A Conversation with . . . Don Kiepert, BS, RPH, MS, and Mark Hibberd, MD, PhD

Looking at challenges and future directions for contrast agents

Don Kiepert, BS, RPH, MS, is president and CEO of Lantheus Medical Imaging, a N. Billerica, Mass.-based provider of products to illuminate the heart and other internal organs. Mark Hibberd, MD, PhD, is senior medical director and head of global medical affairs at Lantheus. Professionally, he is a physician-scientist with training in cardiovascular basic science and in clinical cardiology and echocardiography.
rt image recently caught up with Kiepert and Hibberd to talk about the challenges facing the contrast imaging agent market and future directions for the technology.


rt image: What function do contrast imaging agents perform,  and are there specific modalities they are used for?

Mark Hibberd: Contrast imaging agents are usually injectable drugs that are used with all of the major forms of noninvasive medical imaging – that is, they’re used with ultrasound, with MRI, CT imaging, and with invasive catheter-based angiographic imaging.

There are several different kinds of contrast agents in three main classes. These are the iodinated contrast agents that are used for invasive angiograms and CT scans. There are the gadolinium-based agents which are used for MR scans. And there are the microbubble contrast agents, which are used for echocardiography and for radiological applications of ultrasound.

They’re all fairly different from each other in chemical terms. The difference is that the iodinated and gadolinium-based agents are soluble, whereas the microbubble agents actually are tiny bubbles about 2 to 4 micrometers in diameter, much smaller than a blood cell. They’re not soluble, and they contain inert gases which travel around the bloodstream for a short period of time – a few minutes – and then the bubbles break up and the gases are breathed out through the lungs.

What are these agents used for in general? They’re basically used to improve the diagnostic abilities in certain disease states of all of the types of scans I was referring to. So, you can improve the image quality, and you can see borders and morphological definitions more easily, with these agents. You can identify vascular structures more clearly because these agents are largely contained within the vasculature, and in the case of the microbubble agents, entirely within the vasculature. All of these agents help healthcare providers see the body more clearly, and this helps you make better diagnoses, which improves patient care.

Note that radioisotopes are also used extensively in medical imaging. The radiopharmaceutical agents are different in that they emit signals that can be imaged directly with appropriate detectors.


image: You mentioned gadolinium-based agents. For the past few years, there has been some concern about their connection with nephrogenic systemic fibrosis (NSF). What’s going on with that at this point?

Hibberd: It appeared several years ago and came to public attention. The U.S. FDA was concerned about safety risks associated with the use of high doses of certain of the gadolinium-based agents. The gadolinium-based agents available to the market at that time and, in fact, up to now have been very successful in improving MR images. Physicians began to use higher doses of the gadolinium-injectable drugs.

What happened was this rare syndrome, NSF, occurred in a small subset of the population who had significant renal or kidney damage and poor kidney function. NSF is a body-wide fibrosing disorder which occasionally is lethal, so it’s a pretty nasty and difficult-to-treat adverse effect of receiving too much gadolinium in a situation where your kidneys are also not working well. So it’s made physicians a lot more cautious about how much gadolinium they use when they do MR contrast imaging. And that’s important to Lantheus Medical Imaging because we just acquired a newly approved gadolinium-based agent.


image: What was the former name of that product?

Hibberd: The official name at EPIX Pharmaceuticals Inc. was MS-325, formerly known as Vasovist, and it has actually been marketed in several countries around the world, mostly in Europe, and also in Canada and some other places. It has some strikingly different properties to the other gadolinium-based agents. It improves image quality at least as well, if not better, than the other agents, and the dose of gadolinium is between a third and a half the dose used when the other agents are used. And it has the unique property of staying in the bloodstream considerably longer than the other agents available to the market and to healthcare providers. And so it doesn’t need to be redosed. You have as much time effectively as you want to do your imaging. If you need more time to get better pictures, you can do that without redosing. So it should be easier to use and lower-risk. This agent has never had a case of NSF reported, to my knowledge.


image: What’s the significance of Lantheus’ acquisition of the gadofosveset trisodium product formerly known as Vasovist?

Hibberd: I think it’s very exciting for us and for healthcare providers to know that this agent is going to be finally made available. You may know it’s taken a long time to go through the regulatory process with the FDA, and it will be new to the American marketplace towards the end of this year. By picking up the rights in Canada, we’re going to be able to maintain the supply, which otherwise would be stopped in Canada, and the agent has never been launched in Australia before, so that will be exciting for physicians there, too, I think, when we are able to get it there. I can’t give you an exact time frame for that at the moment.

Don Kiepert: I think I would add that the acquisition of gadofosveset trisodium reinforces our growth strategy to continue to bring to market new diagnostic imaging tools.  The brand fits well within our current product portfolio of leading contrast imaging agents. We are in the ultrasound community, with DEFINITY. We’re also in SPECT imaging, with Cardiolite, which is the most successful radiopharmaceutical ever launched. We’re also in PET imaging, for myocardial perfusion, where we have a co-promotion agreement with Bracco for their rubidium-82 generator which is called CardioGen®. We are also now in Phase II with our own PET perfusion agent that will be unit-dose, and that should be launched some time in 2012. With gadofosveset trisodium, we’re now in the MRA [magnetic resonance angiography] space.

When you look at our company, we’re diversified across these modalities, which allows us to bring in new products because we’ll have the strong relationships with the key users of these different technologies. So I think that’s the other significant thing about the acquisition of MS-325.


image: What are some of the recent significant technological innovations in the field of contrast imaging agents?

Hibberd: I think this new gadolinium MR agent is really going to be very helpful to those radiologists who do magnetic resonance angiography (MRA), which is basically outlining the blood vessels, the arteries, and veins in the body, in any organ system. The agent formerly known as Vasovist is actually the only FDA-approved agent for MRA. The other agents are used for MRA, but they have not been approved by the FDA for that purpose, whereas Vasovist has been approved for evaluation of known or suspected for aortoiliac occlusive disease (AIOD), which is basically the occlusions or blockages in the large arteries that run down the back and into the legs.


image: What are some recent significant developments at Lantheus in the area of contrast imaging agents?

Kiepert: In 2001, we launched a product called DEFINITY, which is a contrast agent that’s used in cardiac ultrasound or echocardiography for suboptimal echocardiograms. DEFINITY is used by echocardiographers to visualize the borders of the heart more clearly. There are approximately 25 million echocardiograms that are done each year, and about 20 percent of those are considered to be suboptimal, so about 5 million echos that are suboptimal.

When a patient has a suboptimal echo, it means one of two things: either the patient is then referred for another, more costly test, such as SPECT imaging, or CTA, or the physician may not be certain and nevertheless may decide to make a diagnostic decision based on a suboptimal image.

The echocardiography community feels that this product has high clinical value. and has a favorable benefit-risk profile. While the penetration rate into this market has been relatively low and slow to grow, physicians have said loudly that this is a product that adds value in the patient care arena.

At the end of 2007, the product received a box warning, and in May of 2008, due to a very strong, unprecedented grassroots effort on the part of the cardiology community, who went to the FDA and petitioned very effectively to modify the box warning, the FDA decided to remove the contraindications from the box. The  box warning now more appropriately reflects the benefit risk ratio of the product.

DEFINITY is a product we have stood behind and significantly invested in. We’ve just completed the CaRES registry to evaluate the safety of the drug, in which more than 1,000 patients were enrolled in the study. There have been a significant number of articles that have been published on the clinical value of DEFINITY, and we’re hopeful that it will grow, as we believe it’s a valuable tool for the cardiologist to diagnose cardiac disease.


image: What can you tell me about the CaRES registry and the report of results about DEFINITY at the American Society of Echocardiography in Washington, D.C., back in the spring?

Kiepert: Yes. We invested significantly in the CaRES study, which is the Contrast Echocardiography Registry for Safety Surveillance, where we were monitoring the use of DEFINITY and safety. This was the first multicenter, Phase IV observational registry that evaluates the use of ultrasound imaging agents in routine clinical practice, specifically in patients with suboptimal echocardiograms.

As the first study of its kind that was conducted in the U.S., the results will provide – we haven’t published the final results yet – important clinical information about the use of DEFINITY in a range of patient types and clinical settings. We’re excited to be able to complete the enrollment. We invested substantially in the trial, and we expect that these findings will demonstrate that DEFINITY is being used in the settings recommended by the American Society of Echocardiography, and that the uses are well tolerated, that this continues to be viewed as an agent with an appropriate benefit-risk profile for use in echocardiography. So that’s kind of a quick summary on the CaRES registry.


image: What can you tell me about results reported at the American Diabetes Association meeting about Cardiolite in treating patients with Type II diabetes?

Kiepert: Cardiolite was used in that study at one-, three- and five-year follow up for purposes of imaging MPI and cardiac analysis in patients with type 2 diabetes and stable coronary artery disease. SPECT MPI with Cardiolite was used to evaluate different therapeutic approaches. The primary endpoint was left ventricular ejection fraction, ischemia burden, and also myocardial scar changes. The study compared treatment with more traditional medications versus cardiovascular intervention with the use of some type of stent. This study was an example of the utility of Cardiolite as an agent that could be used to diagnose and determine the extent and severity of cardiac disease. So that’s basically a summary of how Cardiolite was used in that study.


image: What challenges are facing the contrast imaging market in the near and long term?

Kiepert: Reimbursement continues to be a major challenge facing the imaging market. I think the jury is still out about what impact some of the work that’s being done around healthcare reform will have on the imaging business. Although, as I look at imaging, and I’m frequently asked my view on imaging as it relates to what may happen with healthcare reform, I look at it as being the solution to the problem. With the utilization of appropriate contrast imaging or molecular imaging, you’re able to diagnose patients more accurately, and you’re able to intervene in a more judicious way, so that the therapy can be appropriate for the patient.  You can avoid morbidity associated with incorrect treatments, and you can improve your outcomes. All of that leads to a pharmaco-economic benefit.

So I do believe one of the challenges is making sure that the payer community, CMS included, is aware of the value – not only patient care value, but also the cost value – of the use of imaging. So that’s a challenge.

We also have a challenge in that we are the largest producer of technetium generators, which are the workhorse of the nuclear medicine industry, and we’re dependent on a supply chain that’s fairly fragile. We receive molybdenum-99 from five sites around the world that produce it, and when one nuclear reactor goes down, it creates a shortage of supply, so that this valuable medical product is not available for diagnosing things like cardiac disease or different types of cancer.

We currently have a situation where there is a global moly-99 supply crisis, in that the largest producer of molybdenum, which is the NRU reactor based in Chalk River, in Canada, has been shut down. It provides 35 percent to 40 percent of the world’s required molybdenum. Because of this shutdown, the availability of technetium-99, which is the end product of molybdenum, is impacted; essentially we don’t have as much supply as we need to service the population.

From our company’s perspective, what we’ve done to meet that challenge is we’ve diversified our supply chain. Previously, we received most of our moly-99 from the NRU reactor. Now, we are receiving molybdenum from NTP in South Africa, IRE in Belgium, and just recently, ANSTO from Australia is beginning to supply us with the first LEU [low-enriched uranium]-produced molybdenum that will be used in commercial generators. We recently just announced the fact that we’ve entered into a relationship with ANSTO.

LEU is important because the U.S. government would like to see a reduction in the exportation of HEU, highly-enriched uranium, for non-proliferation reasons. So, the fact that LEU-sourced molybdenum is now available from Australia is a big advantage to the community. We’re the first company to incorporate that sourced molybdenum into our generators, and the FDA recently has given us approval to use that molybdenum in the production of generators.

So the silver lining in this outage from NRU is it’s forced us as a company to fully diversify our supply chain, and we’ve been successful in doing that. Even though we’re not at the level we’d like to be, we’re much further down the path than we would have been if we only received molybdenum from NRU in Canada.


image: What can you tell me about the regulatory climate, as far as introducing new contrast imaging agents. Is that something that has changed with the new administration?

Hibberd: It’s too early to tell whether anything has changed as the result of President Obama coming into office, although I would like to think that people will think of imaging agents like this a little bit more favorably than they have done over recent years because of all of the safety concerns that have been raised by the FDA. I think it’s obvious, that better diagnoses can lead to better patient care, and better ways of using the available therapeutic agents, drugs, and devices that we have for healthcare. I think it’s important that they’re thought about in that way, and not merely as things that make prettier pictures, because physicians are able to use those better pictures to more clearly understand morphology or function of the various organ systems and interpret those new images in ways that allow them to understand human diseases better and therefore take care of their patients better.

And, while any kind of drug, including the injectable contrast agents are likely to have rare side effects which are undesirable, that’s true for all drugs used in medicine. The reality is that most of the contrast imaging agents do have rare side effects, but they are rare. In the meantime, many people derive a lot of advantage from their use. So the benefit-risk balance tends to be strongly in favor of their use in the right circumstances.


image: How about the impact of the current economic situation in terms of the demand for contrast imaging agents?

Hibberd: Haven’t really seen anything yet. The markets that we sell products in at the moment have been stable or growing slowly, so I can’t say that it’s had a direct impact so far. I think down the line, I don’t think it’s so much the current economic climate that’s going to have an impact as perhaps the new administration or others’ attempts to control healthcare spending. I think we’re going to see some shift towards favoring the use of simpler and cheaper technology, and in that context, I think contrast agents which tend to be relatively inexpensive and add a lot of value to imaging are going to be important in that new healthcare environment.


image: What sort of future directions do you see contrast imaging going in in the foreseeable future?

Hibberd: I think it’s going to be a big boom time for contrast imaging. We’ve seen the emergence of fabulous ultrasound, CT, and MR scanners from the device makers over the past five or 10 years. And I think we’ve only just begun to touch the abilities of those new scanners to diagnose and help manage patients. Where a lot of the additional advantages are going to come, I think, is with new, clever, creatively developed contrast imaging agents that allow one to really exploit the advantages of these new machines.

In addition to that, I see two general trends – one, towards improving the quality of simpler, accessible, less costly technology like ultrasound imaging, and I see more and more uses emerging for contrast microbubble agents like Definity, such as in various radiology applications, or in other areas of cardiac applications.

I also see the fancier, more expensive technologies being useful, especially in the triage of patients who need expensive procedures like the placement of ICDs or interventional cardiology procedures like bypass operations or PCI interventions. So those patients who need these therapies are more carefully selected to avoid wasting these expensive procedures when they’re not necessary. So I think there’ll be a great use for the more high-tech type of diagnostic agents in that realm.

Kiepert: When you talk about contrast imaging, there are lots of agents that have been developed for use with contrast, as contrast agents. There will also be lots of agents that will be developed for molecular imaging purposes, so there’ll be a need for both of those.

For molecular imaging, there’s a real need for tools that would allow physicians to identify patients that are likely to respond to different types of therapy – oncology therapy as an example. There are very expensive targeted treatments available, and patients need to have a certain genetic makeup for them to be able to respond to those treatments. So if you could have an imaging approach that could identify patients that would respond, you could make sure that the investment in that therapy is justified, since these therapies are very expensive.

You could also monitor the therapies, so that once you initiate the therapy, you can monitor to see if the patient is progressing appropriately.

In the imaging arena in general, I think oncology is an area that will grow very rapidly. Other growth areas include neurology, in addition to advances that will be made in the cardiac area.


image: What is your vision for Lantheus’ future?

Kiepert: Our vision is to be the leading developer of medical imaging solutions to  improve human life. We think we’re in a strong position to realize that vision, based on the nine products that we have today in the marketplace, based on our pipeline, which includes three very promising agents – one in Phase II for PET perfusion; one that’s just entering Phase I, that will be used to identify patients that are at risk for cardiac events or cardiac death; and then the third, an MRI contrast agent, which will identify vulnerable plaque found in the vasculature. If you look at where we are today, our core competencies as a company, the pipeline in which we’re investing 13 to 14 percent of our revenue, we think that over the next several years our vision will become our reality.

— Mark D.  Marotta