I seldom am able to write about two different ground-breaking developments in medical technology in the same month. But research tends to happen in big jumps as a new receptor or biologic process is discovered; rapid determination of the genetic and protein cascades are uncovered; and multiple teams, often worldwide in scope, attempt to come up with a treatment for a disease that current therapies had little to offer. That is the case this month for a very rare disorder that affects only about 300 people in the United States.
Many reading this column are probably dealing with elevated cholesterol. Medical research has led to numerous treatments for this common disease that can control the cholesterol levels for most patients, albeit sometimes with complex drug combinations or with side effects.
But there is a small subgroup for which all traditional medications fail — people with a homozygous form of familial hypercholesterolemia (HoFH). It was originally described in 1938 based on the physical signs and inheritance pattern, and the genetic cause was discovered by Joseph L. Goldstein, MD, and Michael S. Brown, MD, of Dallas in the 1970s and 1980s. This was such an important breakthrough in the overall understanding of hyperlipidemia that a Nobel Prize in Medicine was awarded in 1985 for their research on the impact of the LDL receptor on lipoprotein metabolism.
This autosomal dominant (non-sex-related) disorder occurs in about 1 in a million people and can lead to death from cardiovascular disease at a very young age, sometimes even preteen. HoFH is slightly more common in certain subpopulations, including French Canadians, Lebanese Christians, and Finns. In addition to cardiac disease, these children develop cerebrovascular disease, cutaneous xanthomas, corneal arcus, and other signs and symptoms typically seen a half century later in the traditional patient.
HoFH is diagnosed when patients are found to have severe elevations of total cholesterol and LDL-C (low-density lipoprotein cholesterol) and there is no other diagnosable cause.
The cause is a malfunctioning LDL receptor gene normally on the short arm of chromosome 19 and comprising roughly 3,000 nucleic acids. This gene codes for a protein of 860 amino acids in length. This protein acts as the primary determinant of hepatic uptake of LDL. Multiple mutations of this gene can lead to a mild-to-severe decrease in the activity of the protein. With a malfunctioning or partially functioning protein, LDL-C can rise to 650 or even 1,000 mg/dL. Remember that our standard for cholesterol levels in the United States comes from the Third Report of the National Cholesterol Education Program Adult Treatment Panel. This panel recommends an LDL-C level of less than 100 mg/dL.
Traditional lipid-lowering attempts, although effective for the general population, have failed in these patients. In fact, one study demonstrated that traditional drugs reduced their LDL-C by about 100 points. Other therapies are apheresis — performed up to several times per week (basically filtering LDL-C from the blood, similar to how dialysis works in kidney failure patients) — portacaval shunt, and partial ileal bypass to reduce reabsorption of cholesterol from the gut. A more effective but drastic therapy is liver transplantation.
All this changed in December 2012, with the approval of lomitapide (Juxtapid) and again in February with the FDA approval of mipomersen (Kynamro). These drugs differ from each other but target the same small population.
Lomitapide is a microsomal triglyceride protein inhibitor that is indicated as an adjunct to a low-fat diet and other lipid–lowering treatments, including LDL apheresis where available, to reduce LDL-C, total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with HoFH.
Juxtapid is an oral medication taken once daily in a dose-escalation manner based on efficacy and tolerability. It carries a black box warning of liver enzyme (transaminase) elevations, which occurred in 34 percent of patients. It also increases hepatic fat with or without transaminase elevations and hepatic steatosis (fatty liver), which may progress to frank liver failure. Juxtapid is available only through a Risk Evaluation and Mitigation Strategy (REMS).
Juxtapid was studied in 29 patients with HoFH in a single-arm, multinational, open-label, 78-week trial. The mean age was 30.7 years. Only 23 (79 percent) of the patients completed the efficacy endpoint at week 29. The primary efficacy endpoint was the percentage change in LDL-C from baseline to week 26. At week 26, the mean change in LDL-C was a 40 percent decrease and the median was a 50 percent decrease.
Juxtapid comes with a number of other safety warnings, including embryofetal toxicity, reduced absorption of fat-soluble vitamins, diarrhea (93 percent), nausea (65 percent), dyspepsia (38 percent), and vomiting (34 percent), among others. There is also a warning of concomitant use of other drugs that inhibit the CYP3A4 metabolic pathway. There is a long list of drugs in this category. Only 19 of the original patients enrolled in the extension study.
Kynamro is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC) and non-high-density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia.
Kynamro is an antisense drug. It basically is a nucleotide that is the mirror image of the mRNA that encodes the apoprotein B-100 protein and blocks its formation. It is given subcutaneously once weekly. It also carries a black box warning concerning transaminase elevations, hepatic steatosis with or without transaminase elevations, and cirrhosis. It is also available only through a REMS program because of these side effects.
Other adverse events include injection-site reactions (10 percent of patients), flu-like symptoms (13 percent), nausea (14 percent), vomiting (4 percent) , headache (12 percent), and others. It does not have any known drug-to-drug interactions.
It is not known what might happen if used during pregnancy. It was studied in 34 patients who showed a mean 25 percent decrease in LDL-C and reductions in other lipoproteins.
Both drugs run rings around traditional cholesterol-lowering therapies for this small group of patients, but long-term outcome is unknown. The endpoints for both drugs were the surrogate endpoints of lowering of LDL-C and other lipid levels, not reduction of end-organ damage. Long-term safety and tolerability also remain unknown. What is known is the very high cost. Kynamro has been priced at $176,000 per year and Juxtapid at $235,000 to $295,000, depending upon the dose.
These new developments offer plenty of hope to patients with heretofore untreatable or partially treatable diseases, but the cost is creating a nonsustainable financial situation for the nation as a whole — something that many are facing in today’s monthly insurance premiums. The Affordable Care Act has little to mitigate these costs, but that is sure to be addressed as time goes on.
The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.