Drug companies should attempt to build a market for metabolic syndrome by getting information in the clinical studies section of labeling as a precursor to a specific indication.

This may provide companies with an "entré" into the market for metabolic syndrome, Pfizer Executive Director of R&D-Cardiovascular/Metabolic Disease David Fryburg said March 29 at the IBC Targeting Metabolic Syndrome Conference in Boston.

No drugs have been specifically approved for treatment of metabolic syndrome, either by FDA or the European Medicines Agency (see ¹ Also see "Outcomes Studies Are Key To Validating Metabolic Syndrome As A Disease" - Pink Sheet, 10 April, 2006.).

Sanofi-Aventis is the frontrunner in industry's efforts with Acomplia (rimonabant). Metabolic syndrome was among the claims included in the NDA for weight loss, although the firm has admitted it is a difficult regulatory target ("The Pink Sheet" March 28, 2005, p. 26). Acomplia is currently "approvable" at FDA for weight loss and "not approvable" for smoking cessation.

Fryburg said that it is unlikely rimonabant will get approved for metabolic syndrome. "I would be very doubtful of it, particularly in the first time around," he said. Instead, the product is expected to have a straightforward obesity indication.

However, "if things go well...[Sanofi might] get it in the clinical trials results section, and that would be an entré," Fryburg said, noting that it depended on labeling negotiations.

Metabolic Syndrome Is Like Pornography - AHA

The metabolic syndrome market is currently constrained by several factors, the most pressing of which is the lack of consensus on a definition for the disease. The American Heart Association, World Health Organization and National Cholesterol Education Project's Adult Treatment Panel are among the organizations that have issued differing definitions.

In fact, in its winter 2005 newsletter the AHA suggested that metabolic syndrome is "a lot like pornography: it is hard to define but we all know it when we see it."

Further complicating the matter, some medical groups have come out against the identification of metabolic syndrome as an independent disease. The American Diabetes Association and the European Association for the Study of Diabetes issued a statement in August contending that metabolic syndrome should not be a separate diagnosis until it is determined that it involves a greater cardiovascular risk than the component risk factors (² [A#00670350016], p. 20).

Part of the problem is that the definitions are based on a patient having a certain number of a set of risk factors. This creates a lack of consistency that is problematic from a development and regulatory viewpoint.

Regulators do not like "pick and mix" diseases, RenaSci Consultancy Director David Heal said at the conference. "This would probably be better if you had all the components in there, even if it reduced the size of the population," he said.

Another problem underscoring the current difficulty with defining metabolic syndrome is that its origination was a means of identifying at-risk patients, not as a research tool, Fryburg noted.

The Science Is Not There Yet

An inadequate understanding of the underlying mechanisms of metabolic syndrome and the science involved in the condition's outcomes is also hindering the acceptance of metabolic syndrome as a disease entity.

Researchers continue to debate whether there is a basic connection to insulin resistance and diabetes, or whether the relationship to cardiovascular disease is the dominant characteristic.

"This is a condition that has multiple causes," Scott Grundy (University of Texas Southwestern Medical Center) pointed out, and "it's an interesting question...[if] for something to be a syndrome, it has to have a single underlying cause."

Risk Factors Are Clearer Targets For Treatment

The lack of understanding about the cohesiveness and underlying mechanics of the syndrome leads to controversy as to whether metabolic syndrome should be diagnosed as single disease or whether its multiple risk factors should be treated independently.

Thus far, it has not been shown that metabolic syndrome offers a greater prediction of risk than the separate risk factors - including obesity, high blood pressure, and high cholesterol.

"Metabolic syndrome generally doesn't predict [cardiovascular disease] or [diabetes mellitus] better than other risk engines," Fyrburg noted. "So, can the current definition of metabolic syndrome be used for drug development? The short answer, I believe, is no. We need to do something else."

A Partnerhsip Approach

Building on the idea of using consortia of multiple stakeholders to collect sufficient data for decision-making purposes that is being championed under FDA's Critical Path initiative, the Pfizer exec suggested that a collaborative approach would help establish a standard metabolic syndrome definition.

The key is "to create a partnership among academia, industry and regulators to develop and validate a model that includes more variables in a continuous manner to create a commonly accepted definition that healthcare providers, and...payers, can readily use."

"This is something that no single pharmaceutical company can do," Fryburg said. "I don't think that Pfizer can do this, I don't think pharma could do this."

Current Development Strategies

In addition to Acomplia, several other pharmaceutical companies are exploring metabolic syndrome. Metabolic syndrome has been included as a claim for Bristol-Myers Squibb's type II diabetes drug Pargluva (muraglitazar). AstraZeneca's dual PPAR Galida (tesaglitazar) is in Phase III for metabolic syndrome, with a second half 2007 filing planned.

Pfizer has previously suggested that combination therapies were the best approach towards metabolic syndrome, highlighting the Caduet combination and the torcetrapib/ Lipitor combination.

Sanofi is currently conducting further clinical trials of Acomplia, including outcomes trials, that could augment the metabolic syndrome claims that were supported by its pivotal trials.

Results of the RIO North America trial showed that in addition to weight loss, patients treated with 20 mg of rimonabant for two years had improvement in multiple cardiometabolic risk factors, including HDL cholesterol, triglycerides and insulin sensitivity, beyond that expected from weight loss alone.

Fryburg noted that although Sanofi documented the change in various cardiovascular risk factors in its clinical trials, it still remains unclear what the criteria were for determining when a patient goes from having metabolic syndrome to not having it.

"There were parameters that were in this study that nicely documented that change, but how these created a composite of Mrs. Smith, you have it or you don't, is really not clear." He suggested a more variable definition is needed: "the dichotomous outcome is too limiting, you have it or you don't and that is really not going to work for developing a drug."

Sanofi is seeking to substantiate its data though a series of "lifecycle management" trials to evaluate rimonabant's effects in patients with specific metabolic disease, such as diabetes or dyslipidemia.

Specifically, Fryburg pointed to Sanofi's Phase III STRADIVARIUS trial that is assessing rimonabant's efficacy in reducing progression of coronary atherosclerosis in patients as assessed by intravascular ultrasound (³ Also see "Sanofi Feels The Weight Of FDA’s “Approvable” Letter For Rimonabant" - Pink Sheet, 27 February, 2006., p. 4).

"Their study will be important to help with this definition [of metabolic syndrome] but otherwise, we're still going to end up with yes or no."

Chicken Or The Egg Syndrome?

The success of rimonabant may help propel metabolic syndrome's acceptance by the medical community, Grundy acknowledged. "It may not be the answer we are looking for, but it would be a step in that direction."

Grundy offered a different approach, that getting effective treatments on the market was necessary in order to generate a uniform definition.

"I remember trying to make a case for cholesterol and the medical field never got its act together for cholesterol until we had a good treatment for it, and then it comes back together very fast, and it's widely accepted now," he said, likening the current situation for treatments of metabolic syndrome to the challenges statins experienced when they emerged on the market.

"If there were to be an effective drug that would treat metabolic syndrome...and if there could be clinical trials demonstrating that it is efficaciously reducing heart attacks and diabetes and so forth, then a lot of the controversy would go away."

Metabolic Syndrome Market Needs Uniform Definition, Effective Therapies

More from Archive

More from Pink Sheet