The world’s biggest drugmakers are racing to market the first medicine to tap into a gene mutation that drops heart-attack risk by as much as 88 percent.
Normally, the PCSK9 gene creates a protein that disrupts the ability of liver cells to remove bad cholesterol from blood, enabling it to accumulate. A mutated form of the DNA found in 3 percent of people lowers levels of the protein, allowing more of the artery-clogging hormones to be swept away.
Just five years after the effects were discovered, more than a half-dozen companies led by Amgen Inc. (AMGN), Sanofi and Pfizer Inc. (PFE) are developing a new family of treatments based on the science. Amgen and Sanofi partner Regeneron Pharmaceuticals Inc. (REGN) will present data from early human trials at the American Heart Association meeting next week. At stake is entry into a market that generated $36.4 billion in worldwide sales last year, according to IMS Health.
“It is the biggest opportunity for lowering cardiovascular risk for the entire pharmaceutical industry,” said Roger Perlmutter, executive vice president for research and development for Thousand Oaks, California-based Amgen, in a phone interview. “Millions of people could benefit from this.”
Current treatments led by Lipitor, the generator of $10.7 billion in worldwide sales last year for New York-based Pfizer, work differently. Known as statins, they are pills taken daily that work by blocking an enzyme the body needs to produce bad cholesterol, or LDL, in the liver.
In comparison, most of the new drugs are proteins, called antibodies, that would be injected once or twice a month.
The newest treatments will take years to develop, and must be vetted in large safety and efficacy studies that could affirm them, or condemn them, before they’re brought to regulators. If they pass those hurdles, a likely use would be in heart patients whose cholesterol remains above target levels even when taking high doses of drugs such as Lipitor, said Perlmutter.
Overall, as many as 30 million Americans take cholesterol pills, according to a survey by the Agency for Healthcare Research and Quality. At least 4 million people may one day benefit from the new drugs, Perlmutter said in a telephone interview.
Amgen, the world’s largest biotechnology company, is testing its drug, AMG 145, in several trials in high-cholesterol patients, including those who can’t tolerate existing treatments such as Lipitor. A single dose of AMG 145 lowered bad cholesterol as much as 70 percent in volunteers, Amgen told analysts in April.
Regeneron, jointly developing its treatment with Paris- based Sanofi, also on Nov. 14 will present early results from a 62-patient study. Second-stage trials showed that adding their PCSK9 drug to high doses of Lipitor lowered cholesterol by 65 percent versus a 17 percent reduction for high-dose Lipitor alone, Sanofi and Tarrytown, New York-based Regeneron said yesterday in a statement.
Sanofi will start final-stage trials of the drug next year, the company has said. Three phases of clinical trials generally are required for U.S. regulatory approval.
Along with working in tandem with existing treatments, the new family of medicines may help roughly 5 percent of heart patients who can’t tolerate the existing pills as well as smaller subset -- roughly 1 in 500 people -- who have inherited forms of high cholesterol.
“The antibodies are really performing in a very exciting fashion,” said George Yancopoulos, Regeneron’s chief scientific officer, in a phone interview. “They seemingly do an even better job at sweeping the LDL out” than existing medicines. “It should be a big commercial opportunity.”
Key Early Research
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, her 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 their cholesterol 15 percent and heart risk by 47 percent.
By comparison, cholesterol lowering “statin” pills such as Lipitor and Zocor only reduce heart attack risk by about a third.
Hobbs and Cohen had been gathering DNA from 3,500 Americans for a heart study. While many researchers at the time 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.
Her team took DNA samples from the 5 percent of patients in her study with the lowest cholesterol levels, then used DNA sequencing machines to scan their PCSK9 genes for mutations that lowered cholesterol. Two percent of African Americans in the study had PCSK9 mutations that reduced cholesterol by 40 percent, according to data published in Nature Genetics in 2005.
The next step was to see if having “good” PCSK9 gene variants lowered heart disease risk.
For this, Hobbs and her colleagues turned to a study that had been following 15,792 middle-aged Americans since 1987. The results became the basis for the 2006 New England Journal of Medicine paper showing that PCSK9 mutations lowered heart risk far more than would be suggested by the reductions in cholesterol levels.
“Helen Hobbs really pioneered this approach of looking at extremes in the population and looking at genetic causes of the real extremes,” said Regeneron’s Yancopoulos.
Other companies pursuing research on this front are Merck & Co., Isis Pharmaceuticals Inc. with partner Bristol-Myers Squibb Co. (BMY), and Alnylam Pharmaceuticals Inc. (ALNY) In July, Pfizer, the world’s biggest drugmaker, began a second-stage testing of its anti-PCSK9 antibody, while Merck is working in the lab on an injected antibody and a pill that could block PCSK9’s effects.
“It has the potential for tremendous efficacy,” said Andrew Plump, vice president in charge of cardiovascular discovery at Whitehouse Station, New Jersey-based Merck, the second-largest U.S. drugmaker.
Hobbs suspects the reason the patients have such a big reduction in heart attacks “is that these people have low LDL their entire life.” This stops plaque from ever building up in the arteries, she said.
Hobbs studied a 38-year-old aerobics instructor who inherited mutations in both of her PCSK9 genes. The woman has no PCSK9 protein in her bloodstream at all and her bad cholesterol ranges from 13 to 24 milligrams per deciliter. Less than 100 is considered good.
The Texas researchers have followed the woman for six years and found no ill-effects from the double mutation, Hobbs said.
“If she had a heart attack, I would be shocked and astounded,” Hobbs said.
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