Fighting heart disease

Cardiovascular disease (CVD) kills 2600 Americans each day – causing nearly 40 percent of all deaths in the United States – and an estimated 17 million people worldwide die of the disease every year.

Despite these sobering statistics, progress has been made. Atherosclerosis – the build-up of plaque in the arteries that underlies most cases of CVD – has been treated with statins for more than 20 years, and they have had a tremendous effect. As Dr. Andrew Plump, Vice President and Franchise Integrator for cardiovascular disease at Merck & Co., points out: “These drugs came to market in 1987 and have made a phenomenal impact. They work primarily by lowering low-density lipoprotein or LDL. Recent meta-analyses have suggested that the use of statins has diminished the morbidity and mortality from CVD by approximately 30 percent.

“But at the same time, we have to think about the 70 percent of patients who still have some risk. Industry-wide, that’s where the majority of effort is currently being focused, trying to attack that 70 percent.”

Of course, the pursuit of treatment for that other 70 percent won’t be all plain sailing. When you’re developing a drug to treat coronary disease, it’s important to show that it has benefits and outcomes, which can mean carrying out very long and expensive trials. “If you go into these types of trials without a strong probability of success,” says Plump, “they’re very risky on a number of fronts: for patients who will be taking these drugs for quite some time, and also financially for the industry.”

Plump explains that the stepping stone into successful outcome trials historically has been through LDL-reducing drugs, with a strong correlation between LDL and coronary events on the one side, and on the flipside the fact that every drug that has been shown to effectively lower LDL without detrimental off-target effects has been shown to decrease cardiovascular risk when studied in an outcome trial. “So LDL is one way of getting into it. When you have a drug that selectively lowers LDL effectively, you have a good sense that it’s going to work in an outcome trial.”

Once we get beyond LDL, however, everything opens up. This was shown with the ILLUMINATE trial, which tested a cholesteryl ester transfer protein (CETP) inhibitor that had off-target effects, and in which the mechanistic hypothesis that was put forward was not borne out by the results. This has also occurred in several other industry examples with drugs that didn’t affect LDL, but for which there was a hypothesis that they would be beneficial in outcomes, and they failed to demonstrate benefit.

“The key issue that we face is how can we better predict, going into an outcome study, that we’re actually going to see benefit? What are the tools we can use to tell us a drug is doing something good once you move away from LDL?”

A new approach

To help answer this question, a new approach has been developed, which has parallels to a method used in cancer research. Plump: “The idea in cancer is that when you have a tumor, the tumor is excised. That then gives scientists and clinicians the opportunity to study the characteristics of the tumor, and by understanding these characteristics, you can define the therapy that’s appropriate for that individual. We’d like to do something similar with cardiovascular disease, but it’s a little bit different, because when you have atherosclerosis and plaque build-up in the artery, you don’t get that excised.”

However, through a unique technology licensed from FoxHollow Technologies, scientists at Merck are able to access samples of plaque from patients. FoxHollow uses a minimally invasive procedure for patients with plaque build-up in the femoral artery, in which a catheter with a knife at the end is inserted into the artery to pare off the plaque and take it out.

“Merck is leveraging the plaque that’s coming out of people who are going in to get these procedures. We’re collecting hundreds to thousands of these samples, and we’re studying biomarkers using a number of different approaches. We’re looking at histology – what does plaque look like? We’re looking at protein biomarkers in the plaque, we’re looking at cholesterol and other lipid markers, and then we’re applying genomics. We’re doing very sophisticated gene expression profiling, we’re doing some proteomics, and we’re doing some hardcore genetics,” explains Plump.

By applying an integrated biomarker-based approach that also includes molecular imaging, Merck researchers aim to identify the molecular and physical characteristics of plaque that drive disease progression and raise the risk of heart attack and other cardiovascular events. These biomarkers can also be used to evaluate how experimental or approved drugs change the profile of plaque and potentially reduce the risk of cardiovascular events.

“By intersecting multiple data sets and understanding this disease process, if our drug is causing certain types of changes in the plaque, we can interpret those changes, if they’re at the right level, as being beneficial, and therefore say, ‘We think we have a drug that if we were to drive to an outcome study, we’d show benefit on the unmet need’. We got very excited about this because we have a very substantive genomics effort at our Merck Research Laboratories facility in Seattle, and we’ve been trying to do just this with oncology.”

At the mention of genomics, many people’s thoughts turn to personalized medicine. Is this the direction in which the research is heading? “I don’t think of it so much as personalized medicine, but more as segmentalized,” Plump says. “I don’t know if the industry will ever be able to make enough medicine so that every person will have a different medication. But certainly there are subsets of individuals who have a common disease but who are very different and for whom a particular medication is appropriate. So long-term, absolutely, that’s our goal.”

His short-term goal is more focused on identifying in broader populations with this disease whether drugs will be efficacious. “We use the word genomic in this context more to define the approach. As opposed to looking at one biomarker – which would be standard methodology – our researchers look at 40,000 biomarkers, and that’s genomic. It’s just the scale at which you’re doing it.”

Having an impact

This research should have a substantial impact on cardiovascular disease, particularly in three areas: diagnostics, therapies targeting high-density lipoprotein (HDL) and the treatment of high-risk patients. In the first case, it’s about understanding the disease process and developing tools that can be used to help make decisions about which drugs to push forward in the pipeline. Although these are essentially internal tools, Plump feels that the technology may, through a variety of methods, be used for diagnostic purposes.

“One of the problems we have right now is when you go to your doctor you’ll have a risk assessment, which will be based on your gender, age, smoking status, your lipid profile and your blood pressure, and it will tell you what your risk of having the disease is. But there’s a gap. There are lots of things that are driving disease in you that we just can’t study, so we’re missing a huge chunk of the pie. We think the diagnostic piece is going to enable us to identify patients who are at higher risk for having the disease and who should therefore be treated with new medications. That’s the first impact.”

The second impact is in therapies to raise high-density lipoprotein (HDL). According to Plump, this is something the industry is currently struggling with. “Part of it is that unlike LDL – if you lower LDL you do something good – we don’t think that all HDL is created equally. So if you have a therapy that raises HDL, how do you know that it’s having a benefit? We think the application of this new technology, along with other emerging imaging technologies that we’re working on, will help us differentiate HDL-raising therapies and tell us whether they’re doing something good, just by looking at what they’re doing to the plaque.”

The third area of interest is high-risk patients: patients with diabetes, or those who have acute coronary syndrome (ACS). “Large numbers of these patients are admitted to emergency rooms with unstable angina, or a heart attack. Subsequently, over the following six to12 months, they have a very high recurrence rate of about 15 to 20 percent. In that 15 to 20 percent, there’s a very high mortality rate, but our hope is that by using these tools we can begin to understand the disease process and predict those individuals with the highest risk, and most importantly, begin to make novel medications that treat that acute coronary syndrome condition.

“One of the things we’ve learned from drug development is that the drugs that tend to treat acute disease also carry over and treat chronic disease. So we’re hopeful that these efforts will not only lead immediately to therapies for acute disease but also longer term to therapies for chronic disease.”

In addition to treatment, one of the ultimate goals of the research is of course prevention. Plump is positive about the achievements already made, “I think we’ve made tremendous progress with the statins. These are phenomenal preventive medicines. In fact,” he adds, laughing, “you’ve seen quotes about statins being added to drinking water. They’re so phenomenally efficacious, and there’s such an opportunity there for prevention."

Hope for the future

What about the future? Plump feels that the work on circulating biomarkers, which has been going on for 50 years, still has a long way to go. “There’s a lot of activity going on. I’m not particularly hopeful that in the near future it’s going to drive towards a biomarker that’s going to tell us whether you have an unstable or vulnerable plaque or not.”

The other area of activity is centered on imaging biomarkers of plaque, work that started seven or eight years ago, and according to Plump is making significant progress. “I still think we’re five to 10 years away from having imaging modalities that can help to define risk, and similarly, those that can tell us more than what size plaque you have, which we know is not particularly important. It’s not the size of the plaque, it’s the nature of the plaque.

“We have a substantial imaging effort internally, and we’re very engaged in trying to develop new imaging methodologies that don’t tell us about plaque volume, because plaque volume is not the cause of a disease, it’s plaque instability. So we’re working very hard with a number of outside initiatives, both private and public, to try to push through novel imaging methodologies.”

One of these is the High-Risk Plaque (HRP) initiative: a collaborative research and development effort among the world’s leading experts in cardiology, pathology, imaging and other key areas of cardiovascular research. The initiative aims to improve the understanding and management of high-risk plaque. According to Plump, it’s a great example of how the public and private sectors should work together.

“A large part of the initiative is to try to develop new imaging biomarkers for plaque. It really points the finger at the fact that we need to be working together. Because when you think about the progress that’s going to come, in both preventing and treating coronary disease, it’s going to come from a combination of multiple types of expertise – imaging companies, biomarker companies, diagnostic companies, pharmaceutical companies – all working together.

“We need to be thinking about coronary disease in an entirely new way. It’s not a disease of plumbing, it’s a disease of instability, and we need to develop new tools to understand it. We have a particular opportunity based on leveraging what’s been done in the oncology field to study the disease directly in the tissue itself, which is entirely unique and incredibly exciting. But we can’t do it alone: there has to be a coherent effort that brings together expertise from multiple different disciplines.”

About Dr. Andrew Plump

Dr. Andrew Plump is VP and Franchise Integrator, Cardiovascular Disease, at Merck & Co., Inc. He has medical training, clinical training in internal medicine and clinical genetics, and laboratory experience in cardiovascular disease and neuroscience.