The Making of a New Disease

Think back: When did you first hear the phrase metabolic syndrome? When did it start to become part of your business and its plans?

Maybe that second step hasn't taken place yet. But for many in pharma it's coming soon. In the past few years, scientists, researchers, and healthcare companies have been paying increasing attention to the concept that obesity, hyperlipidemia, diabetes, and hypertension-and perhaps other diseases, including some cancers-are linked.

And the pace of new developments is accelerating. For example:

• The American College of Cardiology and the American Diabetes Association (ADA) recently launched "Make the Link," a campaign that informs physicians and consumers that type 2 diabetics run an increased risk of heart disease and stroke.

• MSAToday.com, an alliance with a corresponding website funded by unrestricted grants from GlaxoSmith-Kline (GSK), offers physicians information about metabolic syndrome and continuing medical education credit.

• November 2003 saw the launch of the first annual scientific meeting devoted to insulin resistance, which most scientists believe is the cause of metabolic syndrome.

• In early 2004, a new society devoted to metabolic syndrome called the International Society of Diabetes and Vascular Research is expected to launch and begin publishing its own journal.

It's not just that metabolic syndrome has become better understood, better publicized, or better supported by an infrastructure of journal articles, meetings, and associations. Behind those events and dozens more like them something far more basic is happening: A new disease is being born.

Blueprint for a disease

Unlike a new pathogen bursting from the jungle like Ebola or mutating from something familiar like each year's "new" strain of influenza, metabolic syndrome must be both socially and scientifically constructed. Well-known medical facts have been reorganized into a new understanding. And with that knowledge comes the need and opportunity for new research, new modalities of treatment, and, on the pharma side, new market risks, demands, and opportunities.

"Just think of cholesterol," says John Wendel, PhD, a medical anthropologist at Integrated Marketing Associates. "Cholesterol wasn't something people talked about 20 years ago. Merck spent years getting physicians to think about it as a big problem. Now they do."

The emergence of cholesterol reduction as a market was a major event for pharma. Metabolic syndrome promises to be as big or bigger. Like any new disease, this one offers significant challenges to pharma. But for companies that meet them-especially the challenge of finding an appropriate role for medication in treating a disease with a large lifestyle component-metabolic syndrome will be a force reshaping products, companies, and markets for decades to come.

Discovering Syndrome X

The observation that obesity, hyperlipidemia, diabetes, and hypertension frequently can be found together dates back to the late 1970s, when German researchers named the phenomenon "metabolic syndrome." (See "What's in a Name?" page 52.) But no one paid much attention until 1988, when Gerald Reaven, MD, a professor of medicine at Stanford University, articulated the risk factors related to what he called "Syndrome X" during an acceptance speech for the ADA's Banting award. Reaven was also the first to focus on insulin resistance as the underlying cause of metabolic syndrome.

"Nothing helped metabolic syndrome more than the establishment of the ICD9 code." - Yehuda Handelsman, MD

Insulin resistance is the state in which a person's normal level of pancreatic insulin secretion is inadequate to unlock glucose from food and transport it to the body's cells for energy. The condition is thought to be genetic, but it can be aggravated by obesity and physical inactivity because fat cells aren't receptive to insulin. Most patients with type 2 diabetes, though not all, are insulin resistant and take medications to sensitize the body to insulin, address insulin deficiency, or target other problems related to blood-glucose control. But insulin resistance doesn't always lead to type 2 diabetes. Reaven says that most people with insulin resistance don't even develop the disease.

In 1989, Norman Kaplan, MD, professor of internal medicine at the University of Texas' Southwestern Medical Center identified four risk factors for heart disease-upper body obesity, impaired glucose intolerance, high triglyceride levels, and hypertension-and dubbed it the "Deadly Quartet."

Underlying the Quartet: the excessive blood-insulin levels often associated with insulin resistance.

Additional studies in the early 1990s-most notably one by a team led by Ele Ferrannini, MD, who heads the European group for the research of obesity, hypertension, and insulin resistance based in Pisa, Italy-confirmed the basic insights of the preceding years. But it took a decade before a fairly rapid series of developments took metabolic syndrome out of the academic realm and introduced it into the world of medical practice.

First, in 1999, the World Health Organization issued its own description of metabolic syndrome. Yehuda Handelsman, MD, co-chair of the International Committee for Insulin Resistance and medical director of the Metabolic Institute of America, explains, "They again described that same constellation of abdominal obesity, elevated fasting blood triglycerides, low levels of HDL or 'good' cholesterol, high fasting blood sugar, and high blood pressure, and said if somebody has those, they have a high risk of developing diabetes and cardiovascular disease (CVD)."

Timeline

Two years later, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III released a simplified set of diagnostic guidelines. (See "ATP III Criteria," page 51)

"NCEP came out with their guidelines in the JAMA of May 2001," says Christine Beebe, director of education and scientific affairs for Takeda. "That was a call to action for physicians to not only focus on LDL cholesterol, but on metabolic syndrome and this constellation of other risk factors to prevent CVD." More important, metabolic syndrome received its own code in the International Classification of Diseases, Ninth Revision (ICD9). In a world in which a condition isn't really a disease until it becomes part of physicians' paperwork, metabolic syndrome had crossed an important threshold.

"The fact that metabolic syndrome has been identified as an actual disease state is a huge step in the right direction," says Beebe. "Before that, physicians didn't have a reason to focus on these individuals before they developed diabetes or CVD."

Past the Tipping Point

To Handelsman, who can methodically recount the syndrome's genesis, as a parent recounts the maturation of a child, that was the tipping point. "Nothing helped metabolic syndrome more than the establishment of the ICD9 code."

The"Make the Link" campaign, sponsored by the American College of Cardiology and the American Diabetes Association, is an example of the type of cross-pollination of specialties emerging in metabolic syndrome.

Pharma then opened its floodgates and began to publicly fund market development initiatives to make physicians more aware of the role of insulin resistance in diabetes and heart disease. Although physicians knew that the two often existed in the same patients, the initiatives helped to cross-pollinate cardiologists and endocrinologists. Some of those initiatives included:

• Partners Against Insulin Resistance, an educational program underwritten by Takeda Pharmaceuticals North America and Eli Lilly, designed to promote awareness about insulin resistance.

• The first professorship at the University of Liverpool dedicated to obesity research, funded by AstraZeneca-an early mover in the field, having backed "Future Forum," a physician website targeting metabolic and vascular disease management, in 1999.

• "Insulin Resistance: Cardiovascular Risks and Therapeutic Interventions," an interactive satellite videoconference presented by the Endocrine Society and funded by GSK.

The scope of research on metabolic syndrome has widened, and today scientists cite mounting evidence that insulin resistance is related to breast, prostate, and colon cancer, polycystic ovarian syndrome, and nonalcoholic liver disease, among other conditions.

Communications about the new disease have achieved a critical mass. "Today, if you scan the medical journals, there are plenty of articles on metabolic syndrome," says Richard Nesto, MD, chairman of the department of cardiovascular medicine at the Lahey Clinic Medical Center in Burlington, Massachusetts; associate professor of medicine at Harvard Medical School; and co-principal investigator of BARI 2D, a trial evaluating treatment strategies to improve survival in type 2 diabetic patients with coronary artery disease. "And if you look at the websites that have anything to do with high blood pressure, diabetes, cholesterol-many of them supported by drug companies-you'll see there is enough out there that the average mindful physician should have heard about it."

That is fortunate, since by all accounts, physicians are seeing an enormous number of patients with metabolic syndrome, and the number is expected to grow.

What's in a Name?

Population at Risk

Cardiologist Mark McGovern, MD, chief medical officer of Kos Pharmaceuticals, says that the US obesity epidemic is driving metabolic syndrome, and, therefore, increases in type 2 diabetes and heart disease. "It's estimated that 20 percent of the adult population has metabolic syndrome," says McGovern. "Similarly, 20 percent of adults are obese. Within the next decade, by some estimates, obesity will climb to 40 percent of the population. Another frightful statistic from the NIH is that for an American born in the year 2000, the lifetime odds of developing diabetes will be one in three. The American College of Cardiology made another estimate: the prevalence of heart disease will double by the year 2040."

According to some estimates, 86 million Americans will have metabolic syndrome by 2025. Many are already being treated for type 2 diabetes or heart disease. (It is estimated that metabolic syndrome raises the likelihood of heart attack between four and 20 times.) But the real challenge is to find a way to prevent millions of at-risk patients from developing type 2 diabetes and heart disease in the first place.

"In metabolic syndrome, the risk for type 2 diabetes has been there for years before the person becomes formally diagnosed," says Nesto. "So you may see a 60-year-old diabetic who had a heart attack at age 50. But that heart attack may actually have been an early manifestation of this underlying metabolic condition. CVD begins well before the person loses the ability to manage their glucose.

"It used to be that patients who have family histories of early heart attacks had 'bad genes.' But if you look at families with premature heart attacks or strokes, very often they have metabolic syndrome."

Nesto talks to his patients about metabolic syndrome-but he may be one of the few. John Buse, MD, chairperson of the ADA diabetes/cardiovascular disease initiative, which fueled the "Make the Link" campaign, says some doctors wouldn't recognize metabolic syndrome "if it bit them in the face." But others ignore it intentionally because there's not yet enough clinical evidence to determine what to do for patients.

"Until we learn more about the root causes and can test some of these new hypotheses, we're still left with treating individual entities-one drug for hypertension, one to treat lipids, one to treat glucose abnormalities," says Gunnar Olsson, global vice-president of cardiovascular therapy area for AstraZeneca. "So you end up with a cocktail of therapies, unless some of these drugs in development that treat glucose and lipids simultaneously come to fruition." (See "PPAR Pipeline," page 54.)

Even though there are no FDA-approved treatments for the group of symptoms suffered by metabolic syndrome patients, there is still value in communicating to physicians about it. "The problem comes when you have a lot of 'milds'-mild hypertension, mild disturbances in cholesterol, and mild obesity," says Nesto. "No one bothers to treat them because, individually, the risk factors don't look so bad. With metabolic syndrome, you have a collection of mild risk factors, but the risk of that collection is greater than the sum of the parts."

A recent flood of research including the Diabetes Prevention Program (DPP), STOP-NIDM, and the Troglitazone in Prevention of Diabetes (TRIPOD) proved that diabetes drugs administered to high-risk patients can prevent or delay the onset of type 2 diabetes. The Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study demonstrated that pharmacotherapy plus improved diet delayed or prevented the development of type 2 diabetes more than lifestyle modification alone.

"What remains to be tested," says Olsson, "is if any of the therapies treating different parts of metabolic syndrome could have a broader effect on one or more of the risk factors, which could simplify treatment."

Seeking Evidence

The next question for industry to answer is more complex: What are the effects of using cardiovascular and diabetes drugs to prevent or treat heart disease and diabetes? Several clinical trials are already underway to answer that. Three of the most prominent are:

DREAM. In November 2000, GSK and Aventis announced the Diabetes Reduction Approaches with Ramipril (Altace) and Rosiglitazone (Avandia) Medications (DREAM) study. The 4,000-patient trial builds on two earlier studies: TRIPOD and a subgroup analysis done in HOPE (Heart Outcomes Prevention Evaluation), which found that Altace reduced the number of patient self-reported cases of diabetes by 34 percent.

NAVIGATOR. Launched in September 2001, Novartis' Nateglinide (Starlix) and Valsartan (Diovan) in Impaired Glucose Tolerance Outcome Research study is designed to determine whether long-term administration of either drug can reduce or delay the development of type 2 diabetes and cardiovascular disease in individuals with impaired glucose tolerance and at increased risk for CVD. It is the largest diabetes prevention trial ever, with more than 7,500 patients in 40 countries.

BARI 2D. The University of Pittsburgh Graduate School of Public Health, with funding from Bristol-Myers Squibb, GSK, and several public institutions, is conducting the Bypass Angioplasty Revascularization Investigation 2 Diabetes study to determine whether, in patients with type 2 diabetes, initial treatment with angioplasty or bypass surgery is better than initial treatment with a medical program. At the same time,

BARI 2D will compare two approaches to control blood sugar: providing insulin-stimulating medication or providing medication that sensitizes the body to the available insulin.

Right now, thiazolidinediones (TZDs) have garnered the most interest because they work by decreasing insulin resistance. Handelsman says that TZD drugs are being studied for their roles in a variety of other conditions, including congestive heart failure, polycystic ovary syndrome, and liver disease.

However, various medical societies have cautioned against the prophylactic use of type 2 diabetes drugs because of a problematic side effect. Buse says that in animal studies in which those agents were used to prevent diabetes "the mice became massively fat." In addition, European physicians only use TZDs as a last line therapy among type 2 diabetics because the class is associated with edema.

So, thought leaders are looking to other drugs to find effective therapies without the side effects. "It's more than just diabetes drug makers that are interested-it's across the board," says Handelsman. "Gerald Reaven and I were laughing that some of the obesity drug makers are shy in coming on board [to sponsor the World Congress on the Insulin Resistance Syndrome] because not everyone with insulin resistance is obese. Yet 80 percent of obese patients have it. So we push forward for obesity research and treatment."

Based on positive results of the XENDOS trial, Roche will again try to pursue an indication of prevention of type 2 diabetes through promotion of weight loss with Xenical. Obesity products seem promising to treat metabolic syndrome because they have a short-term effect of weight loss, as well as longer-term benefits. Pfizer and Amgen have Phase II and III obesity products in the pipeline that not only aim to treat obesity, but also type 2 diabetes.

However, it remains to be seen how angiotensin II-receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors, and statins fit in. "Type 2 diabetes patients often get a statin because people recognize that they are likely to eventually die of a heart attack," says Buse. "There's less evidence that ACE inhibitors, ARBs, and statins reduce the risk of developing type 2 diabetes."

However, clinical trials are underway. Olsson says AstraZeneca is testing its statin Crestor (rosuvastatin) in the metabolic syndrome population.

Kos Pharmaceuticals also has a few promising treatments. "We have shown in recent trials that Niaspan (niacin) and Advicor (niacin/lovastatin) can be safely used in patients with diabetes with a minimal impact on blood glucose," says McGovern, "and they have tremendous benefits in terms of raising HDL and lowering triglycerides." Kos researchers will present a paper on the use of Advicor for metabolic syndrome at the American College of Cardiology meetings in March.

One of the most promising developments is perioxisome proliferator-activated receptor (PPAR) products. In this era of highly specific therapies, this is one class of drugs that target multiple risk factors and treat underlying insulin resistance and lipid abnormalities, thereby reducing the risk of developing both CVD and type 2 diabetes. And they reduce the number of pills patients must take.

The front-runner for that class, Merck and Kyorin's Phase III compound MK-767, was pulled in late November 2003 because of toxicity issues. Other promising compounds include AstraZeneca's Galida (tesaglitazar), a dual PPAR agonist, which is in phase III development. AstraZenecaestimates it will file its MAA and NDA in 2006.

Opportunities

"Pharma companies are running for this market," says Ajit Baid, manager of Frost & Sullivan's pharmaceuticals group. After all, the metabolic syndrome patient population encompasses feeder markets that are massive in their own right, including patients with type 2 diabetes and CVD.

But most patients are asymptomatic. And many would respond well to lifestyle changes. Finding pharma's niche in a massive, prevention-oriented campaign against metabolic syndrome won't necessarily be easy.

Already, some critics complain that the syndrome is simply the industry's effort to medicalize obesity. "Pharma companies understand the potential market, so they are trying to bring some light to it and push their products towards it," says Nikolaos Karachalias, Datamonitor senior endocrinology specialist.

"It is being medicalized-but not just by the pharma companies," says Buse. "The American Diabetes Association is also doing so by giving it a name and calling it a risk marker. Although there are some overweight people who don't have the syndrome, obesity is, in essence, the problem."

First, pharma companies must harness clinical evidence to show physicians the benefits of using pharmacologic therapy to prevent patients from developing CVD and type 2 diabetes. In addition, there's a need for longer-term trials that address safety, morbidity, and mortality outcomes, according to Jeremy Quirk, PhD, MBA, a cardiovascular analyst for Decision Resources.

In the short run, the key to unlocking the potential of the metabolic syndrome market may lie in the establishment of a "pre-diabetic" state. The diagnostic criteria are already in place. In fact, Nesto says that the ATP III diagnostic criteria make it easier to diagnose metabolic syndrome than using the Framingham risk score for coronary disease. However, in a society in which even hypertension is undertreated, companies face a formidable challenge in moving physicians to think about treating patients 10 or 15 years before they get sick.

"Physicians are wary of defining 35-year-olds who work in an office and don't exercise enough as a target for receiving drugs for the rest of their life," says Quirk. "Especially when they may or may not develop a disease in the future and when the agents have side effects. Physicians are saying 'Show me the evidence.'

Because without it, why would physicians prescribe massively expensive drugs to a patient who appears healthy, when they can just tell them to exercise three times a week?"