Sky-High Genetic Cholesterol Target for Blockbuster Drug

By Michelle Fay Cortez  

Photographer: Patrick T. Fallon/Bloomberg

Cardiologist Dan Rader has an unnerving party trick. When he meets people with subtle signs of sky-high cholesterol, he may ask to feel their Achilles tendons. Several times he’s diagnosed a condition that makes them 20 times more likely to die young of a heart attack.
Rader, head of preventive cardiology and human genetics at the University of Pennsylvania in Philadelphia, is looking for fatty buildups in the knees and ankles or white arcs around the cornea of the eye. The hereditary condition he’s seeking, known as familial hypercholesterolemia, affects as many as 1.5 million Americans -- a group drug companies see as one of the first markets for a set of
potential blockbuster cholesterol drugs.
Diagnosing the patients and their family members won’t only improve their chances for a long and healthy life, it will identify the most robust market for the new drugs. Called PCSK9 inhibitors, analysts estimate the injections will generate more than $2 billion a year each for companies including Amgen Inc., Pfizer Inc. (PFE), Sanofi and Regeneron Pharmaceuticals Inc.
To capture those sales, drugmakers first need doctors to think like Rader and find the patients.
“Most physicians rarely, if ever, make the diagnosis,” said Rader. “On the patient level, there is virtually no recognition whatsoever. FH is essentially unknown.”
Familial hypercholesterolemia, or FH, increases LDL, or bad, cholesterol levels to as high as 400 milligrams per deciliter, compared with a goal level of 100 milligrams. Already at a greater risk of heart attack and early death, patients also have a 50 percent chance of passing it on to their children.

Family Ties

While there’s a genetic cause of FH, doctors diagnose it based on dramatically high bad cholesterol levels and family history, rather than a DNA test.
Patients are typically treated first with statins, like Pfizer’s Lipitor, though the medicines aren’t usually enough. The PCSK9 drugs are likely to be used at first in patients who can’t take statins, have FH, or who for some other reason can’t get their bad cholesterol levels down.
Karol Watson, co-director of preventive cardiology and director of the Barbra Streisand Women’s Heart Health Program at the University of California, Los Angeles, said she wants hard proof that the PCSK9 inhibitors avert heart attacks before she prescribes them broadly. For the 15 percent of patients she sees with FH, though, she will start recommending them immediately.

Drive It Down

“These are individuals with LDL in the 300, 400, 500 range,” she said in an interview. “I have them on four drugs just hoping to get their LDL below 200. We want to drive that down as much as possible.”
A first wave of trials for PCSK9 drugs were designed to show they cut bad cholesterol, which regulators at the U.S. Food and Drug Administration have used as a marker for lowering risk. Along with FH, the drug could be used in patients who can’t take or don’t respond to statins, a population of about 10 million.
Longer trials with thousands of patients are attempting to prove definitively that the PCSK9 drugs reduce risk of heart attacks, stroke and death, which could eventually expand their use into anyone with high cholesterol, a much larger market.
Drugmakers haven’t said how much the injections, which will likely be taken every few weeks or once a month for the rest of patient’s life, will cost. Mark Schoenebaum, an analyst with Evercore ISI, estimates they may charge $4,000 to $5,000 a year.

Taking No Chances

The industry isn’t leaving the discovery of the highest-risk patients to chance. At an American Heart Association meeting last month, the companies highlighted the progress made with antibodies to block PCSK9, a protein that interferes with the body’s removal of cholesterol. The medicines can cut cholesterol more than 70 percent and may be the best hope for getting FH patients to healthy levels.
It’s not the first time the industry and medical community has embarked on a campaign to track down an under-diagnosed group. As a new, better generation of treatments for hepatitis C got closer to market, U.S. public health authorities urged people at risk to get screened, identifying thousands of new patients to drugmakers for treatment.
The market for PCSK9 drugs got another boost last month from a study of a different drug, Merck & Co.’s Zetia, helping calm a debate about cholesterol reduction. A trial of the drug showed that heart risk was reduced when patients got their cholesterol rates even lower than statins could accomplish alone. That bolsters the case for PCSK9s, since it adds to the evidence that FH patients could benefit from cutting cholesterol beyond what statins can do.

Soft Sell

Drugmakers also made a softer sell at the heart meeting. There were massive booths offering beverages and educational materials. Sanofi and Regeneron sponsored the meeting’s mobile app, a map of the convention center, and the convention’s hotel room keys had ads touting drugmakers’ PCSK9 research.
Their work is helping identify people who will benefit from a diagnosis and treatment, said Harlan Krumholz, a cardiologist at Yale University in New Haven, Connecticut. There is also the risk that the effort will go too far, he said.
“With FH, there is a hope and a fear,” he said. “My hope is that the many people who have FH who are currently not diagnosed may be identified and counseled and given the opportunity for treatment,” he said in an interview. “But if they overreach and try to expand the market to people for whom the benefits are less clear, they may be doing a disservice.”

Industry Sponsors

Patients can also turn to the FH Foundation, the first advocacy organization for the disease. It was created three years ago by Katherine Wilemon, a mother and FH patient from San Marino, California, who struggled to find doctors who understood her condition or other people going through the same thing. The foundation is sponsored by Amgen, Sanofi (SAN), Pfizer, Regeneron and other drugmakers, according to its website.
“We are very much supported by the pharmaceutical industry,” said Wilemon, who ran the foundation as a volunteer activity for its first two years and now takes a salary. “That is key in facilitating our efforts. But we are completely independent in how we chose to fulfill our mission.”
It’s not hard for doctors or health care professionals to spot FH once they learn about it. It’s caused by a genetic defect on chromosome 19 that makes it difficult for the body to remove bad cholesterol. Children can have LDL levels greater than 300 milligrams per deciliter, almost 10 times what most people are born with.

Mona Lisa’s Disease

Mona Lisa, the woman famously painted by Leonardo da Vinci, is thought to have been a patient. An analysis of the painting found signs of the disease on Mona Lisa’s eye and hand and concluded that she was “probably the first case of familial hypercholesterolemia,” according to a 2008 study in the journal Current Cardiology Reviews.
It’s the less obvious damage -- plaque buildup in arteries that nourish the heart and brain -- that is most dangerous. Imaging studies can spot the plaque in the carotid arteries leading to the brain in patients as young as 11. By age 50, half of men with the condition have already developed heart disease or died from it, studies show.

Widow-Maker Artery

Wilemon knew at age 15 that her bad cholesterol topped 300, though she had no idea why. By the time she was 38, Wilemon had suffered a massive heart attack. A key artery, one doctors call the widow-maker, was completely blocked.
“It took two additional years to find a physician who truly understood what I have,” she said. “He suggested I have my daughter checked. She was two. She also has it.”
Since high cholesterol has traditionally been treated the same regardless of the cause -- usually with drugs such as Pfizer’s Lipitor, sold now as a generic, or AstraZeneca Plc’s Crestor -- there hasn’t been an urgency to find patients. While those drugs alone can’t control cholesterol for most FH patients, they had few other options.
Wilemon’s foundation is sponsoring a patient registry and encourages screening for family members. It’s also trying to get a separate billing code for the condition.
The drugmakers’ effort around the medicines is already having an effect, Yale’s Krumholz said.
“It has been one of the most remarkable educational marketing campaigns of all time,” he said. “We went from not having any understanding of this class of drugs as practitioners, to saying PCSK9 inhibitors off the tops of our tongues. Now I’m fluent.”