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Arquer Dx Preps Bladder Cancer Test for FDA Submission, US Launch

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NEW YORK (360Dx) – Arquer Diagnostics is preparing a clinical trial that it anticipates launching in the US early in 2019, possibly with a US IVD company collaborator, and using the data to apply for 510(k) clearance with the US Food and Drug Administration, a company official said.

If all goes as planned, the firm could launch the test, called AdxBladder, in the US in 2020 for use as an aid to the detection of bladder cancer recurrence alongside the gold standard treatment cystoscopy, and as a replacement for urine cytology, which has been identified as the largest clinical need, Arquer CEO Nadia Whittley said in an interview.

In the meantime, hospitals in Europe are evaluating the firm's biomarker urine-based test for bladder cancer, which provides a result with a high negative predictive value and operates on a standard laboratory ELISA platform.

About 30 hospitals are currently evaluating the test for potential use, and to collect clinical data that may help Arquer in getting reimbursement for the test, Whittley said.

AdxBladder's technology is based on antibodies to minichromosome maintenance protein — more specifically MCM5, a member of the MCM family of chromatin-binding proteins. The biomarker assay is especially useful in spotting recurrence of bladder cancer and can enable clinicians to significantly reduce the number of invasive cystoscopy procedures that patients must endure when they return for monitoring and reexamination after receiving cancer treatment, Whittley said.

MCM5, the test's biomarker, recognizes cells that are replicating or still have the capability to replicate. Such cells are normally only found in the stem cell compartment of the basal layers of the epithelium. When a mass of replicating cells is present at the epithelial surface, as occurs in bladder cancer, MCM5 cells are shed into body fluids.

In practice, AdxBladder uses mouse monoclonal antibodies and a well-established ELISA technology to identify MCM5 proteins in cells exfoliated into the urine and gives a clear "cancer" or "no cancer" reading according to the level of MCM5 protein detected and indicated by a photometric change.

Further, the firm has initiated UK-based clinical trials to validate a test for prostate cancer, and if the results are promising, it anticipates expanding the study population for this indication in 2019. It has commenced feasibility testing using patient samples for an undisclosed condition with a significant unmet clinical need for a large patient population, Whittley said.

The speed at which clinical trials are completed and tests are launched will depend partly on the success of a fundraising round with no upper limit that the firm initiated this week and anticipates closing around the beginning of next year, Whittley noted.

The firm launched AdxBladder, in Europe and countries accepting the CE mark in October last year at the 37th Société Internationale D’Urologie meeting in Lisbon. It simultaneously presented results of a study involving 577 patients, which showed that the laboratory-based diagnostic test demonstrated a sensitivity of 95 percent for higher risk cancers and a negative predictive value greater than 97 percent for bladder cancers of all grades.

Sunderland, UK-based Arquer had received CE marking for the test earlier in the same month on the back of an 856-patient clinical trial for which it recently submitted a paper to an undisclosed journal. The test's performance numbers for overall negative predictive value and sensitivity for detecting patients with tumors that presented with high grade bladder cancer were confirmed in the larger trial, Whittley said.

"The recently reported results of the AdxBladder prospective study as reported at the Societe International d’Urologie meeting are notable as they demonstrated a high overall sensitivity and negative predictive value in the detection of bladder cancer," Philippe Spiess, a senior member in the department of genitourinary oncology at Moffitt Cancer Center, who is also vice-chair of the National Comprehensive Cancer Network Guidelines Panel for Bladder Cancer, said in an interview.

"However, one must be very cautious in concluding that this test is ready to replace the gold standard for bladder cancer diagnosis which remains office cystoscopy."

The AdxBladder test performed sub-optimally in patients with low-risk disease, which is a common limitation with most urinary diagnostic markers for bladder cancer, and urinary markers tend to not perform as well when they are evaluated outside the setting of a clinical trial, he said.

The major challenge with the adoption of such a test remains whether it detects bladder cancer with enough sensitivity across the entire disease spectrum when applied in a clinical setting outside of a clinical trial, Spiess said, adding that for such a test to be widely adopted across the world, it needs to be cost effective such that all patients can have access to it.

Development of AdxBladder began after the publication of a study in the Lancet in 1999 when researchers described a non-invasive immunofluorometric assay for detection of urothelial cancers based on ectopic expression of the DNA replication protein MCM5.

In 2005, Nick Miller-Jones founded UroSens after he saw the potential of antibodies to MCM5 and spent years "developing a [robust] assay and clinically testing his hypothesis to make sure that he was on to something important," Whittley said.

Early in 2015, UroSens raised £2 million ($2.6 million) and later that year the company was rebranded Arquer Diagnostics. In March 2017, the firm announced that it had been awarded £70,000 in funding under Innovate UK’s Biocatalyst program. Last October, it announced that it had raised £2.1 million through a series B investment led by equity investor Longwall Ventures.

Arquer has established two medical advisory boards, one for the US market and the other to advise it about European and other markets outside the US.

"For once in my experience, both the US and the rest of the world are very much in agreement on where the gap is and what needs to be done," Whittley said. Urologists have identified a greater need in recurrence monitoring than in initial diagnosis, she said.

Bladder cancer recurrence

Bladder cancer has a high rate of recurrence with between 65 and 70 percent of tumors estimated to return within two years. As a result, a significant number of patients need to be tracked for recurrence, with tests involving invasive cystoscopy. Patients who have had high grade tumors return as frequently as three months for testing, and with lower grade tumors, they return every six or nine months, Whittley said

In cystoscopy, a surgeon inserts a flexible cystoscope through the urethra to examine the inside of the urethra and bladder for signs of disease. The uncomfortable procedure exposes patients to the risk of urinary tract infections.

For urine cytology, a sample of urine is examined under the microscope to check for cancer or precancerous cells, but a negative result does not exclude the presence of a tumor because cytology has a low sensitivity and its interpretation is user dependent. Clinicians using cystoscopy miss up to 30 percent of bladder tumors, and the procedure comes with additional health and economic disadvantages including high costs, lengthy procedures, and long waiting lists, the firm said.

Costs for cytology testing varies by country and can range between $17 and $25 per test per patient, Whittley said, adding that multiplying that by the number by two or three and adding expenses associated with personnel to conduct testing drives up overall costs.

The cost to take Arquer's bladder cancer test is country dependent, she said, ranging from $25 to $30 where the system is more expensive. "We have built a model that clearly shows how the cost to correctly diagnose patients is much less with our product, and obviously the cost to incorrectly diagnose associated with a subjective testing is far higher from economic and patient health perspectives.

Emerging companies

Among companies other than Arquer looking to develop diagnostic tests for bladder cancer, Sienna Cancer Diagnostics in August said that it had signed Shaanxi GaoYuan In Vitro Diagnostic Reagents as its exclusive distribution partner in mainland China.

Rehovot, Israel-based Nucleix has a test called Bladder EpiCheck, which relies on multiplexed real-time PCR to analyze a panel of 15 methylation markers associated with disease recurrence. MiR Scientific, formerly MiR Diagnostics, hopes to launch its first clinical cancer test within the next year, likely for bladder cancer, initially under an LDT model, but with long-term plans as FDA-approved kits.

Also an international group of researchers led by the Georgetown Lombardi Comprehensive Cancer Center has developed an immunohistochemistry assay for the STAG2 gene, which they believe can act as a biomarker for papillary non-muscle-invasive bladder cancer.

Whittley said that Arquer's test has benefits over many emerging PCR and genetic marker-based assays because its results are not affected by population variations and its signature doesn't change as a tumor evolves.