Repligen Imaging Aid SecreFlo May Provide Pancreatitis Patients An Endoscopy Alternative
This article was originally published in The Pink Sheet Daily
Executive Summary
A second read of Phase III data revealed statistically significant improvement in MRIs of pancreatitis patients for Repligen’s imaging aid SecreFlo. That finding will be tested by FDA’s Gastrointestinal Drugs Advisory Committee May 31.
The clinical evidence behind Repligen Corp.’s NDA for its imaging agent SecreFlo will likely face tough scrutiny when it goes before an FDA advisory committee in May, as the application was based on a re-read of data from a Phase III trial.
On May 31, FDA’s Gastrointestinal Drugs Advisory Committee is set to take up the NDA for use of SecreFlo with MRI to improve pancreatic duct visualization for the detection of duct abnormalities to enhance clinical decision making in patients with known or suspected pancreatitis. The PDUFA date is June 21.
SecreFlo is a synthetic digestive enzyme that stimulates pancreatic secretions, thus forcing ducts to open and become more visible to magnetic resonance imaging; it may allow pancreatitis patients to avoid invasive – and more expensive – endoscopic diagnostic procedures.
Repligen’s synthetic secretin, also known as RG1068, was fast-tracked by FDA in early 2008, and once filed the application received priority review because of its potential to provide a noninvasive alternative to standard use of endoscopic retrograde cholangiopancreatography (ERCP) to examine and evaluate diseases of the pancreas. But the application was dealt a setback when mixed results in radiologists’ readings in the pivotal Phase III trial, reported in December 2009, sent Repligen to both U.S. and EU regulators asking permission for a re-read.
Deficiencies In CRO Oversight
The trial had co-primary endpoints of improvement in sensitivity of detection of structural abnormalities in the pancreatic ducts using MRI with and without RG1068, as well as minimal loss in specificity. It enrolled 258 patients with a history of pancreatitis at 23 clinical sites in the U.S. and Canada. The predetermined success criteria were a statistically significant outcome from two of the three central radiologists reading the MRI images. Each patient separately also underwent endoscopy as a diagnostic reference.
In the end, one radiologist saw significant improvement in sensitivity, while another showed a trend but no significance. All three showed minimal loss in specificity. Pooled data from all three, not a prespecified endpoint, showed statistical significance in sensitivity. All radiologists also saw statistically significant improvement in secondary endpoints that included improvement in image quality, ability to see all three segments of the pancreatic duct and physician confidence in the ability to identify pancreatic duct abnormalities compared to MRI alone. There were no adverse events attributed to MRI, while 55 were associated with endoscopy, the most common being acute pancreatitis requiring hospitalization.
Mixed results in radiologists’ readings in the pivotal Phase III trial sent Repligen back to regulators asking permission for a re-read.
What A Difference A Re-Read Makes
Following the disappointing results, Waltham, Mass-based RepliGen met with FDA and EU regulators to discuss next steps. The company announced in May 2010 that the authorities had approved its proposal to re-analyze the images based on the numerous deficiencies with the analysis of the images by the contract research organization hired to oversee the data analysis and that regulators in both the U.S. and EU had indicated sufficient confidence in the outcome that the company planned no further trials in that indication.
In March 2011 the company announced positive results from the re-read. This time all three radiologists achieved a clinically and statistically significant improvement in sensitivity with minimal loss (<7.5%) in specificity. In addition, the RG1068-boosted MRI images showed highly significant improvements on image quality and physician confidence in the diagnostic findings compared to MRI alone, Repligen reported. The company announced March 5 that it had submitted a marketing application to EU authorities.
RepliGen is also developing SecreFlo as an agent to improve detection and characterization of pancreatic cancer in combination with contrast-enhanced MRI and computed tomography. The company announced in July 2011 that it had launched a pilot study that will also evaluate which imaging technique is best for pancreatic tumor detection, staging and evaluation for surgery.