Inclisiran, a novel RNA interference agent, has the potential to significantly reduce low-density lipoprotein (LDL) cholesterol with two or three injections yearly, according to research presented during Tuesday’s Late Breaking Clinical Trials session.
The Inclisiran Inhibits PCSK9 Synthesis by RNA Interference: Planned Interim Analysis of a Multi-center Randomized Controlled Dose-finding (ORION) Trial was one of five studies presented during the session.
Inclisiran shows a 50 percent reduction in LDL cholesterol with one dose and a reduction of 55 to 60 percent with two doses, said ORION lead author Kausik Ray, MD, MPhil, from Imperial College London in the United Kingdom. Inclisiran is a PCSK9 inhibitor with a four- to six-month duration of effect.
“The efficacy, safety and dosing profile we see here is likely to produce lasting reductions in LDL cholesterol,” Ray said. “Inclisiran has the potential to improve adherence and very favorably impact cardiovascular outcomes.”
Antibody inhibition of PCSK9 can significantly reduce LDL cholesterol, but requires injections every two to four weeks. The administrative and financial burden invites next-generation agents that are easier to administer, Ray said.
ORION researchers enrolled 501 patents into two study arms and 497 completed the study. The single-dose arm compared 200 mg, 300 mg and 500 mg doses of inclisiran to placebo. The two-dose arm compared two 100 mg, 200 mg and 300 mg doses of inclisiran to placebo.
The primary endpoint was the change in LDL cholesterol at 180 days. Secondary endpoints included LDL cholesterol at 90 days, PCSK9 levels, safety and tolerability. The data presented Tuesday came from a planned, 90-day interim analysis.
Treatment emergent adverse events were similar across all groups, Ray reported. The safety profile was very good. Nearly 6 percent of patients in the drug arms reported myalgia, but reports were not dose-related.
One dose of inclisiran lowered LDL cholesterol by 50 percent with levels gradually rising to a roughly 45 percent reduction at 150 days, Ray reported. Adding a second dose at day 90 pushed LDL cholesterol 60 percent below baseline. There was no significant difference in effect between the 300 mg and 500 mg doses.
A second study, Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV), is the first trial to show regression in coronary plaque volume by intravascular ultrasound (IVUS), said lead author Steve Nissen, MD, of the Cleveland Clinic in Ohio.
The global trial compared statin monotherapy with statins plus evolocumab. A total of 846 patients completed the trial out of 968 who were originally randomized. Patients were treated for 18 months.
The trial showed surprisingly low LDL cholesterol levels — 29 mg/dL across the entire cohort and 15 mg/dL in a subgroup of patients whose baseline LDL cholesterol was less than 70 mg/dL, Nissen reported. LDL cholesterol reductions were 59.8 percent for the statin-plus-evolocumab cohort and 58.3 percent for the low-baseline subgroup.
Atheroma volume declined by 5.8 mm3, or 1 percent, a clinically significant difference, Nissen said. In the statin-only arm, 47.3 percent of patients showed regression in atheroma volume compared to 64.3 percent regression in the statin-plus-evolocumab arm.
“We have never seen atheroma regression on this scale in any prior study,” Nissen said. “Safety looks very good, albeit this group is too small to call results definitive. We have clear evidence that going to lower levels of cholesterol is better.”
A trial testing the safety and tolerability of CSL112, a reconstituted, infusible, plasma-derived human ApoA-I, found a significant increase in cholesterol efflux in patients after acute myocardial infarction.
CSL112 is human ApoA-I, the primary functional component of high-density lipoprotein (HDL) that supports the rapid removal of cholesterol from the macrophages present in arterial plaque. Cholesterol efflux is an independent predictor of cardiovascular risk and the first step in the transport of excess cholesterol by HDL to the liver for removal from the body.
The ApoA-I Event Reduction in Ischemic Syndromes I (AEGIS-I) trial compared low-dose and high-dose CSL112 to placebo in patients who had a spontaneous type 1myo. myocardial infarction within the prior seven days. A total of 1,244 patients were followed for 112 days for clinically significant changes in hepatic and renal function. Cardiovascular events and efflux parameters were secondary endpoints.
Neither of the doses of CSL112 were inferior to placebo for renal or hepatic changes and adverse events were similar across the three groups, reported lead author C. Michael Gibson, MD, from Beth Israel Deaconess Medical Center in Boston. The high-dose group showed a numerical advantage in time to first cardiovascular event, but the difference was not statistically significant.
“This material can cause plaques to de-lipidate and we believe it may have an effect on cardiac outcomes,” Gibson said. “We were grossly underpowered for outcomes (in this study), but we have a very strong basis to proceed to an adequately powered phase 3 trial.”
IONIS-ANGPTL3-LRx, an antisense inhibitor to angiopoietin-like protein 3 [ANGPTL3], reduces plasma ANGPTL3 and lipids in healthy volunteers with elevated triglycerides, according to lead study author Sotirios Tsimikas, MD, from the University of California, San Diego in La Jolla and Ionis Pharmaceuticals.
Using an antisense agent to block the translation of the ANGPTL3 protein is a novel approach to lipid control.
Preclinical data show that ANGPTL3 significantly reduces plasma cholesterol as well as plasma and liver triglycerides in mouse models, Tsimikas reported. The agent can also induce significant reduction in the progression of atherosclerosis.
The proof-of-concept trial had two arms — a single ascending dose arm using 20 mg, 40 mg or 80 mg of IONIS-ANGPTL3-LRx, and a multiple ascending dose arm using 10 mg, 20 mg, 40mg or 60 mg of IONIS-ANGPTL3-LRx for six weekly doses. Volunteers had elevated triglycerides but were otherwise healthy.
The agent reduced plasma levels of ANGPTL3 by up to 83 percent, with similar reductions in triglycerides (66 percent), apoC-III (68 percent), LDL cholesterol (35 percent), total cholesterol (36 percent), HDL cholesterol (25 percent) and non-HDL-cholesterol (40 percent).
“This was a very clean compound, with no injection site reactions, no flu-like symptoms and no dropouts,” Tsimikas said. “And there was a significant reduction in all atherogenic lipids. We think this will be a promising agent for development.”
In the final results of the MILANO-PILOT study, researchers found no signal for therapeutic activity for an HDL mimetic containing ApoA-IMilano and the sponsor elected to stop development of the trial agent, MDCO-216.
The pilot study, Effect of Infusion of ApoA-IMilano HDL Mimetic on Coronary Atherosclerosis in Acute Coronary Syndrome Patients, compared statin therapy to statins plus weekly MDCO-216 dosing over six weeks in 113 patients. The trial was designed to detect a signal for the regression of coronary atherosclerosis, said lead author Stephen Nicholls, MD, PhD, from South Australia Health and Medical Research Institute in Adelaide, Australia.
The primary endpoint was percent atheroma volume and there was no significant difference between the two arms.
“Most of the patients showed improvement in atheroma volume,” Nichols said. “This demonstrates the efficacy of current guideline-based treatment and sets a very high bar for any future therapies.”