Page 17 - Delaware Medical Journal August 2015
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SCIENTIFIC ARTICLE
fact that statins lower LDL-C through upregulation of LDL receptors,
however this mechanism of LDL-C clearance is compromised in FH FH patients is often lower than that seen in the general population.12,13
FIGURE 3
Patient B – Lipid Panel on Mipomersen Therapy.
FIGURE 4
Patient B – Heptic Function Profile on Mipomersen Therapy.
effects demonstrated in the aforementioned trials, adverse
events were common and remain an area of potential concern. Minor gastrointestinal side effects such as nausea, vomiting, diarrhea, and cramps were the most commonly reported events, occurring in 27 out of 29 patients in one study.17 More concerning however, were episodes of hepatic transaminitis and hepatic steatosis. Although transient elevations in aminotransferases were relatively frequent, ranging from 18 percent to greater than 60 percent across the three studies, in all cases levels returned
to normal following decreased dosing or complete cessation
of lomitapide.16-18 Hepatic fat content as measured by NMR Spectroscopy in the Cuchel et al. study increased from an average baseline of 1.0 percent to 8.6 percent at week 26, without further increase over the remainder of the study.17
Mipomersen received FDA approval on January 29, 2013, for treatment of patients with HoFH unable to achieve adequate LDL-C reduction on standard lipid lowering therapy. Through a once weekly injection mipomersen, a second-generation ASO, inhibits apo B-100 translation leading to decreased production of LDL-C, VLDL-C and lipoprotein(a) [Lp(a)].19 Similar to the development of lomitapide, this mechanism takes
Recent advances in pharmacogenetics have led to the development of two recently approved medications for patients with HoFH who are unable to reach target LDL-C goals despite adherence to a low fat diet and maximally tolerated lipid-lowering therapies, including combination treatment with a high potency statin and an adjunct such as ezetimibe, a bile acid sequestrant
or niacin (Figure 5). Lomitapide and mipomersen are currently both available through the Food and Drug Administrations Risk Evaluation and Mitigation Strategy program.
protein (MTP) inhibitor that was approved for orphan drug status by the U.S. Food and Drug Administration on December 21, 2012, as an adjunct to standard lipid lowering therapy for HoFH patients. Through once daily oral administration, lomitapide inhibits MTP, a protein crucial in the assembly of Very-Low Density Lipoproteins (VLDL) and chylomicrons. The novel mechanism of lomitapide is modeled after abetalipoproteinemia, an inherited mutation causing complete absence of MTP production. This, in turn, leads to markedly decreased levels of total cholesterol (TC), LDL-C and apo-B.14,15
patient, 16-week dose escalation study of HoFH patients, which demonstrated reductions in LDL-C and apo-B of 50.9 percent (p<0.001) and 55.6 percent (p<0.001), respectively at a dose of 1.0 mg/kg/day.16 lomitapide was demonstrated in a 78-week, phase 3, open-label dose escalation trial.17 Twenty-nine HoFH patients received 5 mg lomitapide daily, which was titrated to the maximally tolerated dose over a 26-week treatment period. Over this timeframe, LDL-C was reduced by an average of 50 percent (p<0.0001). The maximally tolerated dose was then continued over the remaining
52-week treatment course and an average
LDL-C reduction of 38 percent (p<0.0001)
was seen at week 78.17 Similar results were
demonstrated in a 12-week trial evaluating 84
non-FH hypercholesterolemic patients. Patients were randomly assigned to receive lomitapide alone, lomitapide in combination with ezetimibe, or ezetimibe alone.18 Lomitapide monotherapy percent at the 5 mg/day dose to 30 percent at the 10 mg/day dose. In combination with ezetimibe, lomitapide demonstrated similar yet more substantial LDL-C reductions of 35 percent and 46 percent at the 5 mg/day and 10 mg/day doses, respectively.18
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