Comments from the US Food and Drug Administration on a study of its prostate cancer diagnostic have prompted Canadian biomarker firm Miraculins to conduct a second study of the test, this time looking specifically at men who have elevated levels of prostate-specific antigens but whose PSA scores were found to be inconclusive.
In an interview with ProteoMonitor last week, Miraculins President and CEO Christopher Moreau declined to elaborate on the FDA’s comments on the first study, conducted last year, but said that the resulting discussions with the agency “got us to look at our data in a different way.”
Last summer, the company, based in Winnipeg, Manitoba, studied about 200 men who were given its P2V prostate cancer diagnostic in preparation for submitting the test to the FDA for approval [See PM 06/21/07]. The study included men with exceptionally high PSA levels — that is, greater than 10 nanograms per milliliter — and those with irregular digital rectal exam results.
In November 2007 Miraculins filed a pre-investigational device exemption with the FDA in order to get informal input from the agency about the P2V test, which the company has spent six years developing. The agency’s response suggested the company should look at a more specific group of men for whom the test could be particularly useful: those with PSA scores between four and 10.
According to Moreau, “What we gleaned in our interaction with the FDA is basically that this was the most challenging group” of patients because they are considered to be in a so-called gray zone of prostate cancer risk, and therefore require additional tests or biopsies to reach clearer diagnoses.
What is needed, Moreau said, is a test, for use in conjunction with the PSA test, that would help doctors diagnose such patients more definitively without patients having to spend $2,500 for a biopsy, or endure the discomfort of the procedure.
Last year’s study, conducted at only Canadian sites, covered a broad swath of patients including patients with PSA scores in the four to 10 range. Based on the feedback from the FDA, the company eliminated from the original results patients with especially high PSA scores and irregular DREs and reanalyzed the resulting data.
“We were quite enthused about the results,” Moreau said, “but the issue was that we were down to a relatively small” dataset of fewer than 40 patients. “In terms of having some statistical significance, we felt that the number of cancers that we were left [with] … wasn’t satisfying enough for us to say, ‘Now we’re going to move on to a [pre-market approval application] with this data.’”
The new study is expected to begin in about three to four weeks and will likely wrap up by the end of the year. Stephen Frost, who was appointed the company’s R&D director in April, will lead the study. Miraculins will recruit about 200 patients from Canadian sites, although that number could double if it includes sites in the US, Moreau said. It was not immediately clear if or when the company will recruit patients from the US. The test will use pre-DRE urine collection.
Patients enrolled will have PSA scores of between 2.5 and 10 and have regular DRE results. While a PSA score of four is generally considered the “healthy” cutoff point, Miraculins chose go as low as 2.5 because about 20 percent of men with a score between 2.5 and four have prostate cancer that is missed, Moreau said.
“Our test … has to have some significant impact so that urologists will consider using it in addition to other tools that they’ve got.”
If results from this patient subset satisfy Miraculins, the firm will either file a second pre-IDE submission or conduct a larger study for pre-market approval, Moreau said.
Improving on PSA
The P2V test was designed as an adjunct to the PSA test, regarded as the standard in prostate cancer screening even though it is laced with controversy. For instance, a 1994 study found that only 25 percent to 30 percent of men with elevated PSA scores who undergo biopsies had prostate cancer, meaning that between 70 percent and 75 percent of men underwent the invasive and costly procedure unnecessarily. Moreover, if the cancer is found not to be life-threatening, men who receive aggressive treatment, such a prostatectomy, may be exposing themselves to unnecessary risks.
To address these shortcomings, the free-PSA test was developed to measure the percentage of PSA not bound to proteins in the blood, which makes it more specific than a standard PSA test with fewer false positives. The first such test to be approved by the FDA, in 2000, was manufactured by Beckman Coulter. Last year the agency approved a free-PSA test made by Siemens.
Yet despite their improvements, such tests have not been used widely by clinicians, according to Moreau. Miraculins’ P2V test, which interrogates a panel of two protein biomarkers — PSP94 and vitronectin — would compete with free-PSA tests, and Moreau said the assay would be valuable only if it could significantly outperform the free-PSA test.
Siemen’s test, called the Immulite test, comes in two models. Both have sensitivity slightly higher than 95 percent, while one has a specificity of about 15 percent and the other 24 percent. Beckman’s test, called the Hybritech, has a sensitivity of 95 percent and a specificity of 20 percent.
According to results from a study conducted in 2006 by Miraculins, the P2V has a sensitivity of 93 percent and specificity of 23 percent, though Moreau has said that both measurements are expected to rise when the test is moved to an ELISA format. The P2V was originally developed using the surface enhanced laser desorption ionization time-of-flight platform.
“Our test … has to have some significant impact so that urologists will consider using it in addition to other tools that they’ve got,” Moreau said. “When we get this final data and we review it, our plan would be, obviously, to say, ‘This meets our threshold, which is sensitivity and specificity, and we’re going to carry on.’
“If the test doesn’t meet that [threshold], then we have to make a decision about what our next plans are for the markers,” he said.
Miraculins has a lot riding on the P2V. Trying to tap into a protein diagnostic and therapeutic market estimated to reach $50 billion by 2010, the company had also been developing diagnostics for breast, gastric, and pancreatic cancers but has suspended those programs due to a lack of funding and personnel. The future of Miraculins now hinges in large part on its ability to optimize the P2V and bring it to market.
Moreau said that Miraculins will soon be announcing follow-up studies on candidate colorectal cancer markers it acquired in 2005 as part of its purchase of Europroteome [See PM 06/24/05].
In documents filed with Canadian capital markets regulators, Miraculins posted CAD$1,263 (US$1,281) in revenue during its fiscal first quarter, which ended Feb. 29, down 87 percent from CAD$9,911 during the same period one year ago. The company also said that net loss for the period narrowed to CAD$219,576 from CAD$443,741 in the year-ago period.
The company spent CAD$122,356 on general and administrative expenses. It said it had CAD$131,712 in cash and cash equivalents as of Feb. 29.