Sera Prognostics said this week that it has exceeded enrollment of 4,000 subjects in its Proteomic Assessment of Preterm Risk clinical study supporting the validation of its proteomic test for predicting risk of preterm birth.
The enrollment numbers mark a milestone in the company's plan to commercially launch the test by the end of this year. They also have a broader significance for the proteomics field as an indication of mass spec's viability as a platform for high-throughput clinical validation and implementation.
Based on intellectual property licensed from the University of Utah and Brigham Young University, Sera's preterm birth panel consists of three proprietary peptides plus six additional proteins. The company plans to offer the panel as a mass spec-based test out its CLIA lab, making it one of the more ambitious clinical efforts to date for mass spec-based proteomics. Likewise, Sera's 4,000-plus-subject validation study is among the largest such proteomic studies yet undertaken using mass spec.
According to Gregory Critchfield, Sera's chairman and CEO, the company's PAPR study work has demonstrated that the technology is up to the task.
"We are on track with all of our development – our discovery, our verification, our technology development," he told ProteoMonitor. "We're on track to launch clinically in the fall of this year, and clearly if there were problems with [the mass spec platform] we would not be ready for that."
Sera is validating the panel using multiple-reaction monitoring assays on triple quadrupole instruments. Such assays are viewed by many as the most promising format for clinical proteomics assays, but optimizing them for the clinic has proven a complicated balancing act.
For instance, to increase assay speed – a key factor in validating and implementing protein biomarkers – researchers can reduce chromatography time. This, however, will hurt the assay's sensitivity – another important consideration. Likewise, sensitivity can be improved by using immunoenrichment upfront of mass spec analysis to pull out the proteins of interest. However, this adds sample prep steps, which can reduce throughput and raise assay variability.
In recent months, several researchers have published work indicating that these technical challenges have to a significant extent been overcome (PM 2/15/2013). Critchfield's confidence in Sera's ability to process its 4,000-plus subject validation set using its in-house mass spec workflows adds further credence to this notion.
Critchfield provided few specific details regarding Sera's mass spec workflows, but he did hint at some of the pieces involved. In particular, he cited Agilent's RapidFire product as an important technology for the study. The RapidFire is a high-throughput chromatography system that enables processing and injection of samples into mass spectrometers at rates as fast as one per every seven seconds. In November, researchers from SISCAPA Assay Technologies and Agilent published on a selected-reaction monitoring mass spec-based peptide quantitation workflow incorporating the device (PM 11/16/2012).
Noting this development, Critchfield cited his past position as a board member at biotech firm Biocius, the original inventor of the RapidFire, which Agilent acquired in 2011 (PM 3/4/2011).
"I have a longstanding view of that technology space, and clearly that's one of the reasons we're interested in working with Agilent," he said.
Agilent and Sera this month announced a strategic partnership under which Agilent would help Sera develop assays for its preterm test. Critchfield said that Agilent would be helping Sera on both the equipment side and in process development.
As part of the deal, Sera has purchased multiple Agilent 1290 Infinity UHPLC systems, 1260 Infinity LC systems, and 6490 iFunnel triple quadrupole mass spec instruments.
Speaking more generally, Critchfield called upfront sample prep key to high-volume clinical efforts like that Sera is undertaking. "A number of technologies are being developed on the front end to make mass spec throughput increase," he said, citing immunoenrichment processes like SISCAPA along with the RapidFire. "People who are knowledgeable about this space believe that to realize the goal of extremely high-throughput mass spec, technologies like these need to be developed."
In addition to technology development, regulatory questions surround the use of mass spec in the clinic. Specifically, in June 2011 FDA issued a draft guidance on research-use-only and investigational-use-only in vitro diagnostic products in which it said that device manufacturers like mass spec vendors "should not sell such products to laboratories that they know use the product for clinical diagnostic use."
Whether the agency will follow this draft guidance with any sort of binding regulation remains to be seen, but several vendors have begun registering their instruments with FDA as Class I exempt devices, so as to comply with the guidance.
For instance, Agilent last year registered certain of its Infinity Series 1200 liquid chromatography systems and 6000 Series mass spectrometry systems. And, this month, AB Sciex introduced two new LC-MS/MS systems – the AB Sciex API 3200MD and 3200MD QTRAP – that it has registered as Class I exempt medical devices and is marketing for use as in vitro diagnostic devices.
Critchfield did not specify whether Sera is using instruments registered as Class I exempt for its assays, but suggested that such questions were more a matter for instrument vendors than for test developers themselves.
"The vendors are appropriately interacting with the FDA on that," he said.
Critchfield said that Sera will continue to add patients to the PAPR cohort and aims to complete the study by the middle of this year. The patients are drawn from participating sites in 11 states, with blood samples being prospectively collected from pregnant women between 17 and 28 weeks of gestation who are tracked according to their delivery outcome and maternal and neonatal health.
The Sera panel is intended as a general screening test for preterm birth. There are approximately 525,000 preterm births – defined as birth before 37 weeks of gestation – in the US each year, and according to the March of Dimes, the annual public healthcare cost of caring for preterm infants is more than $26 billion.
In a study published in the November 2010 issue of the American Journal of Obstetrics and Gynecology, the test demonstrated sensitivity of 86.5 percent and specificity of 80.6 percent for preterm birth at 28 weeks of pregnancy. In February 2011, the company presented data at the Society for Maternal-Fetal Medicine's annual meeting in which the test predicted preterm birth at 24 and 28 weeks gestation with 94 percent sensitivity and 85 percent specificity.