Excitement is building among MR users as intravascular contrast media prove their potential to light up arteries throughout the body, while easing one of MR's chief weaknesses as an angiographic tool: the need to sacrifice resolution for coverage.
Intravascular agents, also known as blood pool agents, offer a distinct advantage over conventional MR contrast. Rather than diffusing quickly into the interstitial space, they remain in the blood for extended periods of time. As a result, it is possible to acquire steady-state images over an hour or more, rather than chasing a conventional contrast bolus for a feverish 30 seconds or so.
"This gives one the potential for a higher resolution scan, because the contrast persists in the blood pool phase. That's an important development," said Dr. Thomas Grist, an associate professor of medical physics at the University of Wisconsin in Madison.
Several companies have developed blood pool agents and are putting them through their paces in clinical studies. Dr. Steven Wolff, chief of cardiovascular MRI at Lenox Hill Heart and Vascular Institute in New York City, is participating in a phase III trial of one such agent, MS-325, which is being developed by Epix Medical in partnership with Schering. The trial is evaluating MS-325 for use in aortoiliac arteries.
The ability to acquire images over long periods of time means that studies encompassing large parts of the body, such as the aortoiliac arteries, can deliver a level of quality previously possible only when imaging very defined areas like the carotid bifurcation.
"The quality of the resolution and the signal-to-noise that you get on these images allows you to see things in incredible detail. You get a general study with the quality of a directed study," Wolff said.
Though no one can say with certainty, many industry watchers are predicting that intravascular contrast will play a key role in finally capturing the most sought-after target in noninvasive angiography-imaging of the coronary arteries. Epix has enrolled more than 100 patients in studies of coronary artery imaging thus far. For that reason, in part, MS-325, which was known as AngioMark until Epix inked the partnership agreement with Schering, has captured the confidence of securities analysts.
"We believe that AngioMark's ability to light up the entire vascular system may allow AngioMark-enhanced MRI exams to become primary screening tests for patients suspected of CAD," said Dr. Wade King, a medical device research analyst with Robertson Stephens in San Francisco.
Nycomed Amersham is also intrigued by the possibility of breaking the barrier into noninvasive coronary angiography. The company is pursuing what it calls aggressive exploratory clinical development of its blood pool agent, NC100150, for cardiac imaging, as well as for the imaging of small- to medium-sized peripheral vessels.
A further key step, myocardial perfusion imaging, was the subject of research papers presented at the International Society for Magnetic Resonance in Medicine meeting in April. One study in pigs, led by Dr. Christine Lorenz and colleagues at Barnes-Jewish Hospital in St. Louis, suggested that it might be feasible to combine the use of MS-325, injected during peak stress, with delayed high-resolution imaging to identify myocardial perfusion defects. Epix expects to begin human perfusion studies this winter, said CEO Michael Webb.
Before MR coronary angiography and perfusion imaging become a reality, refinements in scanner hardware, software, imaging algorithms, and postprocessing techniques will be necessary, however.
"There's still a lot of room out there for improvement, based on the fact that you've got something new to play with," Wolff said. "Whether or not that's going to be the enabling thing, I can't predict. I can tell you that I would not bet against MR, with this agent (MS-325), being able to do coronary artery imaging."
Blood pool contrast agents work by a variety of mechanisms. Iron-based products, such as Nycomed's NC100150, also known as Clariscan, take advantage of their large molecular size, which prevents diffusion into body tissues. These agents are disposed of by the liver and spleen as particulate matter.
MS-325, which is gadolinium-based, stays in the blood stream as a result of transient binding to albumin. Albumin binding offers an additional benefit beyond localization in the blood pool, according to Webb. The contrast agent begins to spin much more slowly, at the rate albumin spins, causing a relaxivity gain that produces a substantially brighter signal than would be possible with freely circulating gadolinium.
King has pegged the potential U.S. market for intravascular contrast media, including their use in coronary artery imaging, at $75 million annually. MS-325 could have that market all to itself initially, assuming it receives FDA marketing clearance for use in the aortoiliac arteries in early 2003, as the company hopes. Codevelopment efforts between Epix and Schering will focus on getting gadolinium-based MS-325 to market first, Webb said, with Schering's iron-based agent, SHU 555C, following later. (Schering's development and marketing plans for SHU 555C in Europe and Japan will continue in full force in the meantime).
Nycomed's Clariscan is also likely to enter the market much later than MS-325. In December, the company announced that it had stopped pursuing research with Clariscan for general MRA indications, including the aortoiliacs.
"We feel that with first-pass imaging, the Omniscans, ProHances, and Magnevists of the world do a fairly good job in that arena," said Dr. Ron Robison, senior vice president for global clinical research and development.
Instead, the company expects to review data from ongoing cardiac and peripheral exploratory studies and to decide by mid-2001 whether to go forward with development of Clariscan, and for which clinical indications. Once the decision is made to proceed, it could easily take another four years for the blood pool agent to be cleared for marketing in the U.S.
Intravascular contrast agents have the potential to make MR angiography available almost anywhere, even in hospitals without the most expensive scanners or expertly trained technologists, Webb said.
"When you're using the conventional agents, if you miss the bolus, the party's over. With our agent, you inject it once and the arteries are lit up so long that you can repeat the exam however many times it takes," he said. "That will make angiographic imaging with MRI possible in places like Peoria."
