Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia

Raal, Frederick J.; Kallend, David; Ray, Kausik K.; Turner, Traci; Köenig, Wolfgang; Wright, R. Scott; Wijngaard, Peter; Curcio, Danielle; Jaros, Mark; Leiter, Lawrence A.; Kastelein, John J.P.

doi:10.1056/nejmoa1913805

Cited by 542 publications

(474 citation statements)

References 23 publications

Supporting

Mentioning

445

Contrasting

Unclassified

Order By: Relevance

“…The metabolic changes induced by another way of pharmacologic inhibition of PCSK9, i.e., with the small interfering RNA inclisiran, are similar to those observed under treatment with antibodies against PCSK9 (Raal et al, 2020).…”

Section: Consequences Of Therapeutic Inhibition Of Pcsk9mentioning

confidence: 63%

PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

2020

View full text Add to dashboard Cite

In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2–4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of ∼46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available.

show abstract

Section: Consequences Of Therapeutic Inhibition Of Pcsk9mentioning

confidence: 63%

PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

2020

View full text Add to dashboard Cite

show abstract

“…Compared with the placebo group, the Inclisiran group had no serious adverse reactions. In the subsequent phase III clinical study of Inclisiran, compared with placebo, LDL-C in Inclisiran group was significantly reduced, with the efficacy able to last for more than 18 months ( Raal et al, 2020 ; Ray et al, 2020 ). The introduction of PCSK9 inhibitors is a milestone in the treatment of FH, and Inclisiran provides a new lipid-lowering technology.…”

Section: From Diagnosis Methods To Therapy Strategies Of Fh Based On mentioning

confidence: 98%

PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis

2020

View full text Add to dashboard Cite

Autosomal dominant familial hypercholesterolemia (FH) affects approximately 1/250, individuals and potentially leads to elevated blood cholesterol and a significantly increased risk of atherosclerosis. Along with improvements in detection and the increased early diagnosis and treatment, the serious burden of FH on families and society has become increasingly apparent. Since FH is strongly associated with proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), increasing numbers of studies have focused on finding effective diagnostic and therapeutic methods based on PCSK9 . At present, as PCSK9 is one of the main pathogenic FH genes, its contribution to FH deserves more explorative research.

show abstract

“…Recently, the results of the phase 3 ORION-9 trial demonstrated the safety and efficacy of inclisiran in patients with heterozygous FH [41] (Table 1).…”

Section: Administering Inclisiran Every 6 Months Lowers Ldl-c By Apprmentioning

confidence: 99%

Low-density Lipoprotein-Cholesterol Lowering Strategies for Prevention of Atherosclerotic Cardiovascular Disease: Focus on siRNA Treatment Targeting PCSK9 (Inclisiran)

Sinning

Landmesser

2020

Curr Cardiol Rep

View full text Add to dashboard Cite

Purpose of Review The aim of low-density lipoprotein-cholesterol (LDL-C) lowering therapies is to safely achieve a consistent and long-term reduction in exposure of the vasculature to atherogenic lipoproteins in order to reduce the risk of atherosclerotic cardiovascular (CV) disease and the associated CV events, such as myocardial infarctions and ischemic strokes. This review summarizes the concept and clinical development of a novel molecular approach to efficiently lower LDL-C, a synthetic small interfering ribonucleic acid (siRNA)—inclisiran—directed against proprotein convertase subtilisin-kexin type 9 (PCSK9). Recent Findings The understanding of genes regulating atherogenic lipoproteins and their causal role in the development of atherosclerotic CV disease has substantially advanced over the past years. This has opened the possibility for development of molecular therapies targeting these atherogenic lipoproteins, in particular by RNA-targeted treatment approaches. The most advanced clinical development program is the siRNA-treatment targeting PCSK9 (inclisiran), involving more than 4000 patients in clinical studies. Phase 1 and 2 studies have identified the dose of 300 mg inclisiran for efficient LDL-C lowering. Most recently, three phase 3 studies demonstrated that a regimen of inclisiran every 6 months was feasible and reduced LDL-C by approximately 50% in patients at high or very high CV risk or with familial hypercholesterolemia. Adverse events were similar in the inclisiran and the placebo groups, except for more frequent transient injection site reactions with inclisiran than with placebo. Summary siRNA therapy targeting PCSK9 (inclisiran) applied twice a year efficiently reduced LDL-C by approximately 50% and was safe in recent phase 3 studies. The effects of this treatment on CV outcome are currently further assessed in a large ongoing CV outcome trial.

show abstract

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia

Cited by 542 publications

References 23 publications

PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis

Low-density Lipoprotein-Cholesterol Lowering Strategies for Prevention of Atherosclerotic Cardiovascular Disease: Focus on siRNA Treatment Targeting PCSK9 (Inclisiran)

Contact Info

Product

Resources

About