FDA Requires Confirmatory Trial For Dyax's HAE Drug
By Karen Pihl-Carey
Senior Staff Writer
Nearly four months after investors learned the FDA wanted more clinical data on Dyax Corp.'s hereditary angioedema drug DX-88, the agency recommended that the company complete a confirmatory Phase III trial to validate its patient reported outcome measure.
The extra study means DX-88 likely won't reach the market in the second half of 2007, as expected, but a full year later.
The company's stock (NASDAQ:DYAX) slid 33 cents on Friday, to close at $3.24.
Despite the news, New York-based Cowen and Co. kept an outperform rating on the stock.
"This is a setback for the DX-88 program, as it now seems likely that competitive products will get to the U.S. market before DX-88," said analyst Phil Nadeau in a research note. But with a less than $100 million enterprise value and a product that has solid proof-of-concept data, "the downside is limited."
The FDA supported Cambridge, Mass.-based Dyax's 30-mg subcutaneous dose, squelching any expectations that the company would need to conduct a dose-ranging study. The agency also confirmed that the endpoints used in Dyax's ongoing pivotal Phase III trial, EDEMA3, were sufficient for establishing safety and efficacy.
But a confirmatory placebo-controlled trial, to be called EDEMA4, is needed for the filing of a biologics licensing application, the agency said. The trial will likely involve fewer patients than EDEMA3, which began last December and was designed to include 62 patients.
"I think we can take out a little bit of the complexity of EDEMA3, but it's fundamentally a smaller version of the same thing," said Tom Beck, Dyax's president and chief operating officer.
EDEMA4 will recruit both na ve and non-na ve patients, enabling Dyax to enroll patients rapidly by using some of the same subjects that have participated in EDEMA3. Like EDEMA3, EDEMA4 will use the patient reported outcome (PRO) instrument to demonstrate efficacy, showing that the 30-mg subcutaneous dose of DX-88 is superior over placebo. The confirmatory trial will be in compliance with new FDA requirements regarding the PRO measurement put out in February.
Dyax's endpoint consists of a questionnaire focused on patient response and integrative response that takes into account all of a patient's symptoms, as opposed to a visual analogue scale used by companies developing competing products.
"One of the big challenges in this area is because there is no objective measurement of response, all of us struggle with the same problem of capturing patient response," Beck said. "We've worked hard on ours."
The DX-88 program previously fell under the realm of the Center for Biologics Evaluation and Research (CBER) division of the FDA, but was transferred earlier this year to the Center for Drug Evaluation and Research (CDER) division. When CDER asked for more clinical work in May, Dyax and its partner, Genzyme Corp., also of Cambridge, Mass., expected a dose-ranging study might be needed. The 30-mg dose level was derived from a trial completed with an intravenous formulation, and the companies converted the dose to the subcutaneous form - a move that CBER seemed to accept, but one that CDER apparently questioned. (See BioWorld Today, May 17, 2006.)
DX-88 (ecallantide) is a recombinant small protein identified by Dyax's phage display technology, which selects compounds that bind with high affinity and specificity to therapeutic targets.
More than 75 percent of the patients have been treated in the placebo-controlled portion of the EDEMA3 trial, and about half have been treated several times in the open-label portion of the study. The study should be complete by the end of this year, and will be followed in 2007 with the start of EDEMA4.
U.S. approval, expected in 2008, would be followed by approval in the European Union. Nadeau estimates sales of DX-88 could reach $50 million in 2010.
"We think DX-88's demonstrated efficacy and convenient subcutaneous administration positions it as potentially the best-in-class therapeutic in development for HAE," Nadeau said.
Nevertheless, some potential competitors are nearing the marketplace. Berlin-based Jerini AG has completed both of its Phase III trials of Icatibant, a synthetic peptidomimetic, to treat HAE, and top-line results are expected this quarter. Assuming they are positive, the company intends to file for marketing approval in the fourth quarter.
Other companies developing HAE products include Lev Pharmaceuticals Inc., of New York, which started a Phase III trial in the first quarter of 2005 of its C1-esterase inhibitor; and Pharming Group, of Leiden, the Netherlands, which is developing a C1 inhibitor that had positive results last year in Phase II/III studies and received fast-track designation from the FDA in July.
There are no approved therapies to treat acute attacks in HAE patients, and all of the drugs in development have orphan status. HAE is a genetic disorder caused by a shortage of C1 inhibitor activity and is characterized by painful swelling of soft tissues, including skin regions, the intestine, the mouth and throat. It affects about 10,000 people in the European Union and the U.S.
DX-88 also is being developed independently by Dyax for the prevention of blood loss during heart surgery. The company is planning a Phase IIb trial.
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