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Friday, 12 June 2015

Drug to check cholesterol gets FDA panel nod

An expert committee that advises the Food and Drug Administration recommended on Wednesday that the agency approve the second in a new class of drugs that can drive cholesterol levels down to unheard-of levels. 

Cardiologists hope these new medicines will help prevent heart attacks for millions of Americans, but the results of clinical trials that will definitively settle the question of the drugs' effectiveness will not be in until 2017. 

The panel on Tuesday had advised the FDA to approve the first such drug, alirocumab, made by Sanofi and Regeneron Pharmaceuticals, and on Wednesday recommended approval for the second, a similar drug, evolocumab, made by Amgen. The agency usually follows the advice of its expert committees. 

Based on drastic reducti8ons of so-called bad LDL cholesterol levels and the lack of evidence so far of safety concerns, the panel decided that the drugs would fill a critical unmet need for people at high risk of heart attacks who are unable to get their cholesterol under sufficient control with statins, the mainstay drugs to lower cholesterol that came on the market in the late 1980s. 

Studies have consistently found that elevated levels of LDL cholesterol are a major risk factor for heart disease and that risk drops in lock step with declines in LDL. 

If the FDA approves the drugs, they are expected to change the landscape for heart attack prevention and become blockbusters for the companies that make them. 

The panel unanimously agreed that Amgen's drug sh8ould be approved for people with a rare genetic disorder, homozygous familial hypercholesterolemia, because of th8eir dire need for treatme8nts. They have LDL levels that can soar as high as five times the normal level and they die young from heart attacks. 

The panel voted 11 to 4 in favour of making the drug av8ailable to other at-risk patients for whom statins don't work well. 

Dr. Philip Sager of Stanford said he thought it was "more likely than not" that the drugs would be safe and effective. 

"I do acknowledge the uncertainty," Dr. Sager said, "I am unwilling to wait until 2017 or 2018 to get those results." 

Those who voted no stressed the paucity of safety data. 

"I think we need longer exposures to this new product," said Dr. Peter Wilson of Emory University. 

The drugs are monoclonal antibodies, made by living cells, and must be injected. Amgen has two formulations. One is injected every two weeks, the other once a month. The choice depends on the patient's preference. The effect is the same. The drug lowers LDL levels by 55 to 75 percent even if the starting point is at a level that was already reduced by a statin. 

Cardiologists generally attempt to get LDL levels to 70 in people at high risk, although many cannot reach that goal. The Amgen drug can get LDL to 20, 15 or even lower. Amgen said it saw no sign of adverse effects with very low LDL levels and is offering only one drug dose. Sanofi and Regeneron, whose drug was considered on Tuesday, said it discontinued treatment with its drug or reduced the dose when people's LDL levels got below 25. 

There was no clear answer about what to expect with such low levels, panel members said. 

"Maybe extremely low is just absolutely fine, but there is a lack of data," Dr. Sager said. "On the other hand, there is not much data that having an LDL less than 40 shows much benefit. It's a real conundrum. I don't know what the answer is." 

Researchers discovered a gene, PCSK9, that controls LDL levels. Then they learned that people with a disabling mutation in one copy of that gene appeared to be protected from heart disease, even if they smoke or have high blood pressure. Very few people who have both gene copies disabled ended up with LDL levels of 15 or lower and seem perfectly healthy. So companies rushed to make drugs that mimicked the gene mutation. Sanofi and Regeneron and Amgen are first, but others are not far behind. 

Knowing the high stakes, Amgen prepared for the F.D.A. hearing much like lawyers prepare for a major jury trial. It flew leading cardiologists to its office to serve as a mock F.D.A. committee. 

Dr. Steven Nissen of the Cleveland Clinic, was among those who went. He said he felt a bit uncomfortable agreeing and refused compensation. But he said he wanted to push the company on the quality of its data on the drug. 

"I asked the kind of hard questions that should be asked," he said. He added that he and others pressed on the effects of a very low LDL level. "We tortured them over it," he said. In the end, he said he was convinced that from what was known to date, there was no evidence yet of harm and reason to hope for benefit. 

But Dr. Jerome Avorn, a professor of medicine at Harvard, offered a note of caution. 

"While the preliminary data on both drugs are encouraging, there is no substitute for large randomized clinical trials," he said. And, he added, the very low LDL levels are so unprecedented, that "it would be cavalier to assume that nothing could possibly go wrong." 

"We've not ever done anything like this with drugs before," Dr. Avorn said.