Epix Medical prepares to file NDA for long-lived MR blood pool agent

Researchers present last of clinical results at ISMRM meeting

Judgment day is rapidly approaching for Epix Medical. Luminaries have completed four clinical trials aimed at determining the safety and efficacy of the Cambridge, MA, company's MR blood pool agent, MS-325. The data are now being compiled into a new drug application (NDA), which is expected to be submitted to the FDA within the next several months.

A decision regarding the approvability of the drug, the first contrast agent specifically designed for MR angiography, may be in hand by the middle or end of next year. It could come even sooner, if the FDA grants the company's request for expedited review.

The FDA will announce its decision about a fast-track review within two months of receiving the NDA, according to Epix CEO Michael D. Webb. If granted, a decision from the FDA about approval could be made six months later. Otherwise the decision may take 10 months.

To improve the odds of success, Epix executives met recently with FDA reviewers. They agreed on the contents of the NDA package and, more important, on the filing strategy for a broad clinical indication regarding MRA.

"This gives us a lot of confidence in our regulatory timeline for this submission," Webb said.

In preparation for a best-case scenario, Epix is gathering data about MR usage patterns in the U.S. and hatching plans with colleagues at Berlin-based Schering to market the new drug. Schering bought the worldwide rights to MS-325 more than two years ago (SCAN 1/31/01).

"We are working closely with our partner Schering and expect the European submission for EU marketing approval to occur shortly after the U.S. submission," Webb said.

Epix executives are unabashedly enthusiastic about the commercial prospects of MS-325. Webb believes the clinical data now in hand support FDA approval of the contrast agent for all arteries except the coronaries. If this happens, the agent will be the only MR product on the market specifically labeled for vascular MR applications.

Unlike other drugs that are first to market, MS-325 would have the advantage of established CPT codes for its use and widespread reimbursement for its applications, thanks to the acceptance of MR angiography performed off-label with contrast agents designed for other purposes.

"We believe (the off-label use of MR contrast agents) is indicative of the strong desire of physicians to have an alternative to invasive x-ray angiography," Webb said. "We also believe this indicates a tremendous latent demand for more angiography in a wider population of patients."

His optimism is buoyed by clinical results that show MR angiography with MS-325 compares favorably with x-ray angiography, the gold standard for vascular imaging. MRA did not have to beat XR angiography in its clinical trials, only match it, according to promoters of the would-be product. The ease of use and safety profile of MS-325 will do the rest.

"While providing an accurate visualization of the vascular system, MS-325 may enable radiologists to reduce the frequency of invasive x-ray angiography procedures, which involve the use of catheters," said H. Michael Rook, head of diagnostic and radiopharmaceuticals at Schering.

In x-ray angiography, a radiopaque dye is injected using a catheter threaded through major arteries to the vicinity of a suspected vascular abnormality. Catheters can damage the vasculature, even puncture blood vessels, causing hemorrhage. The radiopaque dye used in the x-ray contrast medium can cause adverse reactions in patients, particularly those with impaired renal function.

MS-325 has neither of these drawbacks. The agent is administered intravenously, negating the need for an invasive catheter. Also it uses a relatively safe gadolinium chelate to boost the MR signal rather than the dye that blocks x-rays.

"Results of the phase III renal study showing that MS-325 is safe in patients with mild renal impairment is something that clinicians have been waiting for," said Dr. Emile R. Mohler III, one of the principal investigators in the MS-325 trials and director of vascular medicine at the University of Pennsylvania Health System. "It is certainly a very positive step toward showing that MS-325 is a preferred approach to the diagnosis of renal atherosclerosis, compared to x-ray angiography."

In their marketing of MS-325, Epix and Schering will emphasize the noninvasive nature of contrast-enhanced MR angiography, the improved safety profile of the drug compared to x-ray contrast agents, and the lower cost of MRA.

"X-ray angiography exposes the patient to x-rays, it carries a 1.5% risk of serious side effects, and it is expensive, costing between $2500 and $6000 per procedure," Webb said. "MRA with MS-325 is minimally invasive, and a whole-body vascular exam could be done for less than $1000."

MS-325 also promises substantial advantages over the contrast agents now being applied off-label to generate MR angiograms. These other agents rapidly disappear from the blood, necessitating two or more doses to obtain diagnostic images. The reason simply is that they were not designed for vascular applications, but rather to enhance the MR visualization of tumors in solid tissues. So these agents quickly "leak" out of circulation.

MS-325, on the other hand, is designed specifically as a blood pool agent. It binds to human serum albumin in plasma, illuminating vessels for up to an hour before the chemical bonds are finally broken and the agent is safely washed from the body.

"Today contrast-enhanced MRA is difficult to perform and, therefore, not routinely done in most community hospitals," Webb said. "MS-325 will make MRA easy and extremely robust. This ease of use will allow hospitals with minimal technical support and even low-field scanners to do excellent MRAs."

The long life of MS-325 in the bloodstream will also support high-resolution 3D imaging of problematic lesions, he said. This will allow detailed measurement of the lumen and percent stenosis, as well as information about the lesion itself, including remodeling of the vessel wall and plaque morphology.

Epix success has been a long time coming. The company has doggedly pursued the commercialization of its MS-325 agent for the past 10 years, beginning in 1993 with the signing of a licensing arrangement with Massachusetts General Hospital, where research on the agent had begun in 1983 (SCAN 2/13/91).

The decades-long effort culminated with the presentation of clinical trial results in mid-July at the annual meeting of the International Society for Magnetic Resonance in Medicine. Data from the pedal and renal trials, presented at the meeting, are being combined with those obtained during earlier clinical trials focusing on peripheral vessels.

Research into the peripheral vessels, reported March 7 at the European Congress of Radiology in Vienna, showed substantially better accuracy for MR angiograms in the aortoiliac region enhanced by MS-325, when compared with unenhanced MRA. Accuracy was comparable to x-ray angiography. Adverse events were mostly mild and transient, typically involving tingling, itching, and nausea (SCAN 3/19/03).

Like the results reported earlier, pedal and renal MR angiography with MS-325 showed strong agreement with XR angiography and better results than unenhanced MRA. As in the previous studies, adverse effects were mild.

"These phase III studies show that MS-325 aids the imaging of blood flow to organs such as the kidneys, and areas of slow blood flow such as the feet," said Dr. Gregory Sorensen, Epix medical director and an associate professor of radiology at Harvard Medical School. "The consistency of the results shown in all four phase III studies demonstrates that MS-325 should enable physicians to make important decisions about the care of their patients with greater confidence and accuracy."

Getting to this point was a Herculean task. The four phase III trials involved 1400 patients examined at more than 80 different clinical sites on four continents. But it has been worth the trouble, Webb said.

"We believe the data from the four phase III trials will present a very compelling NDA submission," he said.