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DxTerity LIFT Study Aims to Discover Biomarkers of Lupus Flare

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NEW YORK (GenomeWeb) – Molecular diagnostics firm DxTerity has enrolled more than 1,000 lupus patients into a study in less than six weeks using social media-based recruiting and proprietary at-home sample collection.

The company presented preliminary data from its Lupus Interval Monitoring to Manage Disease Flare and Enable Treatment Optimization, or LIFT study, at the Personalized Medicine World Congress last month. The company is hoping this study will help it discover a transcriptional biomarker signature that can enable from-home genomic monitoring of lupus patients.

DxTerity's long-term goal is to replace traditional episodic visits to the doctor with longitudinal monitoring that is done easily from home, DxTerity CEO Bob Terbreuggen said in a recent interview. The firm also hopes to layer in use of wearable devices and patient-reported outcomes data.

Terbreuggen further described the firm's plans to develop other products for autoimmune disease monitoring using its at-home blood sample collection technologies. DxTerity is working with pharmaceutical companies for its autoimmune studies, he said, but declined to name them at this time.

The company's at-home sample collection device, called DxCollect, combines a fingerstick collection kit and tubes that contain a proprietary chemistry which stabilizes RNA and DNA at room temperature for up to two weeks. This interval allows plenty of time for samples to be mailed to the lab.

The firm can combine the collection technology with its DxDirect chemistry that was developed during its ongoing Biomedical Advanced Research and Development Authority-funded work on a diagnostic test for radiation exposure.

The chemistry enables RNA detection directly from 100 microliters of whole blood without the need for isolation. The method involves non-enzymatic chemical ligation adjacent to regions of interest, with products captured on magnetic beads using biotinylated capture probes. It also uses universal primers for amplification, and enables simultaneous detection of around 40 genes in a biosignature for a previously-reported cost of around $50 per test.

"As far as we are aware, we have developed the lowest cost, highest throughput way to do multiplex gene-expression" analysis, Terbrueggen said.

More than 23 million people in the US suffer from an autoimmune disease like lupus, rheumatoid arthritis, or multiple sclerosis, and these diseases require frequent physician visits and testing, said Terbrueggen. "A lot of tests that are used today to characterize the status of these diseases are very non-specific," he added.

These conditions also share a feature of being relapsing and remitting, or having periods of more and less active disease. In lupus, a period of very active disease often takes the form of a "flare." The Lupus Foundation of America spearheaded the development of a consensus definition of a flare, defining it as a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms or lab measurements, with the increase considered clinically significant by a doctor and prompting the consideration of a treatment change.

"Lupus disease activity waxes and wanes but the damage is cumulative and irreversible," Paola Daly, the Foundation's director of research, said providing some context on LIFT. A poorly controlled lupus flare can permanently impact the skin, joints, and kidneys.

"Everybody is looking for a biomarker that can signal when a flare is coming," Daly said.

Among the 45 targets being measured by the DxTerity assay is interferon, which has long been known to track with lupus disease status.

Terbrueggen noted that whether or not a patient has high or low interferon expression is a predictor of the severity of disease, but interferon expression is not routinely measured because "there is not a good way to do it without genomics," he said.

The DxTerity test also measures activity of genes associated with T-cell exhaustion, neutrophil and plasmoblast status, as well as other immune-oncology targets. These are measured in the firm's CLIA-certified and CAP-accredited lab, typically using the Thermo Fisher ABI 3500 capillary electrophoresis instrument for readout. DxTerity can run up to 1,500 samples per day, which also lowers costs, Terbrueggen said.

To enroll more patients faster in LIFT, DxTerity is also using a digital recruiting method it calls DxReach. This direct-to-patient clinical system allows the firm to involve patients from across the country without traveling from its lab in Los Angeles.

The technique uses social media, such as Facebook and Twitter, and integrates online qualification of subjects, electronic consent, electronic data capture and reporting, as well as electronic patient reported outcomes, all using a centralized institutional review board. Terbrueggen also noted that more than 80 percent of subjects enrolled in the LIFT study using smartphones.

DxTerity is also involving patients who blog about their odysseys with lupus to spread the word about LIFT and encourage participation. Bloggers are paid a set fee and given general guidance and IRB clearance, but the company does not control what they write about their experience in the study.

"Using social media and online e-consent, we recruited over 1,000 patients in six weeks," Terbrueggen said, adding that the total time from the start of recruitment through the IRB process to the first patient being tested took less than three months.

The firm had a 97 percent success rate for reading out data from the samples on its multi-module autoimmunity profile assay, with failures due to a few patients sending back empty sample tubes by mistake. Terbrueggen noted that there was also a good representation of different ages.

And, of 1,260 samples analyzed so far, about 37 percent had elevated interferon and thus might be candidates for treatments like an anti-interferon alpha monoclonal antibody-based therapy called Anifrolumab from Astra Zeneca currently in Phase 3 clinical trials, for example.

The use of lupus influencers to improve recruitment is novel for an observational study such as this, Daly suggested, and could also be helpful in marketing an at-home test in the future. However, she noted that relying too heavily on this type of recruitment might bias the study sample in favor of internet users, who may or may not have different demographic characteristics. She also emphasized that the Lupus Foundation of America does not endorse any particular research studies.

Recruiting so many patients so quickly is also somewhat novel. "Many lupus clinical trials have a challenging time recruiting enough participants who meet the inclusion criteria," Daly said, noting that this causes trials to run much longer than anticipated, which increases cost. The requirements to prove safety and efficacy also mean that researchers have to recruit a large number of people, she said, but there are only so many patients and lupus is a very heterogeneous disease.

Terbrueggen said the method is so far much faster than traditional trial recruitment through other researchers or key opinion leaders and, using the same method for its "Evaluating Multiple Sclerosis Patients ShOWing A GEnomic Signature of Therapy Response," or EMPOWER study, DxTerity was able to recruit more than 1,000 subjects in nine days.

DxTerity has submitted a few abstracts regarding its LIFT trial for the 2018 European League Against Rheumatism, or EULAR conference, and its radiation test is now in the process of getting approval from the US Food and Drug Administration, Terbrueggen said.

The company expects to build the autoimmunity profiling assay as a next product on the diagnostic test and workflow it plans to clear with its radiation test. After the LIFT study is completed, and researchers have validated the signature for monitoring lupus patients, DxTerity will seek FDA clearance and manufacture a commercial test kit that could be run by any lab.

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