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It seems like nothing is going right for Merck these days. On Monday, the US Food and Drug Administration (FDA) issued a “not approvable”–aka a rejection letter–for Merck’s new cholesterol drug called Cordaptive or MK-0524A. The highly-touted drug, which Merck executives hoped would replace Merck’s blockbuster cholesterol drug, Zocor (which lost patent protection a couple of years ago), can both lower LDL (bad) and raise HDL (good) cholesterol. Although experts believe that these properties should benefit people with high cholesterol, the results from recent clinical trials suggest that drugs that raise LDL and lower HDL cholesterol may have safety problems.

Cordaptive consists of an extended-release form of niacin (a B vitamin) and another agent that inhibits a niacin side effect called flushing — redness, burning and tingling of the face. Niacin has been used to control cholesterol for decades. Abbott Laboratories already sells an extended-release form of niacin called Niaspan.

Despite positive results from recent clinical trials and pending approval by the European Union, the agency rejected Merck’s NDA. Regulators also rejected Cordaptive as a brand name. It is likely that FDA is scrutinizing and proceeding cautiously with new cholesterol medications because of the recent flap over Zetia and Vytorin (which are co-marketed and sold by Merck and Schering Plough). As you may recall, both companies have been accused of trying to protect sales of the two drugs by delaying results of a study that showed Vytorin worked no better than Zocor, which is much cheaper.  Merck’s stock price dropped about 5% yesterday after the company announced that it received a not approvable letter from FDA.

Although MK-0524A may ultimately reach the US market, I wouldn’t count on it anytime soon. Merck has seriously tarnished its reputation with FDA because of the Vioxx, Vytorin and Singular controversies. The old adage, “You reap what you sow” is particularly apt in this instance. Look for more “asset reallocation” moves in Rahway.

Until next time…

Good Luck and Good Job Hunting!!!!!!!!

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Unraveling the Cholesterol Conundrum

By now, I am sure that everyone is sick of hearing about Zetia, Vytorin, cholesterol levels and heart disease. Whether you like it or not, results from the now infamous Enhance study have certainly caused many scientists and physicians to rethink the relationship between cholesterol levels and heart disease and stroke. Conventional wisdom (and current medical dogma) holds that low LDL cholesterol levels reduce the risk and incidence of heart disease and stroke. This belief is now so widespread and entrenched in that the medical community that FDA now approves drugs to prevent heart disease, as it did with Zetia and Vytorin, solely on the evidence that they lower LDL cholesterol levels. Unfortunately, Enhance study results indicate that lowering LDL cholesterol levels alone are not sufficient to reduce the incidence of heart disease or stroke. 

Zetia, one of the active ingredients of Vytorin, lowers blood LDL cholesterol levels by reducing absorption of cholesterol in the gut (from foods that we eat). In contrast, the other ingredient in Vytorin, Zocor, is a statin that acts to lower LDL cholesterol by interfering with its production in the body. The results of the Enhance study, which showed that Vytorin doesn’t reduce the risk of heart disease or stroke any better than Zocor itself, suggest that the only way to prevent heart disease and stroke (by lowering LDL cholesterol) is through statin use. This assertion is supported by results from clinical trials involving Lipitor and Zocor (both statins), which showed that lowering LDL cholesterol also resulted in a lower incidence of heart disease and stroke. This suggests that statins may act to reduce heart disease and stroke by mechanisms other than their LDL cholesterol-lowering properties. Indeed, statins have also been found to reduce inflammation, keep artery walls flexible and healthy and help to maintain LDL and HDL cholesterol balance in the blood.

There were hints along the way which suggested that the relationship between LDL cholesterol and heart disease and stroke were not as straightforward as it seemed. For example, torcetrapib, a Pfizer drug that lowers LDL and raises HDL cholesterol, was being evaluated in clinical studies that were subsequently halted because it increased the risks of heart attack and stroke rather than prevent them. Another example is estrogen replacement therapy which is known to lower LDL cholesterol levels but failed to reduce the incidence of heart attack and stroke in clinical studies. Nevertheless, it did not take much to convince FDA that lowering LDL cholesterol levels alone was sufficient to prevent or reduce the incidence heart disease a stroke. This notion was strongly substantiated by results from clinical studies with Lipitor and Zocor which showed a strong relationship between lowering LDL cholesterol and reducing the risk and incidence of heart disease and stroke. Unfortunately, it now appears likely that the ability of statin drugs to reduce the incidence of heart disease and stroke is related to other mechanisms besides lowering LDL cholesterol. For an excellent historical review and recap of the cholesterol story, I suggest reading an article is this Sunday’s NY Times by Gary Taubes.

So what are the lessons learned from this story? First, I think that it is unwise to make assumptions about cause and effect relationships until all of the data is carefully analyzed and vetted. Second, it is our obligation as scientists, whether we are company employees or not, to point out inconsistencies or problems with prevailing theories regardless of personal or professional consequences. Finally, and perhaps most importantly, FDA must not allow drug companies to influence or affect the type or amount of data that it requires to approve new drugs.

Until next time…

Good Luck and Good Job Hunting!!!!!!

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