can be more easily compared between centralized and decentralized settings in an integrated health network, Persing said.
The 10-color technology was codeveloped with Cepheid's long-time collaborator David Alland, the director of the Public Health Research Institute at Rutgers University. It was first described in the scientific literature in 2016 after initial development had been ongoing for approximately seven years with National Institutes of Health funding.
Early performance data for the XDR-TB assay was subsequently published in the New England Journal of Medicine in 2017. Now, evaluations by FIND are ongoing.
Cepheid initially began collaborating with FIND in 2017, according to Sophia Georghiou, a scientific officer in the FIND TB program and manager of the Xpert MTB/XDR project.
FIND supported Cepheid in the design, development and evaluation of the Xpert MTB/XDR assay, Georghiou said in an email. The organization initially helped to define the design input requirements for the assay to ensure it would meet target product profile and key stakeholder requirements for drug-resistant tuberculosis diagnosis in highburden settings.
FIND also provided input and support during all analytical testing, including provision of clinical samples and materials for testing in these studies, and led independent laboratory and clinical evaluation studies of the design-locked Xpert MTB/XDR assay to generate analytical and clinical performance data for WHO review, Georghiou also said.
Preliminary data from the studies conducted by FIND indicate that the sensitivity and specificity are comparable with current standard culture-based phenotypic drug-susceptibility testing and sequencing, Georghiou noted.
Now, "The launch signifies that the CE-IVD marked Xpert MTB/XDR assay is available for purchase," she said, adding that data from independent, FIND-led analytical and clinical evaluations will be available in the coming months. This data will then form part of the dossier for WHO technology review of the Xpert MTB/XDR assay at the end of this year.
"In general, we are meeting or exceeding WHO recommendation and expectations for accuracy," Persing said.
The chemistries enabling the 10-color detection involve using large Stokes shift or off-axis dyes, such that two dyes that absorb the same wavelength can emit at two different wavelengths.
Recalibrating the GeneXpert instruments to detect these emissions currently needs to happen at the factory, Persing said, so for the low-resource settings the firm serves with some of its approximately 25,000 global placements, delivering a new instrument may be the most feasible way to get them access to the Xpert MTB/XDR test.
Georghiou said that if the test is recommended by WHO, "countries could include it in their national policies and accelerate its scale up, further encouraging assay uptake to lower drug-resistant tuberculosis burden and transmission globally."
Tereza Kasaeva, director of the WHO Global TB Programme, also noted in a statement that WHO is "looking forward to receiving all relevant data on the GeneXpert MTB/XDR cartridge from Cepheid and partners to rapidly proceed with an evaluation of the new test."
Cepheid does not expect XDR testing to be implemented everywhere at first, Persing said, but rather it will likely start out at dedicated TB centers. "TB has been relatively off the radar in the COVID era, but we know that drug-resistant TB is probably going to come back in a way that is worse than before," Persing said.
That said, Cepheid plans to use the technology in other ways going forward. "We expect, longer term, more and more of our tests will be using 10 colors in order to get into the larger respiratory and gastrointestinal panel space in the 20-target range," Persing said.
The plan, he said, is to switch the GeneXpert family of instruments to 10-color detection, as well as the in-development Omni system. Persing also said that the firm expects to have some announcements soon about the Omni, a small, portable instrument that is engineered to be particularly rugged in hot environments.
FIND and WHO are now expected to assist with the rollout of the 10-color XDR-TB test, but precisely what that will look like has not yet been nailed down, Persing said.
These organizations have been "extremely helpful with implementation, recommendations, and guidelines for GeneXpert, and we would hope for the same level of assistance with this technology," Persing said, adding that UNITAID and the Global Drug Facility are likely to also work together to make Cepheid's technology available worldwide.
FIND's Georghiou said that, once the WHO review is complete, "countries will need considerable guidance and support to facilitate the uptake of the technology in high-burden settings."
And, as price can be a barrier to technology uptake, FIND and Cepheid have already agreed to reduce the FIND target market supply price for the Xpert MTB/XDR cartridge based on annual manufacturing volumes of the product from the previous year, Georghiou said. "Additionally, efforts are being made to identify the major cost drivers which could have the most significant impact, and associated plans will be made to target further reductions," she said.