Fig. 7.1
Mechanism of action of statin and mipomersen. (a) Mipomersen specifically binds the apoB mRNA sequence to provide a substrate for RNase H, which hydrolyses the apoB mRNA strand and inhibits apoB synthesis. (b) Statins competitively inhibit HMG-CoA reductase, a rate-limiting enzyme in hepatic cholesterol synthesis, the reduced intracellular cholesterol content induces LDL receptor production and increases LDL catabolism. On the other hand, Mipomersen inhibitors apoB synthesis and reduces the production of atherogenic apoB-containing lipoproteins by the liver (Adapted from [55])
ApoB-100 antisense was originally tested in mice models of hypercholesterolaemia. In LDLr-deficient mice, this antisense therapy lowered LDL cholesterol, consistent with its mechanism of action, and ameliorated atherosclerosis without causing hepatic steatosis [35, 36]. The first human study by Kastelein et al. (2005) showed a maximum of 35 % reduction of LDL cholesterol concentration and 50 % reduction in apoB levels after 4 weeks of multiple-dosing regime in patients with mild dyslipidaemia [37]. However, the majority (72 %) of patients experienced erythema at the injection site. Similarly, another phase I monotherapy trial demonstrated up to 61 % reductions in LDL cholesterol and apoB levels with 300 mg/week doses of mipomersen in subjects with mild-to-moderate hypercholesterolaemia, with injection site reactions experienced at least once in each subject [38]; 18 % of subjects showed consecutive transaminase elevations greater than three times the upper limit of normal. The majority who had increased hepatic transaminase were receiving the 400 mg/week regimen.
Mipomersen has now been evaluated by several phase II and III trials assessing its efficacy, safety, tolerability and utility in patients with severe hypercholesterolaemia as monotherapy (in statin-intolerant subjects) and when combined with statin therapy. These trials continue to demonstrate significant reductions in LDL cholesterol and apoB levels [18, 19, 39–44]. A summary of the trials reported to date is shown in Table 7.1.
Table 7.1
Summary of clinical trials with mipomersen in humans
Author | Phase | Patient population | Co-existing medication | n | Duration | % reduction in LDL-Ca | % reduction in apoBa | % reduction in Lp(a)a |
|---|---|---|---|---|---|---|---|---|
Kastelein (2006) et al. [37] | I | Healthy controls | None | 36 | 4 weeks | 35 | 50 | – |
Akdim et al. (2011) [38] | I | Mild-to-moderate HC | None | 50 | 13 weeks | 45 | 46 | 42 |
Akdim et al. (2010) [39] | II | HC | Statins | 74 | 13 weeks | 36 | 36 | – |
Akdim et al. |(2010) [40] | II | heFH | Statins | 44 | 6 weeks | 21 | 23 | 17 |
Visser et al. (2010) [41] | II | heFH | Statin ± ezetimibe | 21 | 13 weeks | 22 | 20 | 20 |
Visser et al. (2012) [42] | II | HC, statin-intolerance | Ezetimibe, bile acid sequestrant, fibrate, niacin | 33 | 26 weeks | 47 | 46 | 27 |
Raal et al. (2010) [18] | III | hoFH | Statins, ezetimibe, bile acid sequestrant, niacin | 51 | 26 weeks | 25 | 27 | 31 |
McGowan et al. (2012) [43] | III | Severe HC | Statin ± ezetimibe | 58 | 26 weeks | 36 | 36 | 33 |
Stein et al. (2012) [19] | III | heFH with CAD | Stains, ezetimibe, bile acid sequestrant, fibrate, niacin | 124 | 26 weeks | 28 | 26 | 21 |
Thomas et al. (2013) [44] | III | HC, high-risk for CAD | Statin ± other | 157 | 26 weeks | 37 | 38 | 24 |
Santos et al. (2013) [45] | Open-label | heFH and hoFH | Statins, ezetimibe, bile acid sequestrant, niacin | 141 | Up to 104 weeks | 28 | 31 | 17 |
Mipomersen for Familial Hypercholesterolaemia
Five mipomersen trials have focused on FH. Akdim et al. (2010) investigated the efficacy of mipomersen (dose range 50–300 mg/week) over a period of 6 weeks in 44 patients with heterozygous FH. Significant reductions in LDL cholesterol were found with the 200 and 300 mg dosing regimens, with maximal reductions 21 and 33 % from baseline, respectively. Extended treatment to 13 weeks with weekly doses of 300 mg mipomersen resulted in 37 % reduction in both LDL cholesterol and apoB [40]. Similarly, Visser et al. (2010) demonstrated, in 21 heterozygous FH patients with a 13-weekly mipomesen regime at a dose of 200 mg/week, a reduction of 22 and 20 % for LDL cholesterol and apoB, respectively [41]. In a randomised trial of 124 heterozygous FH with coronary artery disease, Stein et al. (2012) showed a 28 and 26 % reduction in LDL cholesterol and apoB concentrations, respectively, after 26 weeks of weekly 200 mg mipomersen injections [19]. A trend towards an increase in intrahepatic triglyceride content was found in both studies [19, 41].
In a phase III study involving 51 homozygous FH all on maximally tolerated conventional therapy, mipomersen (200 mg/week) decreased LDL cholesterol by 25 %, and apoB was similarly reduced by 27 % after 26 weeks [18]. In October 2012, the US Food and Drug Administration (FDA) approved mipomersen, adjunct to lipid-lowering therapy and diet, for the treatment of homozygous FH under a Risk Evaluation and Mitigation Strategies (REMS) program. However, Mipomersen was not approved for use in Europe by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) (see detailed reasons under the subsection on adverse reactions).
Finally, the most recent mipomersen report in FH is a 2 year interim analysis of open-label extension trial. The efficacy and safety was similar to previous randomised placebo-controlled trials. 200 mg weekly injections of mipomersen for up to 104 weeks demonstrated 28 % LDL cholesterol and 31 % apoB reductions. In a subgroup of patients who had undergone liver magnetic resonance imaging, there was also an incremental increase in liver fat in the first 6–12 months. However, regression towards baseline with continued mipomersen beyond 1 year denotes metabolic adaptation [45].
Mipomersen for Severe Hypercholesterolaemia
Four trials have studied patients with primary hypercholesterolaemia that was not specifically ascribed to FH; two were carried out on a background of statins and the others as monotherapy. The first of these trials reported that mipomersen (5 weeks, 7 doses of 100–400 mg/week) in hypercholesterolaemic subjects on stable statin therapy was associated with a 21–52 and 19–54 % reduction (across the dose ranges) in plasma LDL cholesterol and apoB concentrations, respectively [39]. In the same study, a subgroup of patients was assigned to 15 doses of 200 mg/week mipomersen over 13 weeks. A 36 % reduction in both LDL cholesterol and apoB levels was shown [39]. In another study, Visser et al. (2012) found that weekly 200 mg administration of mipomersen to high-risk statin-intolerant patients reduced plasma LDL cholesterol and apoB by 47 and 46 %, respectively, after 26 weeks [42]. Liver fat content was significantly increased, with hepatic steatosis confirmed in two subjects who had undergone liver biopsy [42].
McGowan et al. (2012) demonstrated that in severe hypercholesterolaemic patients on maximally tolerated lipid-lowering therapy, 200 mg/week of mipomersen (over 26 weeks) reduced LDL cholesterol and apoB by 36 % [43]. The most recent study by Thomas et al. (2013) randomised 157 high-risk patients with severe hypercholesterolaemia (LDL cholesterol ≥2.6 mmol/l on a maximally tolerated statin dose) to mipomersen and placebo; randomisation was stratified so that a minimum of 40 % of patients in each group would have type 2 diabetes. After 26 weeks of 200 mg weekly mipomersen, LDL cholesterol and apoB levels were lowered by 36 and 37 %, respectively [44]. Elevations in transaminases and liver fat occurred in some patients, but like other studies, these levels returned towards baseline after cessation of treatment.
Mipomersen and Lipoprotein(a)
A recent study in subjects with varying baseline levels of plasma Lp(a) (34.0–56.3 mg/day) from four phase III trials examined the effect of mipomersen on Lp(a). Mipomersen was shown to consistently and significantly lower Lp(a) levels by a median of 26.4 % across patient groups, despite varying baseline Lp(a) levels [46]. The mechanism of Lp(a) lowering by mipomersen remains to be demonstrated but is likely to involve the reduced production of Lp(a) [47]. The cardiovascular benefit of treating elevated Lp(a) is unknown. Clinical trial evidence is needed to determine whether Lp(a) lowering affects cardiovascular outcomes, although this will require a specific Lp(a)-lowering therapy, such as Lp(a) apheresis or apo(a) antisense therapy [47]. Other new agents such as PCSK9 inhibitors, lomitapide and anacetrapib (a CETP inhibitor) also have Lp(a)-lowering effects, with reductions of 31 % (in heterozygous FH) [48], 19 % (in homozygous FH) [49] and 32 % (in heterozygous FH) [50], respectively. The mechanisms of action of these agents on Lp(a) metabolism is also unclear.
Mipomersen: Adverse Reactions, Contraindications, Economics
Mipomesen is not metabolised by enzymes such as CYP450, and pharmacokinetic studies reveal no clinically relevant interactions with the clearance of statins and ezetimibe [51]. However, injection-site reactions occur in the majority of cases, and every patient experiences at least one injection-site reaction [52]. Other side effects associated with mipomersen include mild-to-moderate influenza-like symptoms and hepatic transaminase elevation (alanine transaminase and aspartate transaminase). Table 7.2 summarises these events from four phase III trials.
Raal et al. (2010) [18] (hoFH) | McGowan et al. (2012) [43] (severe HC) | Stein et al. (2012) [19] (heFH + CAD) | Thomas et al. (2013) [44] (high-risk HC) | All four trials | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
Mipomersen | Placebo | Mipomersen | Placebo | Mipomersen | Placebo | Mipomersen | Placebo | Mipomersen | Placebo | |
n | 34 | 17 | 39 | 19 | 83 | 41 | 105 | 52 | 261 | 129 |
Adverse effects, n (%) | ||||||||||
All events | 30 (88.2) | 13 (76.5) | 39 (100.0) | 16 (84.2) | 83 (100.0) | 38 (92.7) | 97 (92.4) | 42 (80.8) | 249 (95.4) | 109 (84.5) |
Injection-site reaction | 26 (76.5) | 4 (23.5) | 35 (89.7) | 6 (31.6) | 77 (92.8) | 17 (78.1) | 82 (78.1) | 16 (30.8) | 220 (84.3) | 43 (33.3) |
Influenza-like symptoms | 14 (41.2) | 4 (23.5) | 18 (46.2) | 4 (21.1) | 41 (49.4) | 13 (34.3) | 36 (34.3) | 11 (21.2) | 109 (41.8) | 32 (24.8) |
Laboratory abnormalities, n (%) | ||||||||||
ALT ≥ ULN and <2 × ULN | 12 (35.3) | 7 (41.2) | 9 (23.1) | 6 (31.6) | 34 (41.0) | 14 (34.1) | – | – | 55 (21.1) | 27 (20.9) |
ALT ≥2 × and <3 × ULN | 5 (14.7) | 2 (11.8) | 9 (23.1) | 1 (5.3) | 19 (22.9) | 2 (4.9) | – | – | 33 (12.6) | 5 (3.9) |
ALT ≥3 × and <10 × ULN | 4 (11.8) | 0 (0.0) | 11 (28.2) | 0 (0.0) | 11 (13.3) | 1 (2.4)
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