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HelixBind Aims to Circumvent Culture With Rapid Technology to Detect Bloodstream Infections

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NEW YORK – As hospitalizations due to COVID-19 increase, hospital-acquired infections are becoming a more prevalent concern for clinicians and patients.

Typical methods of determining infections using culture often take days to return results, cutting down on valuable time for the appropriate treatment to be applied. 

But Boxborough, Massachusetts-based startup HelixBind is moving closer to commercializing its rapid technology to determine bloodstream infections in approximately three hours without having to wait for culture. The firm's RaPID platform, and the first test on it for the most common bloodstream infections associated with sepsis, provides species-level detail for a broad menu of bacterial fungal pathogens, allowing it to "detect and characterize all of those bugs at concentrations of only a few cells per milliliter of blood" according to HelixBind CEO Alon Singer. 

The RaPID/BSI test is the first for the automated RaPID platform and incorporates single-use plastic disposable cassettes operated by a small benchtop instrument. The size is a selling point, Singer said, because it was designed "to slot into even the smallest hospital lab," and is about the size of "a desktop PC from 10 years ago." Although Singer declined to provide significant details about the eventual cost, he said it would be priced competitively.

HelixBind had been performing clinical studies ahead of the formal clinical trials for 510(k) clearance from the US Food and Drug Administration. The coronavirus pandemic has put many clinical studies on hold, including HelixBind's, and Singer said the firm anticipates continuing the studies this fall. It has completed an initial clinical assessment of the technology with Tufts Medical Center in Boston and Sloan Kettering Memorial in New York. Initially, the company was hoping to start FDA trials by the end of 2021, but the timeline has been pushed back as a result of the pandemic.

In June, the National Institutes of Health awarded the company $3 million to expand the capabilities of the platform. It previously received an expanded $4 million contract from the Combating Antibiotic Resistant Bacteria Accelerator program that had originally been awarded in 2018.

Despite the benefits of detecting bloodstream infections directly from blood without culture, there are also some challenges, Singer said. "First of all, you have a very low concentration of microbial cells that are swimming in a sea of human cells," he noted. To help alleviate the issue, HelixBind developed sample preparation innovations allowing them to use larger volumes of blood while eliminating any false positives caused by free microbial DNA that could be present.

Instead of the traditional method of lysing the sample and searching for the microbial DNA, which Singer compared to finding a needle in a haystack, HelixBind's technology "first burn[s] down that haystack and then looks for the needle in the embers" by selectively lysing the human cells and exposing their genomic material. Using electrostatics, the instrument removes that human genomic material, which allows for focus on the intact microbial cells. Singer declined to go into more granular detail since the technology is proprietary but did say it was developed in-house.

Another challenge when detecting infections directly from blood is differentiating between the variety of microbial cells in order to guide appropriate treatment, which is difficult because there are very low numbers of targets to work off, Singer said. To differentiate between those targets, HelixBind uses a hybrid artificial nucleic acid that "quite simply, outperforms any DNA technology that we're aware of today," he noted.

The firm uses a gamma-modified peptide nucleic acid (PNA) to bind within the helical structure of double-stranded DNA "with unparalleled sensitivity and specificity," Singer said, declining to provide additional details, citing the company's proprietary chemistry.  

According to the US Patent and Trademark Office database, Helixbind has been awarded at least two patents covering its technology. One, US Patent number 9,663,830, awarded in May 2017, covers methods and compositions for diagnosing sepsis based on gamma peptide nucleic acids. The method relates to the composition of gamma peptide nucleic acid probes. 

"Additionally, the present disclosure provides for methods and kits using [gamma PNA] probes for the prognosis of sepsis," the patent abstract said. 

The other patent, US Patent number 10,730,041, awarded earlier this month and titled "Integrated fluidic devices and related methods," covers devices that may be used to diagnose the presence of bacteria in patient samples. According to the patent abstract, the technology may be especially useful for diagnosing multiple disease-causing bacteria in patient samples simultaneously.  

"In an exemplary embodiment, increased detection sensitivity of microbial pathogens present in a patient sample (e.g., blood) is performed by selectively removing human nucleic acid prior to sensitive detection of microbial infection," the patent abstract said.

According to Singer, it’s the combination of technologies that is the key to HelixBind's capabilities. "There is no single technological breakthrough that is sufficient to overcome all these challenges," he said. "Only when they're combined at a systems-level approach do we get the results that we're looking to get." 

Most of those results haven't been published yet, but one study published in mBio in 2016 found the RaPID platform had 96 percent sensitivity and 90 percent correlation to blood culture findings. The study used 63 remnant hematology specimens that had been drawn in parallel to blood culture and were one to two days old. However, Singer noted that two of the samples that came back negative after culture were found positive by HelixBind and determined to be false negatives. The false negatives were likely the result of patients already being on antibiotics, which Chief Business Officer David Steinmiller said was a very common occurrence when using culture to detect infections.

Arthur Rabson, one of the authors of the study and the director of tissue typing and molecular pathology at the Tufts University School of Medicine, emphasized the benefit of HelixBind's rapid turnaround time and called it "a huge advance."

"Having a rapid diagnosis is, you know, very important for the patient right at that moment when the person is in the emergency room," Rabson said.

Singer also noted that users don't need to be specially trained to run tests on the RaPID system. "We've transitioned the entire assay to be implemented on, really, a fire-and-forget system," Singer said. Reagents are already loaded into the single-use cassette, which is room-temperature stable for over a year. Users just have to snap the sample collection tube into the cassette, put the cassette into the instrument, and press Go. HelixBind plans to provide the disposable cassettes to users, Singer said.

As for competitors in the space, he said there aren't many. While some companies have introduced molecular tests to improve the culture process and reduce turnaround time on the back-end using PCR, he said it's not enough to make a significant impact. The other major competitor in the space detecting bacteria directly from blood is T2 Biosystems, whose T2Bacteria Panel covers five pathogens at a time, compared to HelixBind's 21 pathogens.

Roger Smith, vice president of science research and development at T2, however, mentioned that "the T2Bacteria Panel covers five pathogens – they make up 90% of deadly ESKAPE pathogens and more than 60% of all bacterial pathogens identified today." He added that "the panel is the only FDA-cleared test to identify sepsis-causing bacteria directly from whole blood, and is not predicated on blood culture positivity." Smith also said that the company also has the T2Candida Panel, which is "the only FDA-cleared direct-from-blood fungal pathogen detection assay, providing same-day results directly from a whole blood specimen for the most clinically relevant fungi."

"We have also launched our T2Resistance panel in Europe, which detects 13 resistance genes directly from blood. Taken together, our direct-from-blood pathogen detection panels detect 23 targets," he added. "It is important to note that T2 Biosystems has announced the development of a single 40-member panel that will detect more than 250 species of pathogens that cause bloodstream infections. This expanded panel will use the same proven technology used by the T2Bacteria and T2Candida panels. We have already demonstrated feasibility for this panel and are currently in product development."

Alternatively, some companies may provide offsite next-generation sequencing services for hospitals who send a blood sample for analysis of the infection, but that method also has a long turnaround time dependent on sending the sample to a central laboratory. HelixBind's platform, Singer emphasized, "is really designed to fit into the flow of care, right into the hospital environment."

The instrument is also scalable, so it can be placed in small hospitals with only a few cases each day, as well, or bigger hospitals that could place multiple instruments on a single bench, Singer said.

The RaPID system can be used for a variety of specimens, but the "bread and butter" is for specimen types and syndromes that are particularly complicated, Singer said. "Bloodstream infection is probably the greatest unmet need both as a technical challenge, as well as … the dire global situation with bloodstream infections," he said.

However, HelixBind isn't only focused on BSI and has a pipeline of other tests in development, although Singer declined to specify the exact infections those tests would detect. He said that the firm's technology would help with pathogens that are particularly low culture or in situations where clinicians need to differentiate treatment between two very similar bugs.

Last month, the NIH awarded HelixBind $3 million to evaluate its early detection test for Lyme disease which detects DNA from tick-borne bacteria Borrelia burgdorferi. The company has clinical studies planned for 2021's tick season and the money will be used to support those clinical studies.

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