Companies look ahead to the next developments in contrast agents.

Generally speaking, today’s contrast agents work well, but they are not perfect. There is a subset of patients (primarily those with kidney problems) who can experience significant adverse outcomes as a result of their use, and as today’s patients grow both older and sicker, the population of that subset grows larger. Subsequently, there is a demand for contrast agents that do not hold these same risks, but because current agents do work so well, developing better agents is a bigger challenge than one might expect.

“New agents have to prove they are better than current agents in at least that subset if not all patients,” said Don Black, MD, vice president of research and development for the medical diagnostics division of GE Healthcare, Waukesha, Wis. The better the compound a manufacturer is trying to replace, the more difficult it is to develop a new compound. Black uses a number of metaphors to make his point, including building a better mousetrap, designing a car that runs differently rather just being designed differently, and producing a drug better than aspirin.

“People suggest that aspirin is not a very good drug because of its side effects, but even with these issues, it performs pretty well. Finding something better has proven difficult,” Black said. The same is true of contrast agents.

Thus far, there hasn’t been a clear benefit of newer agents, though manufacturers are looking to minimize adverse effects and improve the safety profile of these agents. It’s expected to be a number of years before anything truly different is available, but manufacturers are working on it.


One of the primary concerns regarding the use of today’s contrast agents is the risk of damage to the kidneys, although lesser side effects can include warmth, itching, and flushing. “For the most part, the agents—iodine- or gadolinium-based—are removed by the kidneys, and so the patient needs reasonable kidney function to begin with to tolerate the doses,” Black said.

Patients with impaired renal function are at risk of nephrogenic systemic fibrosis (NSF). Also known as nephrogenic fibrosing dermopathy, the condition is initially characterized by swelling and tightening of the skin in the extremities leading to inhibited mobility. Research has found it may affect other body systems, including organs.

Unfortunately, however, patients with impaired renal function are often in need of imaging studies to diagnose or monitor other conditions. On the other hand, many of the contrast agents are well tolerated by many different patients. “Millions of people take these products in routine procedures, so they must be well tolerated,” Black said.

It is therefore up to the patient and the physician to determine whether to move forward. “The user wants to evaluate the risks and benefits before administering any drug to the patient. It’s critical to follow the prescribing information and make sure it’s the right patient at the right time being given the right drug,” said Herbert Neuman, MD, chief medical officer and vice president of regulatory affairs for imaging solutions and pharmaceutical products with Covidien, Mansfield, Mass.

Physicians generally do a good job of protecting their patients, but manufacturers are still faced with trying to eliminate the risk altogether. “You have to understand what is going on with the kidney, and that is not entirely clear,” Black said.


As researchers attempt to better understand kidney physiology, they are also exploring agents with new properties that might reduce the risk while improving capabilities. Some, like Covidien, are looking to increase the specificity of agents. “Targeting traits of a product allows the contrast molecule to go to a specific place through an affinity for a certain cell or protein,” Neuman said. Specific tumors may be identifiable by proteins on the cell surface; receptors and antibodies may also play roles.

Researchers are also looking to improve relaxivity, which refers to a compound’s ability to relax protons. “Relaxivity is essentially how tightly wound a molecule is and impacts how it can tolerate the magnetic field strength of an MR scanner,” Black says. Higher relaxivity may lead to better contrast agents.

One significant area of development is nanoparticles. Most agree that agents of this nature represent the future of contrast. “It’s a highly experimental field, but the appeal is that nanoparticles can be more flexible and have more room in terms of what you can put inside them. So they can be more powerful but small enough to move through blood vessels,” Neuman said.

The benefits expected to result include smaller doses and better imaging, although because the materials are in early developmental stages, more research needs to be conducted to know for certain what the advantages and disadvantages are.

To be approved by the FDA, any nanoparticle agent will have to prove that it is safer and possibly also better. “Agencies, such as US FDA, have strict and robust criteria and processes for approving new agents on the market,” Neuman said. Contrast agents, whether older iodine- or gadolinium-based agents or newer nanoparticles, must submit a new drug application, or NDA, to the FDA, which requires significant safety data. But exactly what data will be required has been unclear up to this point. “What explicitly will be required for nanoparticles is too soon to know, but we will work with agencies as we go through the development cycle to be sure new agents meet approval guidelines,” Neuman said.


EPIX Pharmaceuticals Inc, Lexington, Mass, is going through just such a process now as it seeks approval for its gadolinium-based contrast agent Vasovist for use in magnetic resonance angiography (MRA). FDA approval had been hindered by uncertainty regarding what should be required to ensure safety and efficacy.

With the entry of a new administration at the agency, an agreement for an approval process was finally reached. It focused on three primary end points: sensitivity (an improvement), specificity (no worsening), and uninterpretable images. To achieve the required end points, EPIX needed to have the studies used to collect data reread by three new and independent radiologists (two of which had to achieve the end points—all three did) and to complete a statistical reanalysis of the data according to FDA direction.

EPIX expects to resubmit its application by midyear and to receive word within the 180-day legal limit. Should approval be granted, Vasovist will be the first agent given FDA approval for MRA indications, according to Michael Kauffman, MD, PhD, CEO of EPIX. Several agents, including Vasovist, have been approved in Europe, but in the United States any MRA use has been off-label. “Currently in the US, we use off-label to the tune of around $125 million,” Kauffman said.

Standard gadolinium agents are used at about three times the recommended dose. “The three-x has come about because physicians are aware of what is needed to properly give images of blood vessels,” Kauffman said. The challenge, he explains, is that gadolinium agents are designed to move out of the blood vessels and into the brain and other tissues. As a result, imagers have about 5 minutes to capture pictures of the blood vessels before the concentration of the contrast agent in the blood becomes too low. “This doesn’t give the physician and radiology technician much time to better position the patient or to look at different vessel beds. And because the dose is so high, you can’t give the patient a second dose,” Kauffman said.

By contrast, Vasovist is designed to stay in the blood vessels and therefore requires a smaller dose. The agent is a standard gadolinium agent that has been altered to stick to the blood protein albumin. “It does not form an actual bond but sticks, and the attraction allows it to stay in the blood,” Kauffman said.

The “stickiness” produces excellent resolution because the agent does not leak out of the vessels while at the same time provides longer time periods in which to capture images. “The labeling ex-US is up to an hour,” Kauffman said. Imagers, therefore, have plenty of time to better position patients and to capture pictures of additional vessel beds.

Although the initial approval application is focused on MRA use, EPIX would eventually like to see indications extended throughout the body for imaging of all blood vessels. The risks are the same as gadolinium-based agents that carry a black box warning about NSF, and Kauffman notes Vasovist is expected to sport the same warning. But he also reports that to date, Vasovist has not been related to any such cases. “The data includes more than 10,000 patients in Europe, where [Vasovist] is already approved, and we have not heard of a single case [of NSF],” Kauffman said.

While the additional FDA-required data is collected and analyzed, EPIX is already looking ahead to new development. The company has designed an agent intended to detect clots using MRI. “Instead of sticking to albumin, the agent sticks to fibrin,” Kauffman said. EPIX, however, does not expect to develop it further, but another firm may choose to do so. The company is instead focused on development of another derivatized gadolinium contrast agent that will target heart imaging.

Kauffman expects that approval of Vasovist will help to reinvigorate the industry, which has had difficulty obtaining new approvals and therefore research and development interest and funds over the past few years.

Down the Road

Research into nanoparticle agents has not experienced similar challenges, in part because the work is still in such early stages that FDA approvals will not be sought until further into the future and in part because the agents hold so much promise. Luna Innovations Inc, Roanoke, Va, is developing a nanoparticle platform that it believes will not only eliminate concerns about NSF but will also enable greater specificity.

Don Black, MD
Herbert Neuman, MD
Michael Kauffman, MD, PhD, CEO

The technology utilizes carbon nanospheres that hold gadolinium inside and chemical groups outside. The covalent bonds trap the gadolinium in the Fullerene cage, where they cannot escape. “You have to heat it to 1,000 degrees Fahrenheit to release the gadolinium, which is not a condition you would ever find in the human body,” said Robert Lenk, PhD, president of Luna Innovations’ nanoWorks division.

The breakthrough, according to Lenk, was determining how to use the carbon structure to achieve high-resolution images for MRI, a breakthrough that was associated with higher relaxivity. “Chelates have a relaxivity of about 3.8 compared to a relaxivity of 200 for this nanoparticle. This means you can get a meaningful image with much less material,” Lenk said. This also means the resulting agent is inherently safer.

In addition, chemical groups can be attached outside of the molecule to increase the agent’s specificity. “The platform technology can then be used to develop a whole portfolio of different targeted agents to do the same thing you do with nuclear medicine without radioactive material or specialized equipment,” Lenk said, noting that the MRI machines available in most community centers would be compatible.

Last fall, the company won a grant from the National Heart, Lung, and Blood Institute to develop an agent that would help image plaque on arterial walls. “We are early in the program, but if successful, it could be a breakthrough in diagnosing patients with heart disease. You’ll be able to visualize plaque building in small as well as large arteries, and distinguish stable from unstable plaque,” Lenk said. Other potential developmental targets include metastatic cancer and inflammation sites; possible benefits include earlier diagnoses and better patient management.

These benefits, however, have not been studied in humans yet, and Lenk acknowledges there are still many questions to answer before any agent is approved, including what, if any, risks might be associated with the material’s use. “We can say it’s well tolerated in animals, but as with any new entity, the effects are unknown until you do the clinical trials,” Lenk said.

Currently, the company is working with the National Cancer Institute, Bethesda, Md, which selected Luna’s agent for preclinical characterization by the Nanotechnology Characterization Laboratory. The information will provide some basis for manufacturing and ultimately FDA approval. The characterization is expected to be completed within 1 year, but there is no target date for submission to the FDA. “It’s premature at this point,” Lenk said.

However, the medical community will wait. Iodine- and gadolinium-based agents have been around for 20 to 30 years, and they work well for most patients. As demand grows for agents that work for the rest of the patient population, companies come closer to delivering a better mousetrap—or gadolinium trap, as the case may be.

Renee Diiulio is a contributing writer for Medical Imaging. For more information, contact .