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advantage of a known inheritable genetic mutation that causes hypobetalipoproteinemia. However, although lomitapide prevents the production of both chylomicrons and VLDL-C, mipomersen does not have an effect on the production of chylomicrons.
With an initial dose-escalating trial in healthy volunteers demonstrating a reduction in LDL-C of 50 percent from baseline, patients.20 lipid lowering therapy in heterozygous FH (HeFH) patients
was illustrated in a six-week, 44 patient trial. Despite patients having already achieved a >50 percent reduction in LDL-C on combination statin and ezetimibe therapy, mipomersen led to a further 21 percent reduction in LDL-C.21 Similarly, a 28-week, 124 patient study found that mipomersen was able to reduce LDL-C by 28 percent, on top of maximally tolerated statin therapy regardless of baseline LDL-C level.22 was demonstrated in homozygous FH (HoFH) patients in a 51-patient, 26-week placebo-controlled trial where mipomersen reduced the mean LDL-C from 205 mg/dL to 151 mg/dL, a drop of 24.7 percent. This was in contrast to the placebo group, which saw a decline in mean LDL-C of 3.3 percent.23
Within the aforementioned trials, in addition to remarkable cholesterol lowering capabilities, adverse events were common and led to treatment termination in 11.4 percent to 17.7 percent of patients. The most frequently reported events were injection- site reactions (76-97 percent)21-23 occurring in almost half of patients in one study.22 Less frequently, elevations in hepatic transaminases were observed, with levels greater than three times the upper limit of normal occurring in 14 to 14.5 percent of patients.22,23
CONCLUSION
From initiation of therapy, patient A and patient B have achieved substantial decreases in TC, LDL-C, and apo-B on lomitapide and mipomersen, respectively. Similar to trial results, we have seen that, in addition to standard lipid lowering therapy, including maximally tolerated statins, both lomitapide and mipomersen are able to achieve substantial dose-dependent cholesterol reductions. for both patients and has allowed patient A to discontinue bi-weekly plasmapheresis. Although elevations in hepatic transaminases have been seen in both cases these have resolved in patient A and mipomersen eventually had to be discontinued in
At 41 and 64 years of age, not unexpectedly, both of our patients
Currently, HMG-CoA reductase inhibitors (statins) remain the
FIGURE 5
Mechanisms of action of pharmacogenetic-based treatment options for familial hypercholesterolemia (FH). In comparison with the newer therapies approved by the Food and Drug Administration that inhibit low-density lipoprotein (LDL) production, HMG-CoA reductase inhibitors, the current mainstay of therapy in FH, inhibit the rate-limiting enzyme in cholesterol (Ch) synthesis in the liver but ultimately are effective due to upregulation of the LDL receptor. Mipomersen, an antisense oligonucleotide, binds to apoB-100 messenger RNA (mRNA) thereby inhibiting apoB-100 translation in the liver. This ultimately leads to decreased production of all lipoproteins containing
apoB. Lomitapide, a microsomal triglyceride transfer protein inhibitor, works in the hepatocytes and enterocytes to inhibit
the production of chylomicrons and very low density lipoprotein (VLDL) by inhibiting the incorporation of triglycerides onto nascent apoB. Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease that binds to hepatic LDL receptors and targets them for degradation. PCSK9 inhibitors allow the LDL receptor to be recycled and used to eliminate more low-density lipoprotein- cholesterol from the circulation. IDL = intermediate-density lipoprotein; LDL-R = low-density lipoprotein receptor; MTP = microsomal triglyceride transfer protein; TG = triglyceride.
mainstay of pharmacological therapy due to their ability to lower LDL-C and CHD events. However, despite the introduction of additional agents such as ezetimibe and bile acid binding resins, FH patients are still far from achieving reasonable cholesterol
Advances in pharmacogenetic technology have led to the
to be approved in over a decade. The use of lomitapide and mipomersen as adjunctive therapy in HoFH patients will help them achieve lower lipid levels and improve their cardiovascular the paucity of long-term safety data, we must remain cautiously optimistic as the ultimate acceptance of these agents into clinical practice remains to be seen.
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Del Med J | August 2015 | Vol. 87 | No. 8
