The medicine, one in a class of drugs targeting the PCSK9 gene, reduced patients’ average LDL cholesterol levels to as little as 34 milligrams per deciliter after 12 weeks in the mid- stage study, presented today at the American College of Cardiology meeting in Chicago. Less than 100 mg/dL is considered optimal for LDL, according to the Mayo Clinic.
“It’s a ‘wow’ study,” said James McKenney, the trial’s lead investigator and chief executive officer of National Clinical Research, a Richmond, Virginia-based company that runs studies. “Instantly you’re seeing all those patients you could not get to the level you’d like for them to be at, now you have a medicine that unquestionably can.”
About 25 percent of U.S. adults 45 and over take cholesterol-lowering statins, according to the National Center for Health Statistics. Statins include pills such as Pfizer Inc. (PFE)’s Lipitor, the world’s best-selling medicine in 2010 with revenue of $10.7 billion. Almost a third of statin users don’t get enough of a benefit, leaving them more vulnerable to heart disease and in need of additional therapy, McKenney said in a telephone interview.
The 183-patient trial, funded by Paris-based Sanofi and Tarrytown, New York-based Regeneron, produced results reminiscent of the cholesterol-lowering advances achieved by statins two to three decades ago, McKenney said. Patients for whom statins work can see their cholesterol reduced by as much as 50 percent, lowering heart risks, he said.
Amgen Inc. (AMGN), in Thousand Oaks, California, New York-based Pfizer and Whitehouse Station, New Jersey-based Merck & Co. (MRK) are also developing treatments targeting PCSK9, said Chris Raymond, an analyst with Robert W. Baird & Co. in Chicago. The gene creates a protein that disrupts the ability of liver cells to remove bad cholesterol from blood, enabling it to accumulate.
The study presented today evaluated five doses of Regeneron and Sanofi’s medicine, dubbed REGN727 or SAR236553, compared with a placebo. It found that 50 milligrams of the drug injected once every two weeks lowered LDL cholesterol by 40 percent, while 300 milligrams dosed every four weeks reduced LDL by 48 percent. The most-effective dose was 150 milligrams injected every two weeks, shown to lower LDL by 72 percent.
Patients took Lipitor at doses of 10, 20 or 40 milligrams for at least six weeks before starting the study, and still had LDL levels higher than 100 mg/dL. All groups continued taking Lipitor throughout the trial. Those on placebo -- Lipitor with no additional therapy -- had an LDL decline of 5 percent.
The most-frequent side effects were reactions at the injection site, the companies said in a statement. One patient on the medicine developed a skin rash, and six on the medication ended treatment early because of adverse events.
“When we look at the safety profile of this drug, it looks promising,” said Bill Sasiela, vice president of Regeneron’s cardiovascular and metabolic group. “If you look across the spectrum of the six patients who stopped early, there wasn’t any pattern as to what was driving their discontinuations.”
A study presented yesterday evaluated patients who started on a 10-milligram dose of Lipitor and were switched to either a higher dose of Lipitor, 80 milligrams, alone or in combination with SAR236553/REGN727. It found patients on the medicine plus higher-dose Lipitor had an average reduction in LDL of 73 percent after eight weeks, compared with 17 percent for patients taking only the Pfizer drug at a higher dosage.
Amgen also presented data from an earlier-stage trial on its anti-PCSK9 drug yesterday. The data showed its antibody lowered bad cholesterol by as much as 81 percent over six weeks in a short-term study in 51 patients already taking statin drugs such as Lipitor, according to a statement. Even patients on the highest doses of drugs such as Lipitor had large cholesterol reductions of up to 63 percent after getting the antibody, according to the results.
The Amgen treatment is being tested in six second-stage trials involving 1,900 patients, with results expected later this year, said Michael Severino, Amgen’s chief medical officer.
“We are moving forward very aggressively,” Severino said in an interview. The PCSK9 drugs “have the potential to save a lot of lives.”
Regeneron and Sanofi’s drug is the furthest along in trials, Baird’s Raymond said. The companies plan to start the third phase of studies in the second quarter, Elias Zerhouni, Sanofi’s president of global research and development, said in the statement.
The companies may need to run a larger study to assess the cardiovascular outcomes of the medicine, Raymond said.
“Given FDA’s conservatism, we think the working assumption is a large outcomes study requirement,” Raymond wrote in a March 21 note to clients. “Under a best-case scenario, REGN727 revenue remains at least a few years away.”
Anti-PCSK9 medicines also may help about 5 percent of heart patients who can’t tolerate the existing pills as well as smaller subset -- about 1 in 500 people -- who have inherited forms of high cholesterol.
Key research on PCSK9 came from Helen Hobbs, an endocrinologist and genetics researcher at University of Texas Southwestern Medical Center in Dallas, and her colleague Jonathan Cohen, a geneticist at the medical center.
In a 2006 study in the New England Journal of Medicine, Hobbs’s team found that 2.6 percent of black people studied had mutations in the PCSK9 gene that lowered bad cholesterol by 28 percent and reduced heart disease risk by 88 percent. The study found that 3.2 percent of 9,524 white people had variants in the PCSK9 gene that lowered cholesterol 15 percent and heart risk by 47 percent. Cholesterol-lowering statin pills such as Lipitor and Merck’s Zocor reduce heart attack risk by a third.
Hobbs and Cohen had been gathering DNA from 3,500 Americans for a heart study. While many researchers were looking for common gene variants that modestly influence heart risk in broad populations, Hobbs went looking for rare genetic mutations that had a dramatic effect.
“Those of us in the business suddenly have a lot of enthusiasm for the potential benefit it may give to further lower LDL cholesterol, and more importantly, further lower heart disease,” said McKenney, the lead investigator on Sanofi and Regeneron’s trial. “The hope is now high that we may have a second agent to add to a statin to achieve this risk reduction.”
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