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Cleveland Diagnostics Study Finds Its IsoPSA Test Outperforms Standard PSA Testing

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NEW YORK (GenomeWeb) – Researchers associated with protein biomarker firm Cleveland Diagnostics have published interim data from a clinical study investigating the performance of the company's IsoPSA test for prostate cancer.

The analysis of 132 patients found that the IsoPSA test significantly outperformed standard PSA testing both for detection of prostate cancer and assessing the likelihood of aggressive disease.

The results were taken from a subset of patients taking part in a larger multi-center prospective trial for the test. Recently, the company reported interim trial data for 132 patients with the ultimate goal of enrolling approximately 1,000 patients in the multi-center trial, Mark Stovsky, a urologist at the Cleveland Clinic and chief medical officer of Cleveland Diagnostics, told GenomeWeb. He added that the company hoped to complete the full trial by the end of the year.

The test employs Cleveland Diagnostics' Solvent Interaction Analysis (SIA) platform, a protein biomarker discovery and assay technology that uses different protein isoform populations to assess patient disease states. Largely developed by Boris Zaslavsky, Cleveland Diagnostics' chief science officer, the platform differs significantly from conventional protein biomarker testing approaches.

Typically, such work has revolved around efforts to find specific proteins whose expression levels differ between healthy and disease states. Researchers have also looked for specific protein isoforms that could help them distinguish between patients with and without a given condition.

Cleveland Diagnostics' SIA approach, on the other hand, looks not at levels of individual proteins or protein isoforms, but rather at bulk levels of protein isoforms associated with a given disease.

Essentially, the SIA platform consists of a two-phase aqueous solution containing various molecules like polymers and salts. Upon being added to this solution, patient samples will separate into the two phases, with different proteins moving to different phases according to their interactions with the various polymers and salts contained within. By testing different combinations of molecules, the researchers aim to develop two-phase solutions that separate patient proteins in a diagnostically useful way — the idea being that under the right conditions, a cancer-related protein isoform will move to the opposite phase from healthy protein isoforms, and that disease can be detected by analyzing the amount of proteins in each phase.

For instance, in the case of the IsoPSA test, the company has developed an SIA assay that separates cancer-related PSA isoforms into one phase and PSA isoforms not linked to cancer in the other phase. They then measure the total amount of protein in each phase via ELISA and use the ratio of the two as their score. In this way, they are able to take into account the full variety of protein isoforms, as opposed to selecting just a handful that appear relevant to the disease.

"We do know that there are certain changes in PSA that are related to cancer, and those include things like truncation, phosphorylation, and other post-translational modifications," Stovsky said. "But we don't need to specifically identify all of these myriad changes. We don't need to know what each of them are to have a diagnostically accurate test. Rather, what is really important is that we can separate all of the isoform structures that are related to cancer from those that are not."

Such an approach, he noted, enables the company to account for the great heterogeneity of diseases like cancer.

"Prostate cancer, and many other cancers, are heterogeneous diseases, so there may be thousands of PSA isoform structures that are related to the diagnosis of cancer that are not even looked at or identified in [conventional] tests," he said. "By looking at the entire PSA isoform distribution we have been able to develop a test with high diagnostic accuracy based on our study results to date"

How broadly applicable the approach is remains to be seen. "There is no guarantee that we will always be able to find the particular chemistries that actually separate [sample proteins]" in such a way as to enable clinicians to distinguish between disease states, Cleveland Diagnostics CEO Arnon Chait told GenomeWeb. To date, though, the company has had success in conditions including breast and ovarian cancer and Alzheimer's disease, he said.

In the prostate cancer study, the IsoPSA test was able to distinguish between benign patients and those with prostate cancer with an AUC of .80, compared to .58 for standard PSA.

It was also in a group of 118 patients (40 with positive biopsies and 78 with negative biopsies) able to distinguish between highly aggressive and less aggressive forms of the disease with an area under the curve of .85, compared to .61 for standard PSA testing. The study authors noted that had these findings been translated into clinical practice, they would have resulted in 37 avoided biopsies among low-risk patients, with one delayed diagnosis; and the correct identification of 19 high-risk patients requiring biopsies with only 3 unneeded biopsies.

Chait and Zaslavsky first tried to commercialize the SIA technology through biotech firm Analiza, which they launched in 1997 and now run as a CRO. In 2006, they launched spin-out AnalizaDx with the goal of applying the platform to protein biomarker diagnostics, and in 2013, they launched Cleveland Diagnostics as a joint venture with the Cleveland Clinic, moving the technology from AnalizaDx to this new firm.

Cleveland Diagnostics hopes to launch the IsoPSA test in the US by the end of the year, Chait said, adding that the company did not plan to develop its own CLIA facility but would instead sell the test through existing clinical labs. He said the firm was still working to identify the best price for the test, however, he said it would likely be less than $100 but more than the roughly $25 a conventional PSA test costs.

Initially, the company will offer the test as a tool for assessing whether a patient with high PSA likely has an aggressive cancer that requires a biopsy or can be monitored instead. Longer term, Chait said, the goal is to offer IsoPSA as a better performing version of the standard PSA test for early detection and general screening purposes.

With regard to the initial intended use, the test will be entering a market with no shortage of competitors. On the proteomic front, products including Opko Diagnostics' 4Kscore test and Metamark's Promark test tackle similar questions, while in the genetics arena companies including Genomic Health and Myriad Genetics have developed tests (Oncotype DX prostate and Prolaris, respectively) targeting the prostate cancer prognostic space.

The firm is also running clinical studies for the assay outside the US, with a pair of studies ongoing in Nigeria and additional studies planned for Kenya, South Africa, and China. The company has signed an agreement with healthcare company Global Health Management Informatics to offer the test in Africa, and Chait said he expects the test will be available in Nigeria beginning this summer.

He noted that its relative simplicity makes it potentially well-suited to resource-constrained markets where biopsies are not easily available. "Biopsies are very expensive, so if you can bring an inexpensive protein test that tells you, 'Listen, you should really go get a biopsy,' you can make a difference in many millions of lives," he said.

In addition to prostate cancer, the company is also pursuing tests for ovarian and breast cancer and Alzheimer's disease, Chait said. He noted that Cleveland Diagnostics currently has roughly 10 employees with plans to expand its staff to 15 or so over the next six months.