Lomitapide and Mipomersen

Rader, Daniel J.; Kastelein, John J.P.

doi:10.1161/circulationaha.113.001292

Cited by 231 publications

(121 citation statements)

References 82 publications

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“…This makes their comparison of a short-term moderate 200 mg weekly dose of mipomersen with a microsomal triglyceride transfer protein inhibitor, such as lomitapide, which substantially inhibit the enzyme at doses approved for the treatment of homozygous familial hypercholesterolemia, specious when it comes to potential for developing hepatic steatosis. Despite the elegant animal and short-term human turnover studies reported by ReyesSoffer, the findings are not supported by a considerable body of clinical data and contradict those reported in subjects with hypercholesterolemia, particularly familial hypercholesterolemia (1,3,4 ). It has been well demonstrated even in short-term, 13-week, clinical trials with weekly 200 mg of mipomersen that reduced LDL-C by 22%, that there was a doubling of intrahepatic triglyceride, a measure of hepatic fat content, as assessed with 1H magnetic resonance spectroscopy (1 ).…”

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confidence: 62%

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The Effects of Mipomersen on Inhibiting Hepatic VLDL Apolipoprotein B100 Synthesis and Propensity for Hepatic Steatosis

Raal

Stein

2016

Clinical Chemistry

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Mipomersen is a 20-nucleotide, second-generation, antisense oligonucleotide that inhibits human apolipoprotein B (apo B)-100 3 production by binding to and preventing translation of apo B messenger RNA. As apo B-100 is an essential structural component of VLDL, intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a), decreased hepatic production of apo B by mipomersen should lead to reduced circulating concentrations of all of these atherogenic lipoprotein particles (1 ).However, Reyes-Soffer et al., in a stable isotope study of 17 healthy volunteers without hyperlipidemia and presumably on a restricted fat diet, reported that mipomersen 200 mg weekly for 7 weeks, although reducing VLDL and its apo B and triglyceride content, did not reduce the production rates of VLDL apo B but surprisingly increased its clearance (2 ). The study did, however, find modest reductions in IDL-and LDL apo B-associated production and postulated that these lipoproteins were decreased independently and directly rather than being a consequence of reduced VLDL production. The authors postulated that, due to the partial inhibition of apo B synthesis by mipomersen, compensation occurred by increasing the proportion of newly synthesized apo B directed to VLDL production, which in turn helped maintain hepatic lipid homeostasis (2 ). In addition, there was increased loading of triglyceride onto VLDL apo B, resulting in larger, triglyceride-enriched VLDL particles. The authors concluded that, "Targeting apo B synthesis may lower levels of apo B lipoproteins without necessarily reducing VLDL secretion, thereby lowering the risk of steatosis associated with this therapeutic strategy." They also hypothesized, based on their studies, that apo B inhibition with mipomersen could result in less hepatic steatosis than seen with inhibition of microsomal triglyceride transfer protein, which they reported as being rate limiting to the production of VLDL, with the implication it would be less likely to result in hepatic triglyceride accumulation than lomitapide. However, the studies as performed by suffer from a number of problems that make the results unlikely to be extrapolatable to any differences between these mechanisms regarding hepatic steatosis in clinical practice. First, the study in humans with mipomersen was performed in healthy normolipidemic subjects on presumably restricted fat diet with normal or lower apo B and triglyceride production rates that are not reflective of familial or other forms of hyperlipidemia. The second problem is the duration of treatment of only 7 weeks with mipomersen 200 mg per week, which is less than a third the time required to achieve steady state with any dose of the drug that, without a large loading dose, is reported to be at least 26 weeks for weekly dosing (1 ). A third and perhaps the most significant problem is that the reduction in apo B synthesis with mipomersen is dose related. This makes their comparison of a short-term moderate 200 mg weekly dose of mipomersen with a microsomal triglyceride t...

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confidence: 62%

“…As apo B-100 is an essential structural component of VLDL, intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a), decreased hepatic production of apo B by mipomersen should lead to reduced circulating concentrations of all of these atherogenic lipoprotein particles (1 ).…”

mentioning

confidence: 99%

The Effects of Mipomersen on Inhibiting Hepatic VLDL Apolipoprotein B100 Synthesis and Propensity for Hepatic Steatosis

Raal

Stein

2016

Clinical Chemistry

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“…Mipomersen is an antisense oligonucleotide that reduces the production and secretion of VLDL via inhibition of the mRNA of ApoB as well as serum levels of LDL-C [17]. In trials in HoFH patients and in severe HeFH patients with CHD, mipomersen reduced the LDL-C with 25%-28% from baseline, respectively [18,19].…”

Section: Oligonucleotide Antisense Inhibitorsmentioning

confidence: 99%

“…It initiates the incorporation of lipids, especially triglycerides, into ApoB as a critical step in the assembly of chylomicrons in the enterocytes and VLDL in the hepatocytes [17]. Inhibition of MTP will lead to a reduced secretion of VLDL and chylomicrons, and therefore to reduced plasma levels of LDL-C.…”

Section: Mtp Inhibitorsmentioning

confidence: 99%

Novel pharmacological treatments for children and adolescents with heterozygous familial hypercholesterolemia

Wiegman

Hutten

2017

Expert Review of Clinical Pharmacology

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“…While statins should be the first-line therapy for patients with FH, a significant number of patients are unable to reach their recommended LDL-C target without additional and/or alternative treatments, while others are unable to tolerate statins [2,7]. Excitingly, the US Food and Drug Administration recently approved new therapeutic agents for HoFH, including mipomersen and lomitapide [8]. Mipomersen has also shown great promise for HeFH patients with coronary artery disease and severe hypercholesterolemia and for individuals at high risk for CAD [9].…”

Section: Familial Hypercholesterolemiamentioning

confidence: 99%

The Role of Genetic Counselors for Patients with Familial Hypercholesterolemia

Sturm

2014

Curr Genet Med Rep

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Familial hypercholesterolemia (FH) is the most common inherited cause of premature coronary heart disease and leads to significant morbidity and mortality. Genetic counselors are specialized health care professionals with advanced degrees and training in both medical genetics and psychosocial counseling. FH patients and their families require focused education regarding the heritable nature of their disease, the risk to family members, the necessity of cascade screening, and the availability of genetic testing. Patients and families may also benefit from additional services genetic counselors provide, such as psychosocial support and other resources. All of these services are well-established components of the genetic counseling process. Therefore, genetic counselors can serve as a valuable resource to FH patients, their families, and the multidisciplinary team of clinicians providing care for these patients.

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Lomitapide and Mipomersen

Cited by 231 publications

References 82 publications

The Effects of Mipomersen on Inhibiting Hepatic VLDL Apolipoprotein B100 Synthesis and Propensity for Hepatic Steatosis

The Effects of Mipomersen on Inhibiting Hepatic VLDL Apolipoprotein B100 Synthesis and Propensity for Hepatic Steatosis

Novel pharmacological treatments for children and adolescents with heterozygous familial hypercholesterolemia

The Role of Genetic Counselors for Patients with Familial Hypercholesterolemia

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