General Information

Juxtapid (lomitapide) is an oral inhibitor of the microsomal triglyceride transport protein (MTP). The inhibition of MTP blocks the hepatic secretion of very low density lipoproteins and the intestinal secretion of chylomicrons.

Juxtapid is specifically 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-highdensity lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia.

Juxtapid is supplied as a capsule for oral administration. Before beginning treatment: Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin, Obtain a negative pregnancy test in females of reproductive potential and Initiate a low-fat diet supplying <20% of energy from fat. The recommended starting dosage of Juxtapid is 5 mg once daily, and the dose should be escalated gradually based on acceptable safety and tolerability. The maintenance dosage of Juxtapid should be individualized, taking into account patient characteristics such as goal of therapy and response to treatment, to a maximum of 60 mg daily. See drug label for any dose modifications.

Clinical Results

FDA Approval
The FDA approval of Juxtapid was based on a multinational, single-arm, open-label, 78-week trial in 29 adults with HoFH. After a six-week run-in period to stabilize lipid-lowering treatments, Juxtapid was initiated at 5 mg daily and titrated to daily doses of 10 mg, 20 mg, 40 mg, and 60 mg at weeks 2, 6, 10, and 14, respectively, based on tolerability and acceptable levels of transaminases. Subjects were instructed to maintain a low-fat diet (<20% calories from fat) and to take dietary supplements. After efficacy was assessed at Week 26, subjects remained on Juxtapid for an additional 52 weeks to assess long-term safety. During this safety phase, the dose of JJuxtapid was not increased above each patient’s maximum tolerated dose established during the efficacy phase. The primary efficacy endpoint was percent change in LDL-C from baseline to Week 26. Twenty-three (79%) patients completed the efficacy endpoint at Week 26, all of whom went on to complete 78 weeks of treatment. The primary efficacy endpoint was percent change in LDL-C from baseline to Week 26. At Week 26, the mean and median percent changes in LDL-C from baseline were -40% (paired t-test p<0.001) and -50%, respectively, based on the intent-to-treat population.

Mechanism of Action

Juxtapid (lomitapide) directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL. The inhibition of the synthesis of VLDL leads to reduced levels of plasma LDL-C.

Literature References

Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, Averna MR, Sirtori CR, Shah PK, Gaudet D, Stefanutti C, Vigna GB, Du Plessis AM, Propert KJ, Sasiela WJ, Bloedon LT, Rader DJ; for the Phase 3 HoFH Lomitapide Study investigators Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2012 Nov 1. pii: S0140-6736(12)61731-0

Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, Ikewaki K, Siegelman ES, Gregg RE, Rader DJ Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. The New England Journal of Medicine 2007 Jan 11;356(2):148-56