Future of lucrative cholesterol drugs murky

Doctors are waiting for new preventive heart medicines beyond popular statin therapies, but a tough regulatory climate and fierce debate over the effectiveness of some newer drugs has clouded the future of cholesterol treatments.

The uncertainty is roiling investors looking to cash in on what has traditionally been the most lucrative arena of the pharmaceutical sector.

Sudden plunges in sales of newer cholesterol drugs, that had been expected to grow strongly for years, and unexpected U.S. Food and Drug Administration rejections or delays of medicines have sparked steep declines in share prices.

“Today investors are probably feeling like a successful investment in a new lipid franchise is something that’s going to take a long time to materialize,” said Leerink Swann analyst Seamus Fernandez.

Fernandez expects the FDA will start requiring outcome studies for novel cholesterol treatments—proof that a medicine actually reduces heart attacks or strokes rather than just alters levels of blood fats.

The FDA was stung by intense criticism over drugs such as Merck & Co’s withdrawn painkiller Vioxx and GlaxoSmithKline Plc’s diabetes treatment Avandia, that had serious safety issues revealed long after they were approved and in wide use. The agency now appears more focused on the risk element of the risk/benefit ratio of new drugs.

“I think the FDA is beginning to understand that unless they set the bar high enough we may not fully understand how a drug works,” said Dr Steven Nissen, chairman of cardiovascular medicine at Cleveland Clinic, who has been an outspoken critic of the agency and drugmakers.

Nissen was also in the middle of the debate over extensive use of the new cholesterol medicines Vytorin and Zetia—sold in a joint venture by Merck and Schering-Plough Corp—after delayed results of a failed study led to plunging sales and patients’ questioning their medicines.

Though few will argue against a focus on patient safety, many cardiologists fear a more conservative FDA will delay new therapies that could cut the risk of heart attacks and strokes further than the 30 percent seen with Statins such at Pfizer Inc’s Lipitor and AstraZeneca’s Crestor.

“I do worry about the pendulum swinging too far. I don’t want it to swing so far that we keep innovative medicines off the market,” Nissen said.

NEED FOR NEW DRUGS

Heart disease remains the No.1 killer in the United States and many patients need something in addition to Statins to get their cholesterol to target levels, doctors say.

“Statins are really magic,” Nissen said. And while he acknowledges the need for drugs that further lower bad LDL, or raise good HDL, cholesterol, he worries drugmakers “are taking on riskier drugs to find incremental benefit.”

That may be the case with Merck’s recently rejected Cordaptive, which combines well-known HDL raiser niacin with a novel agent designed to reduce the uncomfortable flushing that makes it difficult for patients to tolerate niacin at high enough doses to achieve a therapeutic benefit.

Neither the company nor the FDA has disclosed why the agency declined to approve the drug.

“The anti-flushing agent is a totally new compound and a totally different mechanism than has ever been fooled with in the cholesterol field,” said Dr. Carl “Chip” Lavie, director for preventive cardiology at Ochsner Medical Center in New Orleans.

“It’s not like this is a wonder drug,” he said of Cordaptive. “All this is is to make niacin a little bit more tolerable. The FDA is being pretty gun shy on safety of medicines in general and especially in the cholesterol field.”

Despite some high profile failures, doctors are still looking for agents that can significantly raise HDL.

“We’ve certainly not given up on HDL,” Lavie said. “If you can raise HDL in a good way, safely, there’s still lots of potential for HDL raising therapy.”

But he expects regulators to proceed with extreme caution, perhaps delaying new therapies for years.

RAISING “GOOD” CHOLESTEROL

“Don’t forget about torcetrapib,” Lavie said of the sudden, unexpected failure of Pfizer’s experimental HDL-raiser that belongs to a new class of medicines called CETP inhibitors.

Pfizer ended development of the drug in late 2006 after safety monitors found an unacceptably high rate of deaths in those taking torcetrapib in a large, late-stage trial.

“It looked extremely promising, raised HDL unbelievably. It should have banged down coronary disease but instead mortality went up,” Lavie recalled.

Nissen said CETP inhibitors being developed by Merck and Roche still have a very good chance of succeeding.

But Lavie cautioned, “There’s not a chance that a CETP inhibitor is going to be released without showing long-term safety and clinical event reduction.

“Who cares what your blood test looks like; what we really care about is that it reduces heart attacks and strokes.”

The FDA has said that using surrogate goals in clinical trials—reduction of known risk factors rather than actual cardiac events—is acceptable.

“We think LDL is an extremely well validated endpoint,” Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research, told Reuters.

But a debate is raging over whether outcomes studies that measure heart attack and stroke reduction should be required to approve new heart drugs. Those studies typically take at least five years to complete.

“Consensus is emerging that it may be acceptable to approve a drug based on valid surrogate endpoints, but only if a large clinical outcomes trial is underway,” Nissen said of one potential compromise.

“If you make patients wait 5 to 7 years for outcomes trials that’s too long,” Nissen said. “We need new medicine. The patients are waiting.”