New agents, targets becoming part of lipid management

By Fred Gebhart

High-dose statins, ezetimibe and PCSK9 inhibition are not the final word in lowering lipids. During a Late-Breaking Science session last month, investigators revealed new findings and approaches to manage lipids:

  • Icosapent ethyl slowed atherosclerotic plaque progression.
  • Twice-yearly inclisiran safely reduced LDL-C by half.
  • A novel RNAi agent reduced serum triglycerides.
  • Another RNAi agent lowers serum triglycerides, VLDL-C, HDL-C and LDL-C.
  • Treating LDL-C to <70 mg/dL improved secondary prevention after stroke.

EVAPORATE

Interim results of the randomized, double-blind trial of icosapent ethyl  versus placebo in statin-treated patients with elevated triglycerides identified a mechanism by which icosapent ethyl may reduce cardiovascular events.

At nine months, patients in the treatment arm showed significant improvement in four secondary outcomes: slowing total plaque progression by 42% (p=0.0004); non-calcified plaque by 19% (p=0.0001); fibrous plaque by 57% (p=0.011); and calcified plaque by 89% (p<0.001). Fibrofatty plaque showed a nonsignificant increase (p=0.650).

Progression of low attenuation plaque, the primary endpoint, was 74% versus 94% (p=0.4692) and not statistically significant.

The REDUCE-IT trial reported a positive effect for icosapent ethyl added to statin therapy to reduce initial and total cardiovascular events but did not fully investigate the mechanism, said Matthew Budoff, MD, professor of medicine at the University of California in Los Angeles and endowed chair of preventive cardiology at the Lundquist Institute.

EVAPORATE randomized 80 patients with coronary atherosclerosis on statin therapy with persistent high triglycerides (135-499 mg/dL) and LDL-cholesterol (40 and 115 mg/dL). Patients took either 4 grams icosapent ethyl daily or placebo. All had multidetector computed tomography at baseline, nine months and will have another at 18 months.

“We undertook EVAPORATE to see if there was a reduction in the rate of plaque progression, an anti-atherosclerotic effect, with icosapent ethyl,” Budoff said. “We saw reductions in four of five measures and met four of five endpoints in this interim analysis.”

Final 18-month results will be reported later.

ORION-9

Inclisiran, a small interfering RNA that reduces LDL-C by blocking hepatic production of PCSK9, showed a 50% reduction in LDL-C at 17 months in patients with heterozygous familial hypercholesterolemia (HeFH) with no safety signals.

Results suggest the potential for twice-yearly treatment with inclisiran for elevated LDL-C, said Frederick J. Raal, MMED, PhD, director of carbohydrate and lipid metabolism research and professor and head of endocrinology and metabolism at the University of the Witwatersrand in Johannesburg, South Africa.

The 18-month trial compared 300 mg inclisiran versus placebo at day one, day 90 and every six months in 482 patients with HeFH. Patients’ baseline LDL-C was over 150 mg/dL. Most patients (over 90%) were on statins, about 80% on high-intensity statins, and more than half on statin plus ezetimibe.

Patients in the treatment arm compared to placebo showed a 45% observed time-averaged reduction in LDL-C from day 90 to day 540.

“Although the genetic confirmation of HeFH is of interest, especially for screening family members, one treats the phenotype and elevated LDL-C, and not the genotype,” Raal said. “And because the treatment effect is maintained over six months, only two injections per year are required to assure a potent and durable reduction in LDL-C.”

AROAPOC3100

The first of two RNA interference (RNAi) trials successfully mimicked the effects of a genetic variant that significantly lowers serum triglycerides and reduces the risk of cardiovascular events without producing any evident adverse effects.

A single dose of ARO-APOC3 resulted in a dose-dependent mean maximum reduction in plasma triglycerides up to 64% (p=0.0001) and up to 68% in VLDL-C (p<0.0001). The reductions were stable out to 16 weeks, suggesting a three-month dosing interval, said Christie Ballantyne, MD, J.S. Abercrombie Chair in Atherosclerosis and Lipoprotein Research at Baylor College of Medicine in Houston, Texas, and chief of cardiology and cardiovascular research.

ARO-APOC3 silences the APOC3 gene coding for apolipoprotein C-III, a component of triglyceride-rich lipoproteins in the liver, said Ballantyne, who is also director of the Center for Cardiovascular Disease Prevention at Houston Methodist DeBakey Heart and Vascular Center.

People with an APOC3 loss-of-function mutation have extremely low plasma triglycerides and corresponding low cardiovascular disease risk with no known deleterious effects.

In this phase 1 trial, healthy volunteers with triglycerides >80 mg/dL at baseline received a single subcutaneous dose of placebo or ARO-APOC3 of 10, 25, 50 or 100 mg. All were followed for at least four months to assess safety, pharmacokinetics and changes in circulating APOC3, VLDL-C, LDL-C, HDL-C and triglycerides.

A single dose as low as 10 mg reduced circulating APOC3 by 72%. The dose-dependent mean HDL-C increased from the baseline of 30%  to 69% (p<0.0001) with a 100 mg dose.

“We saw a deep and durable response even at the 10 mg and 25 mg doses sustained out to four months,” Ballantyne said. “Being a therapy with very long duration of action is of particular benefit to people with hypertriglyceridemia and cardiovascular disorders.”

AROANG31001

The similar phase 1/2A trial of ARO-ANG3 in healthy volunteers showed mean maximum dose-dependent reductions from baseline in plasma triglycerides up to 66% (p=0.0002) and 65% for VLLDL-C (p<0.0001).

There were also mean maximum reductions in LDL-C (up to 30%, p=0.0004) and in HDL-C (up to 26%, p<0.0001). The durability of response supports quarterly or less frequent dosing, said Gerald Watts, DSc, MBBS, PhD, Winthrop Professor at the University of Western Australia School of Medicine and Pharmacology in Perth.

ARO-ANG3 targets angiopoietin-like protein 3 (ANGPTL3) in the liver, a key regulator of lipid and lipoprotein metabolism with multiple potential modes of action, Watts said. Loss-of-function mutations in ANGPTL3 lead to low LDL-C, VLDL-C, HDL-C and triglycerides. People with this mutation have reduced risk of cardiovascular events with no known adverse phenotype. The agent is an attempt to recapitulate the natural effects of this loss-of-function mutation.

Twenty-four healthy volunteers with elevated lipids (TG>100 mg/dL, LDL-C >70 mg/dL) received single subcutaneous doses of placebo or investigational agent ARO-ANG3 of 35, 100, 200 or 300 mg. Sixteen received placebo. All were followed for at least four months to evaluate safety, harmacokinetics and changes in serum triglycerides and lipids.

“ANGPTL3 results in a sustained reduction in ANGPTL3 messenger RNA and protein silencing,” Watts said. “This is a new mechanism for potential addressing residual risk of CVD in patients with dyslipidemias.”

Multidose studies in patients with NAFLD, hyperlipidemia on statins, familial hypercholesterolemia and severe hypertriglyceridemia are under way, he said.

Treat Stroke to Target

The first trial of treating LDL-C to a specific target in stroke patients showed a reduction in cardiovascular events.

Treating stroke patients with atherosclerotic disease to LDL-C less than 70 mg/dL showed a 22% relative risk reduction in the primary endpoint of ischemic stroke or undetermined stroke, MI, urgent coronary or carotid revascularization or death versus treating to a target of 100 mg/dL.

Treating to target is a familiar approach for many cardiovascular risk factors, including blood pressure and body mass index. Treating LDL-C to target in stroke patients has never been tried.

“We can treat LDL-C to less than 70 mg/dL after stroke to reduce the risk of subsequent cardiovascular events,” said Pierre Amarenco, MD, professor and chair of neurology at Paris University in France. “And we do it with no significant increase in intracranial hemorrhage and no increase in newly diagnosed diabetes.”

The multicenter trial was based on a post-hoc analysis of SPARCL, published in 2006. In the SPARCL trial, stroke patients who achieved an LDL cholesterol level of less than 70 mg/dL had a 28% risk reduction for subsequent major coronary and vascular events.

SPARCL prompted guidelines from the AHA and the European Stroke Organization calling for “intensive” statin therapy to lower lipid levels following a transient ischemic event or ischemic stroke of atherosclerotic origin, Amarenco said. Neither guideline established an LDL-C target.

Treat Stroke to Target randomized 2,873 patients in France and Korea following ischemic stroke or TIA with evidence of atherosclerosis to intensive statin with or without ezetimibe therapy with a target of either less than 70 mg/dL or 100 mg/dL. The primary endpoint was a composite of stroke, MI, unstable angina or TIA with revascularization, and vascular death. The trial was halted early due to lack of funding, limiting median follow-up to 3.5 years.

“A Comparison of Two LDL Cholesterol Targets After Ischemic Stroke” was published simultaneously in the New England Journal of Medicine.

 

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