Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

Santos, Raúl D.

doi:10.1161/atvbaha.117.310675

Cited by 13 publications

(14 citation statements)

References 19 publications

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“…Long-term data from TAUSSIG suggests a mean response rate of evolocumab in FH of 21.2% [24]. The issues with variability of response to PCSK9 inhibitors in HoFH indicate a need to carefully select therapies based on available genetic profiling [25]. Expert opinion underscores the limitations of PCSK9 inhibitors in HoFH and suggests that they may not have the broad applicability required to reduce the burden of LA, certainly for HoFH patients with receptornegative mutations [26].…”

Section: Standards Of Carementioning

confidence: 99%

Lomitapide–a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia

Stefanutti

2020

Curr Atheroscler Rep

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Purpose of Review Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by high levels of Low density lipoprotein cholesterol (LDL-C); overt, early-onset atherosclerotic cardiovascular disease (ASCVD); and premature cardiovascular events and mortality. Lomitapide is a first-in-class microsomal triglyceride transfer protein inhibitor for the treatment of HoFH. This review provides an update on data emerging from real-world studies of lomitapide following on from its pivotal phase 3 clinical trial in HoFH. Recent Findings Recent registry data have confirmed that HoFH is characterized by delayed diagnosis, with many patients not receiving effective therapy until they are approaching the age when major adverse cardiovascular events may occur. Data from case series of varying sizes, and from a 163-patient registry of HoFH patients receiving lomitapide, have demonstrated that lomitapide doses are lower and adverse events less severe than in the phase 3 study. Lomitapide enables many patients to reach European Atherosclerosis Society LDL-C targets. Some patients are able to reduce frequency of lipoprotein apheresis or, in some cases, stop the procedure altogether-unless there is significant elevation of lipoprotein (a). Modelling analyses based on historical and clinical trial data indicate that lomitapide has the potential to improve cardiovascular outcomes and survival in HoFH. Summary Real-world clinical experience with lomitapide has shown the drug to be effective with manageable, less marked adverse events than in formal clinical studies. Event modelling data suggest a survival benefit with lomitapide in HoFH.

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Section: Standards Of Carementioning

confidence: 99%

Lomitapide–a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia

Stefanutti

2020

Curr Atheroscler Rep

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“…[16][17][18] Furthermore, LDLR expression varies considerably in patients with HoFH, even in those with identical LDLR sequence variations, and marked interindividual variability in response to LDL-C-lowering therapies has been observed in these patients treated with anti-PCSK9 monoclonal antibodies. 17,[19][20][21][22] This variability in the response to LDL-C-lowering therapies remains unexplained; however, residual LDLR expression in patients with HoFH is suggested to be an important contributor. 19,23 In this study, there was substantial variability in the LDL-C-lowering response to inclisiran treatment, possibly because of the different genotype subgroups with varying treatment effects; the reduction in LDL-C level was of greater magnitude in patients with higher residual LDLR function.…”

Section: Discussionmentioning

confidence: 99%

Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial

Raal,

Durst,

et al. 2024

Circulation

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BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. Phase 2 of ORION (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C–lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was −1.68% (95% CI, −29.19% to 25.83%; P =0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was −60.6% with inclisiran treatment ( P <0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non−high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03851705.

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“…LDL-C-lowering therapy is categorized as LDLR dependent, that is, improving direct LDL clearance by upregulation of the LDLR, or LDLR independent, when the reduction in LDL-C is driven by either increased LDLR-independent clearance or decreased production of LDL and its precursors (Figure). 6,[12][13][14] The efficacy of statins, ezetimibe, and PCSK9 inhibitors depends on residual LDLR function and may be limited in patients with HoFH. On the contrary, the microsomal transfer protein inhibitor lomitapide and evinacumab act totally independently of the LDLR and are more consistently effective in lowering LDL-C in these patients independently of their residual LDLR activity.…”

Section: Articles See P 343 and P 354mentioning

confidence: 99%

“…Baseline mean±SD LDL-C was 315.3±134.0 mg/dL overall but higher in those randomized to placebo (356.7±122.4 mg/dL versus 294.0±136.3 mg/dL). It is important to note that null/null LDLR genotypes that would hamper response to PCSK9 inhibition 6 were more frequent in those randomized to inclisiran (27% versus 15.8%). There was overall no difference (−1.68%; P =0.90) in LDL-C levels compared with placebo at day 150 despite a 60.6% average sustained reduction in free PCSK9 plasma concentrations with inclisiran.…”

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confidence: 99%

LDL-C–Lowering Therapies for Adults and Children With Homozygous Familial Hypercholesterolemia: Challenges and Successes

Santos,

Cuchel

2024

Circulation

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Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

Cited by 13 publications

References 19 publications

Lomitapide–a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia

Lomitapide–a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia

Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial

LDL-C–Lowering Therapies for Adults and Children With Homozygous Familial Hypercholesterolemia: Challenges and Successes

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