Like any patient at risk of a heart attack, Kennedi Thompson has been counseled by her doctor to eat a low-fat diet and take prescription statins to reduce her cholesterol. Unlike most others facing heart disease, Kennedi is 3 years old.
She has a rare genetic disorder that has pushed her cholesterol level to four times that of a healthy adult. If left untreated, the disease -- called homozygous familial hypercholesterolemia, or HoFH -- can spur a patient’s first heart attack or stroke in their teens, give them the arteries of an octogenarian by age 20, and kill by the time they’re 30.
The estimated 3,000 Americans with HoFH may get new hope next week. Advisers to the U.S. Food and Drug Administration meet Oct. 17 and Oct. 18 to debate the risks and benefits of two experimental drugs for the disease, from Aegerion Pharmaceuticals Inc. and Isis Pharmaceuticals Inc., partnered with Sanofi’s Genzyme unit. The advisory panels’ recommendations often influence approval decisions.
“I’m crossing my fingers, crossing my toes, crossing everything that they get passed,” said Christian Jacobs, a 20-year-old college student who was diagnosed with HoFH at 2 and last week was preparing to have stents implanted to unclog his arteries.
Patients with HoFH have inherited faulty genes from both parents that cause their cholesterol management to malfunction. They lack working receptors for LDL cholesterol, the so-called bad form of the fat in blood that leads to clogged arteries and heart attacks. When LDL receptors don’t work properly or are missing, patients can’t effectively clear LDL cholesterol from the blood.
That leads to extremely high LDL cholesterol from a young age, said Daniel Rader, a professor of medicine and pharmacology at the University of Pennsylvania in Philadelphia. Patients develop heart disease as children and teenagers, and cholesterol-lowering statins such as Pfizer Inc.’s Lipitor do little to help them reach healthy levels, Rader said.
The experimental drugs, which may not be considered appropriate for most of the broader adult population with high cholesterol due to their side effects, act in the liver to limit production of LDL. Aegerion’s lomitapide is a once-daily pill that inhibits a key protein to prevent production of the precursor to LDL, called very low-density lipoprotein, or VLDL. Isis’s mipomersen, a once-weekly injection, inhibits another protein instrumental in the formation of LDL cholesterol. The FDA is set to decide on both drugs by the end of January.
Aegerion, based in Cambridge, Massachusetts, showed in a late-stage trial reported in January that patients taking lomitapide had an average reduction in LDL cholesterol of 38 percent after 78 weeks.
Isis, based in Carlsbad, California, says its drug reduced LDL cholesterol by 25 percent in HoFH patients in two late-stage trials, compared with 3.3 percent for those on placebo.
Side effects will be a focus of the advisory committee meetings, analysts said. Both are associated with a buildup of fat in the liver, which can lead to inflammation and potentially liver failure over time, said Scott Grundy, director of the Center for Human Nutrition at the University of Texas Southwestern Medical Center in Dallas.
Aegerion’s drug is tied to gastrointestinal problems like diarrhea, which patients can manage by maintaining a low-fat diet, according to Chief Executive Officer Marc Beer. Isis’s has been shown to cause skin reactions at the injection site.
“Despite these two drugs not being perfect, they’ll probably squeeze through the panel,” said Eric Schmidt, an analyst with Cowen & Co. who has a “neutral” rating on Isis shares and owns Aegerion stock in a personal account.
“I think the countervailing force is going to be that there’s a clear unmet medical need,” said William Tanner, an analyst with Lazard Capital Markets LLC in New York who rates Aegerion shares as “neutral” and doesn’t cover Isis or Sanofi. “This is a uniformly fatal disease.”
Tanner estimates lomitapide may draw $300 million or more in annual sales for Aegerion, based on a price of about $300,000 a year per patient, similar to the cost of other drugs for diseases with few treatment options.
Isis and partner Paris-based Sanofi, France’s largest drugmaker, may draw $480 million in worldwide sales from mipomersen, also known as Kynamro, Schmidt estimated. He based his projection on a price of $90,000 to $120,000 per year per patient and broader expansion into treatment for patients with just one copy of the faulty gene that tampers with LDL receptors. Stephen Willey of Stifel Nicolaus & Co. estimates peak Kynamro revenue of $500 million to $900 million annually, depending on usage in less severely ill patients and monitoring requirements from the FDA.
Aegerion declined less than 1 percent to $13.97 at the close in New York. The shares have fallen 17 percent this year. Isis dropped 1.8 percent to $12.26 and the shares have gained 70 percent for the year.
The companies aren’t initially seeking approval for treating children, though physicians may use the medicines off-label in younger patients.
Kennedi Thompson’s parents, Sean and Angelina, have helped manage her disease with a lean diet and a cocktail of cholesterol-lowering drugs. Her total cholesterol was close to 800 milligrams per deciliter a short time after she was first tested, Sean Thompson said, but treatments have brought it down to 419 mg/dL. A healthy level is considered to be less than 200 mg/dL, according to the American Heart Association.
“It is extremely scary,” said Thompson, who works as a clinical analyst and lives with his family in Albrightsville, Pennsylvania. “We know there’s a risk that she will have some type of cardiac event in her late 20s or early 30s, even with treatment.”
Older patients can undergo LDL apheresis, a cumbersome process similar to dialysis that scrubs excess fat from the blood. Christian Jacobs drives 2.5 hours each way from Columbus, Ohio, to Cleveland every other week for apheresis treatments, which take three to four hours and can be extremely painful because of the large needle used. The cholesterol that’s been stripped from his blood ends up in a bag at the bottom of the machine, he said.
“You can actually see it’s a yellow bag of cholesterol,” Jacobs said last week after a session. “It reminds me of, like, jellyfish, just clumps of cholesterol floating around in this bag. It’s so encouraging to know it’s not in me anymore.”
Apheresis can reduce Jacobs’ cholesterol to 100 or 150 mg/dL, he said, though by the next week it’ll have rebounded to 500 mg/dL. Jacobs takes 18 pills a day and estimates the cost of his apheresis and medicines at about $250,000 a year. He’s a patient advocate for Aegerion and Genzyme, and has received travel funding from the companies to speak at events, he said.
Jacobs participated in a clinical trial of mipomersen from October 2009 to February 2011. The medicine rid him of fatty buildups on his skin that were the first tip-off of his disease when he was a toddler. The only side effect he experienced was scar tissue where the needle was inserted in his abdomen, he said.
While Jacobs hopes the new medicines could mean he wouldn’t have to undergo apheresis, the therapies should be considered additive treatments rather than replacements, according to Rader, the University of Pennsylvania professor.
Rader helped shepherd the development of lomitapide for HoFH after Bristol-Myers Squibb Co. abandoned it when the company determined the side effects made it impractical for lowering cholesterol in a broader patient population. The New York-based drugmaker donated the compound to the University of Pennsylvania, and Rader tested it in 6 patients with the rare disease. He now is chairman of Aegerion’s U.S. scientific advisory board and owns stock in the company.
Jacobs said when he took mipomersen, his cholesterol hovered in the 200 mg/dL range, after being close to 600 mg/dL for most of his life.
“I’m hoping these medicines go through and I can feel that way again,” he said. “I’m only 20 years old and there’s so much I want to do. Instead of thinking about the future and what I could be doing, I’m thinking: ‘Am I going to have a heart attack tonight?’”