Cholesterol would not be the household word it is today if treatments hadn’t been discovered. In the ’70s, Japanese researchers identified compactin, which inhibited cholesterol synthesis and lowered LDL levels. But in large doses, compactin caused cancer in dogs, so compactin research hit a dead end. Still, the promise of an agent that reduced “bad” LDL cholesterol level was tantalizing. Merck launched a large-scale trial of lovastatin in 1984, and the FDA approved the drug, sold as Mevacor, in 1987. The statin era, which transformed the prevention of heart disease and remade the pharmaceutical industry, was upon us.
Now we may be starting another chapter in the cholesterol saga, but this time cost may be an antagonist. Last year, the FDA approved two new cholesterol-lowering agents, alirocumab (Praluent) and evolocumab (Repatha). These are fully humanized monoclonal antibodies that inactivate proprotein convertase subtilisin–kexin type 9, hence the shorthand, PCSK9 inhibitors. They are indicated for two groups: those with a rather severe form of hypercholesterolemia called heterozygous familial hypercholesterolemia, and those with atherosclerotic cardiovascular disease who need additional lowering of their LDL. Sure, the PCSK9 inhibitors would have garnered some attention as a new class of drugs, but it’s their price—roughly $1,000 a month—that vaulted them into the headlines and the current storyline of high-priced medications and what are we going to do about them.
Late last year, the FDA approved a cholesterol-related drug that will be even more expensive. Sebelipase alfa, marketed by Alexion under the brand name Kanuma, is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme. It’s approved as a treatment of patients with a diagnosis of lysosomal acid lipase deficiency (LAL-D), a rare autosomal recessive genetic disease affecting between 1 in 40,000 and 1 in 500,000 people.
LAL is an enzyme responsible for the breakdown of cholesterol esters and triglycerides in the liposomes, the small organelles that function as recycling centers inside our cells. Lack of LAL activity leads to an accumulation of these compounds within cells. The liver, spleen, and gastrointestinal tract are particularly affected. Damage to the LAL gene, which sits on the 10th chromosome, can lead to either partial or complete absence of LAL activity.
In infants born with complete LAL inactivity, symptoms occur within weeks after birth, causing vomiting, diarrhea, poor weight gain, and massive enlargement of the liver and spleen. These infants seldom survive past their first birthday. This presentation is named Wolman disease after the doctor who first described it in 1956.
If the gene is less damaged, it is called cholesteryl ester storage disease (CESD) and symptoms vary according to how much residual LAL activity is left. Some patients aren’t diagnosed till they are middle aged. CESD is easily mistaken for other forms of hypercholesterolemia first diagnosed in middle age such as heterozygous familial hypercholesterolemia, the genetic disease treated with PCSK9 inhibitors.
The anticholesterol drug Kanuma is made from eggs laid by genetically modified chickens. Istockphoto
Kanuma’s developer has chickens to thank for its product. The treatment agent is derived from the eggs of genetically engineered chickens. Human LAL DNA is spliced into the genome of chicken embryos. When they mature, they lay nonfertilized eggs that contain human LAL DNA in the egg white that is then isolated and purified in ways similar to other biotech drugs. This line of chickens is sustained by artificially inseminating females with semen collected from roosters that have been genetically engineered.
All of this happens in what has got to be one of the world’s most closely watched, high-tech henhouses. Each producing hen is maintained in a productive mode for 90 days, and then tagged with a unique identification number. Eggs are collected daily for harvest of the egg white and isolation of the LAL. Few chickens have been measured and observed so closely, and extensive data were provided to the FDA on their health and well-being.
Kanuma was studied in two groups of patients. The first study was an open-label, escalating-dosage, non–placebo-controlled study of nine rapidly progressive LAL-D patients who presented in the first six months of life. At one year, 6 of the 9 patients were still alive as compared with a historical expectation of none surviving to one year.
The second study was a multicenter, double-blind, placebo-controlled trial in 66 pediatric and adult patients with LAL-D, but not the rapidly progressing kind. Kanuma was given as an IV infusion at a dose of 1 mg/kg every other week for 20 weeks in the double-blind period. At the start of the trial, 94% of these patients had LDL levels of 130 mg/dL or greater, and 58% had levels of 190 mg/dL or more. About 1 in 4 of those in the high-cholesterol group were on statin therapy. At the completion of the 20-week trial, a statistically significant improvement in LDL was observed in the Kanuma treated group as compared with the placebo group.
The average reduction in LDL levels was 33 mg/dL. A LDL level of less than 130 mg/dL was achieved in 13 of 32 patients treated with Kanuma, compared with only 2 of the 30 placebo-treated patients. But the effect of Kanuma on cardiovascular morbidity and mortality has not been established.
The studies hint of some liver benefits from Kanuma. People taking the medication experienced a drop in alanine transaminase values and liver fat content. But it’s just a hint, and it’s uncertain how those effects relate to the progression of liver disease.
About 3% of patients experienced hypersensitivity reactions consistent with anaphylaxis. One in five patients experienced signs and symptoms that may be related to hypersensitivity. Other adverse events were diarrhea, vomiting, fever, rhinitis, anemia, headache, and a host of nonspecific reactions.
But the real toxicity might be a financial one. A single, 20 mg vial is priced at $10,600. The dosage is 1 to 3 mg/kg every week for rapidly progressive disease and 1 mg/kg every other week for pediatric and adult forms of LAL-D. The price tag for a year of treatment for a child could easily be $250,000 and for a typical adult it could be three or four times as much.
The progress made over the past 60 years is simply remarkable. Since the first description of Wolman disease, scientists have identified the chromosome affected, the exact nature and DNA sequence of the LAL gene, and a number of specific mutations of this gene that account for various presentations of LAL-D. They isolated a normal human LAL gene, transferred it into a chicken, and created a way to isolate the exact enzyme responsible for this genetic condition.
But it’s also easy to get caught up in technological feats and the march of progress and lose sight of how much patients really benefit. Only 13 of the 66 patients in the mild LAL-D trial were able to reduce their LDL levels to 130 mg/dL or less. One in three of the infants with the severe form of the disease still died in the first year of life. The most striking deficit is lack of proof that administration of Kanuma over long periods makes a meaningful difference in progression of liver disease or decrease of cardiovascular morbidity or mortality. This evidence will take years to accumulate, making this a continuing story for Tomorrow’s Medicine.