Many patients with HoFH have significantly elevated LDL-C levels despite treatment with conventionally used lipid-lowering medications. This is because many of those medications ultimately exert their effects by up-regulating LDL receptors.
Juxtapid approaches the problem from a different angle – by reducing LDL-C production.
Normally, the body regulates LDL-C levels in the bloodstream through a tightly-controlled process of LDL production and catabolism. LDL receptors play an important role in cholesterol homeostasis. They are predominantly expressed in the liver and are responsible for removing LDL-C from the circulation.
In patients with HoFH, the normal process for maintaining LDL-C homeostasis is disrupted. While mutations in several genes can result in HoFH, most often the the LDL receptor is the defective gene, and LDL receptors may be absent or defective. Consequently, the body does not effectively remove LDL cholesterol from the blood. As a result of this, most patients have high levels of circulating LDL-C levels if untreated.
Patients with HoFH May Not Get the Full Benefit of Conventionally Used Cholesterol-Lowering Medications
Many conventionally used cholesterol-lowering medications may not work as well in patients with HoFH because they ultimately exert their effects by up-regulating LDL receptors.
For example, statins are commonly given to patients with HoFH to lower LDL-C. These drugs work by inhibiting the HMG-CoA reductase enzyme, which controls cholesterol production in the liver. Through a feedback mechanism the decrease in cholesterol production in the liver results in upregulation of the LDL receptor.
In patients whose LDL receptors are defective or absent, the LDL cholesterol lowering effect of statins is typically blunted. As a result, despite intensive treatment, most patients with HoFH still have severely elevated levels of LDL-C.
How Juxtapid Works
Juxtapid is a first-in-class lipid-lowering medication for patients with HoFH.* Juxtapid reduces LDL-C production by directly inhibiting microsomal triglyceride transfer protein, or MTP.
One of the primary sites of expression of MTP is in the liver. MTP facilitates the assembly of apo B-containing lipoproteins to produce nascent VLDL, a pre-cursor of LDL-C. Juxtapid inhibits MTP and thereby prevents the assembly of apo B-containing lipoproteins. Inhibition of VLDL synthesis in the liver, in turn, leads to a reduction in levels of plasma LDL-C.
With its unique mechanism of action, Juxtapid can be added to a low-fat diet and other lipid-lowering therapies, including apheresis where available, to potentially help further reduce LDL-C levels in appropriate adult HoFH patients.
Risk of Hepatotoxicity
Because of this mechanism of action, there is a risk of hepatotoxicity associated with the use of Juxtapid. Juxtapid can cause elevations in transaminases. Juxtapid also increases hepatic fat, with or without concomitant increases in transaminases. Hepatic steatosis associated with Juxtapid treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.
*Juxtapid is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B) and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
Limitations of Use:
- The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH.
- The effect of Juxtapid on cardiovascular morbidity and mortality has not been determined.