Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.

Addressing dyslipidemic risk beyond LDL-cholesterol

The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the 2020 European Society of Cardiology (ESC) Congress—The Digital Experience. The studies reviewed include clinical trials on novel RNA interference-based lipid-lowering therapies AKCEA-APOCIII-LRx and vupanorsen (AKCEA-ANGPTL3-LRx); the EVAPORATE trial assessing the effects of icosapent ethyl on coronary plaque volume progression; the LoDoCo2 trial evaluating the efficacy of low-dose colchicine in cardiovascular disease risk reduction among patients with chronic coronary artery disease; as well as the EMPEROR-Reduced trial evaluating cardiovascular and renal outcomes with empagliflozin in patients with heart failure and reduced ejection fraction. In addition, we review the BPLTTC analysis on blood pressure treatment across blood pressure levels and CVD status and discuss findings from the BRACE CORONA study that examined continuing versus suspending angiotensin-converting enzyme inhibitor or angiotensin receptor blockers in patients on these antihypertensive medications who were hospitalized with COVID-19 infection. The studies presented at the 2020 digital ESC Congress highlight the continuing advancements in the field of CVD prevention.

/pdf/highlights-from-studies-in-cardiovascular-disease-prevention-4wvk4o3vt3.pdf

Highlights from Studies in Cardiovascular Disease Prevention Presented at the Digital 2020 European Society of Cardiology Congress: Prevention Is Alive and Well

While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their un...

N-Acetyl Galactosamine Targeting: Paving the Way for Clinical Application of Nucleotide Medicines in Cardiovascular Diseases.

Therapeutic RNA-silencing oligonucleotides in metabolic diseases

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often ＞400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.

https://www.jstage.jst.go.jp/article/jat/29/8/29_RV17065/_pdf

Advancements in the Treatment of Homozygous Familial Hypercholesterolemia

\n \n \n Elevated LDL-C and triglyceride rich lipoproteins (TRLs) are independent risk factors for cardiovascular disease (CVD). Genetic deficiency of angiopoietin-like protein 3 (ANGPTL3) is associated with reduced circulating levels of LDL-C, triglycerides (TGs), VLDL-C, HDL-C and reduced CVD risk, with no described adverse phenotype. ARO-ANG3 is a RNA interference drug designed to silence expression of ANGPTL3. Single doses of ARO-ANG3 have been shown to reduce ANGPTL3, TGs, VLDL-C and LDL-C in healthy volunteers (HVs, AHA 2019). We report the effects of multiple doses of ARO-ANG3 in HVs with a focus on the duration of action.\n \n \n \n ARO-ANG3 was administered subcutaneously to HVs on days 1 and 29 at doses of 100, 200 or 300 mg (n=4 per group). Measured parameters included ANGPTL3, LDL-C, TGs, VLDL-C and HDL-C. Follow up is ongoing.\n \n \n \n All HVs have received both doses and follow-up is currently through week 16 (12 weeks after second dose). Mean nadir for ANGPTL3 levels occurred 2 weeks after the second dose (−83–93%) with minimal change for 200 and 300 mg but 16% recovery for 100 mg at week 16. Mean TGs and VLDL-C reached nadir earlier (3 wks, −61–65%) without apparent dose response and minimal change for any dose at wk 16. LDL-C nadir occurred 4–6 wks after the second dose (−45–54%), again with minimal evidence for dose response or change through wk 16. HDL-C was reduced 14–37% at wk 16. ARO-ANG3 was well tolerated without serious or severe adverse events or dropouts related to drug. The most common adverse events have been headache and upper respiratory infections.\n \n \n \n Genetic deficiency of ANGPTL3 is a cause of familial combined hypolipemia and is associated with a decreased risk of CVD. Using RNAi to selectively suppress ANGPTL3 production reproduces these genetic effects with a duration of at least 12 weeks following a second dose and with good tolerability over 16 wks. ANGPTL3 inhibition results in lowering of LDL-C and TRLs which may confer protection against CVD in patients with atherogenic mixed dyslipidemia.\n \n \n \n \n Type of funding source: Private company. Main funding source(s): Arrowhead Pharmaceuticals\n

RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia

\n \n \n Individuals with triglycerides (TGs) ≥1,000 mg/dL (11.1 mmol/L) are at increased risk of acute pancreatitis. Genetic studies indicate that individuals with apolipoprotein C-3 (APOC3) loss-of-function mutations have low TGs, reduced cardiovascular risk and no observed adverse phenotype. RNA interference (RNAi) with ARO-APOC3 has shown deep and durable knockdown (KD) of APOC3 after single doses in healthy volunteers (HVs, presented at AHA 2019) with good tolerability. We report here initial results using multiple doses of ARO-APOC3 to silence APOC3 expression in HVs.\n \n \n \n ARO-APOC3 was administered subcutaneously to HVs on days 1 and 29 at doses of 10, 25 or 50 mg (n=4 per group). Measured parameters included plasma concentrations of APOC3, LDL-C, TGs, VLDL-C and HDL-C.\n \n \n \n All HVs have received both doses and follow-up for most parameters is available through week (wk) 14 (10 wks after second dose) for the 10 and 25 mg doses and through wk 10 for 50 mg. Mean nadir for APOC3 levels occurred at wk 3 for 10 mg (−73%) and remained similar at wk 10 (−66%), at wk 6 for 25 mg (−90%) with no change at wk 10 and at wk 2 for 50 mg (−94%) unchanged at wk 8. TGs fell faster in the 50 mg group (wk 1: 10 mg −41%; 25 mg −47%; 50 mg −72%). By wk 6 the 25 and 50 mg results were similar (−68% and −74%, respectively) and remained similar through wk 14. 10 mg was less active with a nadir of −56% and mean reductions between 42% and 56% post-nadir. VLDL-C values mirrored TGs. LDL-C reductions were more modest and did not manifest a dose response. Mean nadirs (−23–26%) occurred 4–6 wks after the first dose, again with minimal change through 10–14 wks of follow-up. Consistent with genetic studies, HDL-C increased to a maximum at approximately wk 8 (10 mg +42%, 25 mg +48%, 50 mg +84%). ARO-APOC3 was well tolerated without serious or severe adverse events or dropouts related to drug. The most common adverse events were mild injection site AEs and headache.\n \n \n \n Genetic deficiency of APOC3 is associated with substantial reductions in TGs, VLDL-C and increases in HDL-C without an adverse phenotype. Using RNAi to selectively suppress APOC3 production mimics these lipid and lipoprotein effects, with a duration of at least 10 weeks following a second dose and with good tolerability over 16 wks using doses ranging from 10 to 50 mg. Investigation of optimal dosing regimen is ongoing, especially with respect to dosing interval. This therapeutic approach has potential for treating patients with chylomicronemia at risk of pancreatitis.\n \n \n \n \n Type of funding source: Private company. Main funding source(s): Arrowhead Pharmaceuticals\n

RNA interference targeting apolipoprotein C-III with ARO-APOC3 in healthy volunteers mimics lipid and lipoprotein findings seen in subjects with inherited apolipoprotein C-III deficiency

J San Martin

Papers

RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia

RNA interference targeting apolipoprotein C-III with ARO-APOC3 in healthy volunteers mimics lipid and lipoprotein findings seen in subjects with inherited apolipoprotein C-III deficiency