Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension

Santos, Raúl D.; Duell, P. Barton; East, Cara; Guyton, John R.; Moriarty, Patrick M.; Chin, Wai; Mittleman, Robert S.

doi:10.1093/eurheartj/eht549

Cited by 118 publications

(74 citation statements)

References 25 publications

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“…Despite targeting the biogenesis of TRL, these therapies have major therapeutic effects in lowering LDL rather than TRL levels and therefore are not ideal agents for the treatment of the atherogenic dyslipidemia complex, although they could be considered for the treatment of very severe cases of genetic HTG not responding to other therapies (106,107). These therapies are currently approved in some countries for the treatment of homozygous familial hypercholesterolemia.…”

Section: Microsomal Triglyceride Transfer Protein Inhibitors and Apobmentioning

confidence: 99%

“…The apoB antisense drug (mipomersen) is administered by subcutaneous injection, and injection site reactions and flu symptoms frequently develop in treated patients. Both mipomersen and the oral microsomal triglyceride transfer protein inhibitor (lomitapide) can also cause hepatotoxicity (106,107). These therapies are currently reserved for the treatment of a very rare life-threatening genetic condition.…”

Section: Microsomal Triglyceride Transfer Protein Inhibitors and Apobmentioning

confidence: 99%

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Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

et al. 2016

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Notwithstanding the effectiveness of lowering LDL cholesterol, residual CVD risk remains in high-risk populations, including patients with diabetes, likely contributed to by non-LDL lipid abnormalities. In this Perspectives in Diabetes article, we emphasize that changing demographics and lifestyles over the past few decades have resulted in an epidemic of the "atherogenic dyslipidemia complex," the main features of which include hypertriglyceridemia, low HDL cholesterol levels, qualitative changes in LDL particles, accumulation of remnant lipoproteins, and postprandial hyperlipidemia. We briefly review the underlying pathophysiology of this form of dyslipidemia, in particular its association with insulin resistance, obesity, and type 2 diabetes, and the marked atherogenicity of this condition. We explain the failure of existing classes of therapeutic agents such as fibrates, niacin, and cholesteryl ester transfer protein inhibitors that are known to modify components of the atherogenic dyslipidemia complex. Finally, we discuss targeted repurposing of existing therapies and review promising new therapeutic strategies to modify the atherogenic dyslipidemia complex. We postulate that targeting the central abnormality of the atherogenic dyslipidemia complex, the elevation of triglyceriderich lipoprotein particles, represents a new frontier in CVD prevention and is likely to prove the most effective strategy in correcting most aspects of the atherogenic dyslipidemia complex, thereby preventing CVD events.

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Section: Microsomal Triglyceride Transfer Protein Inhibitors and Apobmentioning

confidence: 99%

Section: Microsomal Triglyceride Transfer Protein Inhibitors and Apobmentioning

confidence: 99%

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

et al. 2016

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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 ).…”

mentioning

confidence: 63%

“…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 ).…”

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 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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“…показали ста-бильное уменьшение концентрации ХС-ЛНП на 28% начиная от 26 нед. до окончания наблюдения [9], преимущественно воздействуя на наиболее атероген-ные подфракции мелких плотных липопротеидов низкой плотности (ЛНП) [10]. Окончательные резуль-таты оценки эффективности мипомерсена у 104 больных, получавших терапию более 12 мес.…”

Section: препараты на основе антисмысловых олигонуклеотидов (асо)unclassified

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

2018

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Development of innovational biotechnological medications based on humanized or completely human monoclonal antibodies or antisense oligonucleotides has opened a novel epoque in lipid disorders treatment. High efficacy of such biological drugs influencing the main chains of lipid metabolism (apoprotein B100, apoprotein (a), apoprotein CIII, proprotein-convertase subtilisin-kexin type 9, antipoetin like protein 3) does open a perspective for correction of severe and statin-resistant forms of dyslipidemias, with a possibility to achieve almost complete remission of the disease. However, the evidence of safety of antisense oligonucleotides drugs demands for broader investigation. Such drugs might be used in patients with orphan diseases or serious lipid disorders, not having alternative treatment. Vice versa, the drugs based on the human monoclonal antibodies thank to evidence are started to be in clinical use at the moment.

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Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension

Cited by 118 publications

References 25 publications

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

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

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

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