NEW YORK – OpGen is forging its core technologies into highly multiplexed molecular diagnostic assays to detect pathogens and resistance genes. While companies in the rapid antimicrobial resistance (AMR) space in general have struggled to achieve a good valuation of their technologies and remain financially solvent, OpGen's collaborations have recently made a difference to its bottom line.
The company submitted to the US Food and Drug Administration a test for bacterial isolate samples recently and is also in the process of setting up clinical trials for a direct-from-urine assay for urinary tract infections. Both assays are currently commercially available for research use only, and studies on their performance have been presented at recent conferences.
The strategy for the Gaithersburg, Maryland-based company is to pursue successive FDA clearances for its test – called the Acuitas AMR Gene Panel – for two different sample types, namely pure bacterial isolates and unprocessed urine.
Both tests use the Qiagen EZ-1 Advanced XL for DNA extraction followed by the Thermo Fisher Applied Biosystems QuantStudio 5 for PCR. They also use the firm's cloud-based Acuitas Lighthouse Software – which relies in part on a bacterial database from Merck containing genotype and phenotype data from 15,000 clinical isolates – to predict antibiotic resistance.
"The testing process is highly automated, with about 20 minutes of hands-on time, and results are available in under three hours," OpGen CEO Evan Jones said in a recent interview.
The bacterial isolates test is the first in the pipeline and closest to commercialization. It detects five common bacterial pathogens and 47 antibiotic resistance genes from bacteria that have been grown in culture from a patient's sample.
OpGen completed clinical trials in February for the test. The process involved examining more than 1,000 clinical bacterial isolates at four participating sites: Johns Hopkins University School of Medicine, Wadsworth Center at the New York State Department of Health, University Hospitals Cleveland Medical Center, and International Health Management Associates (IHMA), a contract research organization.
OpGen submitted the bacterial isolates test to the FDA in May.
The "direct-from-urine" assay, called AMR Gene Panel Urine, is essentially the same AMR gene panel for a UTI indication. It requires a distinct clinical trial and a de novo FDA submission, Jones said.
OpGen plans to complete the clinical trial for this test and submit it to the FDA by year-end or Q1 2020.
Sites will begin testing in a matter of weeks, but internal testing is already underway.
"The sites have been selected and we are currently working through the set-up logistics," Evans said. The UTI test is also currently commercially available for research use only, he added.
Generally speaking, PCR-based methods for bacterial resistance testing are believed to be faster than culture-based testing and less expensive than sequencing-based testing.
However, considering that phenotypic resistance is not always completely correlated with genotype, culture is usually more definitive. And, resistance genes are constantly evolving, so sequencing may be more thorough than even the most highly multiplexed PCR.
That said, the OpGen tests have fared well compared to culture and sequencing in recent assessments.
For example, a clinical verification study for the urine test looked at more than 500 remnant urine specimens that had been collected and tested at Beth Israel Deaconess Medical Center, Geisinger, and Intermountain Healthcare. In data presented at ASM Microbe in June, the researchers showed that the panel had 90 percent agreement with quantitative culture for semi-quantitative pathogen detection, and that the phenotype predictions the software provided had more than 90 percent average total agreement with antibiotic susceptibility testing for E. coli and K. pneumoniae, two pathogens that are the most common causes of UTIs.
"These data support our view that an Acuitas product offering that provides test results in under three hours versus two days with the current standard of care has the potential to fundamentally transform care for patients with urinary tract infections," Jones said.
Intermountain also presented data at the conference that showed the three-hour Acuitas workflow could potentially be used to guide early, empiric antibiotic use in patients with UTIs from antibiotic resistant bacteria, compared to culture-based methods.
Jones also said he sees multiplex PCR as a potential surrogate for sequencing in molecular epidemiology. The Acuitas Lighthouse Software profiles bacteria detected by the Acuitas AMR Gene Panel by using the inputs of pathogen and resistance gene data, he said, adding, "The benefit is that potential outbreaks can be identified within hours compared to the weeks it takes to identify by whole-genome sequencing in routine clinical environments," he said.
Whole-genome sequencing does have higher resolution, Jones acknowledged, but it is more expensive and takes longer, so it could be better utilized as a confirmatory test for PCR-based methods like Acuitas.
Researchers at Wadsworth presented data at ASM Microbe this year also supporting this conclusion. They retrospectively evaluated 80 clinical isolates from two healthcare-associated outbreak investigations, as well as unrelated strains representing a range of antibiotic resistance genes, and developed a whole-genome sequencing pipeline to compare to the Acuitas results.
The two methods produced concordant clustering dendograms for the two outbreaks. There were slight discrepancies, but both methods detected two distinct outbreaks, and picked out out other strains as unrelated. The authors noted that the WGS method had increased resolution and was able to identify additional resistance genes, but further noted that it has a longer turnaround time, although they did not specify how long each method took.
However, the OpGen technology "can be used as a front-line tool in clinical settings for transmission and outbreak detection with follow-up confirmation of isolate relatedness by WGS," the authors wrote.
A high concordance with WGS "is one of the key capabilities that supports the use of the OpGen suite of Acuitas products in the New York State Infectious Disease Digital Health Initiative," Jones commented.
The leap to profitability
The space encompassing multiplexed molecular diagnostic pathogen identification and resistance detection is growing but may still be a bit tenuous, financially.
"Public companies in the rapid testing for antimicrobial resistant pathogens [space] have struggled to achieve fair valuations for the technologies that they have developed," Jones explained.
By way of comparison in the space, Curetis sells its fully automated, FDA-cleared Unyvero instrument and highly multiplexed PCR-based tests for pathogen identification and genetic resistance testing and also offers next-generation sequencing-based testing as a service through its subsidiary, Ares Genetics.
Curetis' lower respiratory tract infection assay, called the Unyvero LRT Panel, detects 19 bacteria and 10 resistance markers in a sample-to-answer workflow. The platform had a list price around €60,000 (US$66,570), although the majority of systems are placed as reagent rentals, and the assay cartridges are in the €200 range, as previously reported.
But despite having an FDA-cleared system, Curetis announced late last year it would eliminate up to 30 percent of its global workforce as part of a strategic reorganization. And the firm reported last week that it was delaying its financial reporting and that it had hired an investment bank to help it review strategic options for securing the money it needs to continue operations for at least the next 12 months.
In March, OpGen closed a $5.4 million public offering, providing funds to support its regulatory and commercial activities, among other things.
But Jones pointed out that he had previously indicated on a call to discuss OpGen's second quarter earnings that his company is also actively considering multiple financial alternatives, "including strategic financings and other transactions," he said.
These alternatives include "potential partnering arrangements, business combination transactions, and M&A in order to obtain sufficient financing to continue operating the company and realizing appropriate benefit for our stockholders," Jones said.
This firm is also generating income through collaborative development projects. OpGen has partnered with Wadsworth and Ilúm Health Solutions, a subsidiary of Merck's Healthcare Services and Solutions, to build an AMR tracking tool for the state healthcare system. The firm reported a $500,000 milestone payment in Q1 this year related to the collaboration, accounting for half of its quarterly revenues.
"During the second quarter of 2019, we successfully met our second milestone of the three that define the first phase of this project," Jones said. To wit, OpGen completed the custom development of the Acuitas Lighthouse allowing it to be integrated with Merck Ilúm software, and deployed Acuitas AMR Gene Panel research-use-only systems in two of the three anticipated health systems.
Simultaneously, the Wadsworth Center achieved an important milestone with their validation of the Acuitas AMR Gene Panel and received a conditional New York State Department of Health Clinical Laboratory Evaluation Program (CLEP) approval, Jones said.
"The conditional approval authorizes Wadsworth to use the Acuitas test while review of the validation packages is finalized by the Department of Health," he explained.
This is an important designation, which comes from an extensive evaluation of the product by Wadsworth, Jones also said, noting that the collaborators will now move into data collection with the sites "as we continue to discuss project extension beyond this first year."