An expert group recommended on Tuesday that the Food and Drug Administration approve a powerful new drug to protect against heart attacks. If approved, it would be the first in a major new class of medicines in a generation that significantly lower levels of cholesterol, the leading cause of heart disease. Dr. Joshua W. Knowles, a Stanford cardiologist, called the medicines “a triumph of the modern genetic revolution.” The idea for such drugs arose from genetic studies about a decade ago and has tantalized cardiologists ever since. Early results of clinical trials raised hopes that the therapies would be critical new additions to the treatment arsenal for those at risk of heart disease, the biggest killer of Americans. People who have taken them have seen their LDL cholesterol, the so-called bad cholesterol, plunge to remarkably low levels. But definitive evidence of the drugs’ effectiveness in reducing heart attacks and deaths will come only after large clinical trials are completed in 2017. The panel, in a 13 to 3 vote, recommended the approval of Sanofi and Regeneron Pharmaceuticals’ drug, alirocumab. On Wednesday, the committee will turn to Amgen’s drug, evolocumab. The F.D.A. usually follows the recommendations of its advisory panels, but not always. The agency says that if it approves the drugs based on their effects on cholesterol, the approval will not be rescinded even if trials now underway fail to show the drugs reduce the risk of heart attacks and deaths. Once a drug is approved doctors can prescribe it to patients other than those for whom it was intended, although insurers generally will not pay. The drugs are injected every two weeks or once a month, depending on the formulation. The companies are asking that they be approved for use in three groups: patients with high levels of LDL cholesterol who cannot lower it enough with statins, the mainstay drug for cholesterol lowering first introduced in the late 1980s; people at very high risk because they have already had a heart attack or have diabetes and cannot get their levels low enough with statins; and people with high levels of LDL who cannot tolerate statins. Doctors often aim for LDL levels of 70 for people at high risk. The problem for the expert group was to decide if there was enough evidence to approve the Sanofi drug without waiting for results from the large clinical trials. Those who voted no said drugs should not be approved until clinical trials established their efficacy, and voiced the worry that people participating in the trials would drop out once the drugs were approved so they could be sure to get the medicine, not a placebo. “We need clinical outcomes,” said Dr. Peter Wilson of Emory University. Some on the panel felt comfortable recommending approval only for a narrow group of people with a genetic condition, heterozygousfamilial hypercholesterolemia, who cannot control their cholesterol with statins alone. Others favored allowing use of the drug by the much larger group of people at high risk of heart disease for whom statins are insufficient. The group’s chairman, Dr. Robert J. Smith of Brown University, argued for broader availability of the drugs. He said he sees patients in his own practice with out-of-control cholesterol who are at very high risk because, for example, they have already had a heart attack. Two years is a long time for them to wait for clinical trial findings. “I am unwilling to subject patients to that wait,” Dr. Smith said. The companies and many independent cardiologists say they have reason to believe the drugs will perform as expected. Lowering LDL cholesterol has generally been found to protect against heart disease. And, they say, the drugs were designed to mimic mutations in a gene, PCSK9, that protects people from getting heart disease, even if they smoke or have high blood pressure. But the drugs have caused trepidation among insurers and others who would have to pay the bills because the drugs are certain to be expensive — perhaps $10,000 a year — and millions of people are likely to qualify to take them if they are approved for the broader group. Sanofi estimates that 11 million Americans might qualify. Amgen puts the number at eight million. So far, it looks as if just about everyone who takes the new drugs responds. LDL cholesterol levels plunge by 40 to 65 percent, even if the starting level was achieved with a statin. Safety studies so far have found the drugs seem to have no more side effects than a placebo, but the large clinical trials are needed to get more substantial information. Meanwhile, pharmaceutical companies see the tantalizing prospect of multibillion-dollar blockbuster drugs, and are racing to get them to market as rapidly as possible. Sanofi bought an F.D.A.-backed voucher for $67.5 million that gave them an expedited review. The company says the F.D.A. agreed to decide whether to approve its drug by July 24. Amgen, which did not pay, expects an answer by Aug. 27, the company says. Pfizer also has a drug in this new class, but it is further behind in development. The powerful effect of the gene, PCSK9, that the drugs block was discovered when researchers found people who were born with one copy mutated so it did not function. They seemed to be protected against heart disease. Then researchers found two young women with both copies knocked out. Both had astonishingly low cholesterol — 14 for one and 15 for the other. That indicated that it might be safe to block the action of the gene with a drug and drive LDL levels very low. But people with the gene mutations had lower cholesterol levels their entire lives. With cholesterol-lowering drugs, most people start treatment in middle age, after heart disease is established. Would it be better to start much earlier in someone with high LDL? How low should LDL go? The evidence so far says that lower is better and that there is no known point at which the increasing benefits of dropping LDL levels even out. Some people in the clinical trials, in fact, have gotten their LDL levels as low as 15. Is that good? A bit nervous about very low levels, Sanofi decreases the drug dose when LDL falls below 25. Then there is the question of cost. The new drugs, like many new cancerdrugs, are monoclonal antibodies, produced from living cells at great expense. The companies will not say what they plan to charge. But Dr. William Shrank, chief scientific officer at CVS Health, estimates they will cost $7,000 to $12,000 a year. If drugs were restricted to people with dangerously high cholesterol levels who cannot get their LDL low enough with statins, the cost would be $16 billion, he estimated. If people who are intolerant to statins are included, that would add another $20 billion. If people with a history of heart disease are included, the bill for the drugs rises another $150 billion. “Managed pharmacy care, indeed the health care system, has never seen a challenge like this to our resilience in absorbing costs,” Dr. Shrank wrote in Health Affairs. Dr. Harlan M. Krumholz, a Yale cardiologist, worries that the patient population who take the drugs will expand beyond limited categories. Already, he said, the companies are conducting aggressive education campaigns and slipping brochures under doctors’ doors at medical meetings. “We need to watch this carefully,” he said. “These drugs should be reserved for people who have no choice.” “There are some people, a relatively small group, who are at very elevated risk because they don’t tolerate statins or because statins don’t have enough of an effect,” he said. “This is a way for patients to make a choice, to know the final evidence is not in but to decide they are willing to try these drugs.” Source
