Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).

Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk.

BACKGROUND: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).

On-treatment platelet reactivity through the thromboxane A2 or P2Y12 platelet receptor pathways is not affected by pelacarsen.

BACKGROUND: Pelacarsen decreases plasma levels of lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPL). It was previously reported that pelacarsen does not affect the platelet count. We now report the effect of pelacarsen on on-treatment platelet reactivity. METHODS: Subjects with established cardiovascular disease and screening Lp(a) levels ≥60 mg per deciliter (~ ≥150 nmol/L) were randomized to receive pelacarsen (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or placebo for 6-12 months. Aspirin Reaction Units (ARU) and P2Y12 Reaction Units (PRU) were measured at baseline and the primary analysis timepoint (PAT) at 6 months. RESULTS: Of the 286 subjects randomized, 275 had either an ARU or PRU test, 159 (57.8%) were on aspirin alone and 94 (34.2%) subjects were on dual anti-platelet therapy. As expected, the baseline ARU and PRU were suppressed in subjects on aspirin or on dual anti-platelet therapy, respectively. There were no significant differences in baseline ARU in the aspirin groups or in PRU in the dual anti-platelet groups. At the PAT there were no statistically significant differences in ARU in subjects on aspirin or PRU in subjects on dual anti-platelet therapy among any of the pelacarsen groups compared to the pooled placebo group (p > 0.05 for all comparisons). CONCLUSION: Pelacarsen does not modify on-treatment platelet reactivity through the thromboxane A2 or P2Y12 platelet receptor pathways.

APOC3 inhibition with volanesorsen reduces hepatic steatosis in patients with severe hypertriglyceridemia.

ApoC-III inhibits lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. It is unknown whether targeting apoC-III affects hepatic steatosis in patients with hypertriglyceridemia. We studied the effect of volanesorsen, a potent antisense oligonucleotide targeting APOC3 mRNA, on hepatic fat fraction (HFF) assessed by MRI in patients with severe hypertriglyceridemia (SHTG, triglycerides ≥500 mg/dL), familial partial lipodystrophy (FPL, triglycerides ≥200 mg/dL) and familial chylomicronemia syndrome (FCS, triglycerides ≥750 mg/dL). The data were evaluated individually in COMPASS (SHTG), APPROACH (FCS), and BROADEN (FPL) trials. The baseline absolute HFF were elevated in all three trials and ranged from 6.3-18.1%. In COMPASS, compared to placebo, volanesorsen significantly reduced the absolute HFF by -3.02% (95% CI, (-5.60, -0.60), p = 0.009) (placebo-adjusted % change from baseline -24.2%, p = 0.034) from baseline to 6 months. In APPROACH a non-significant absolute -1.0% (95% CI, -2.9, 0.0, p = 0.13) reduction in HFF was noted from baseline to 12 months (placebo-adjusted % change from baseline -37.1%, p = 0.20). In BROADEN volanesorsen significantly reduced the absolute HFF by -8.34% (95% CI, -13.01, -3.67, p = 0.001) from baseline to 12 months (placebo-adjusted % change from baseline -52.7%, p = 0.004). In all 3 trials individually, a strong inverse correlation was present between the baseline HFF and the change in HFF in the volanesorsen groups, but not in the placebo groups. In conclusion, apoC-III inhibition with volanesorsen has favorable effects in HFF in patients with different etiologies of hypertriglyceridemia.

Efficacy and safety of pelacarsen in lowering Lp(a) in healthy Japanese subjects.

BACKGROUND: Pelacarsen is a liver-targeted antisense oligonucleotide that potently lowers lipoprotein(a) [Lp(a)] levels. Its safety and efficacy in diverse populations has not been extensively studied. OBJECTIVE: To assess the effect of pelacarsen, including monthly dosing of 80 mg, in subjects of Japanese ancestry. METHODS: A randomized double-blind, placebo-controlled, study was performed in 29 healthy Japanese subjects treated with single ascending doses (SAD) of pelacarsen 20, 40 and 80 mg subcutaneously or multiple doses (MD) of pelacarsen 80 mg monthly for 4 doses. The primary objective was to assess the safety and tolerability in healthy Japanese subjects; secondary objectives to assess the pharmacokinetics of pelacarsen; and exploratory objective to determine the effect of pelacarsen on plasma Lp(a) levels. RESULTS: No serious adverse events or clinically relevant abnormalities in any laboratory parameters were noted. In the MD cohort, mean plasma concentrations of pelacarsen peaked at ∼4 hours and declined in a bi-exponential manner thereafter. In the SAD cohorts, the placebo-corrected least-square mean (PCLSM) percent changes in Lp(a) at Day 30 were: -55.4% (p=0.0008), -58.9% (p=0.0003) and -73.7% (p<0.0001) for the 20 mg, 40 mg, and 80 mg pelacarsen-treated groups, respectively. In the MD cohort, the PCLSM at Days 29, 85, 113, 176 and 204 were -84.0% (p=0.0003), -106.2% (p<0.0001), -70.0 (p<0.0001), -80.0% (p=0.0104) and -55.8% (p=0.0707), respectively. CONCLUSIONS: Pelacarsen demonstrates an acceptable safety and tolerability profile and potently lowers plasma levels of Lp(a) in healthy Japanese subjects, including with the 80 mg monthly dose being evaluated in the Lp(a) HORIZON trial.

Assessment of the Effect of Organ Impairment on the Pharmacokinetics of 2'-MOE and Phosphorothioate Modified Antisense Oligonucleotides.

The pharmacokinetics (PK) of 2'-O-methoxyethyl and phosphorothioate antisense oligonucleotides (ASOs), with or without N-acetyl galactosamine conjugation, have been well characterized following subcutaneous or intravenous drug administration. However, the effect of organ impairment on ASO PK, primarily hepatic or renal impairment, has not yet been reported. ASOs distribute extensively to the liver and kidneys, where they are metabolized slowly by endo- and exonucleases, with minimal renal excretion as parent drug (<1%-3%). This short review evaluated the effect of organ impairment on ASO PK using 3 case studies: (1) a phase 1 renal impairment study evaluating a N-acetyl galactosamine-conjugated ASO in healthy study participants and study participants with moderate renal impairment, (2) a phase 2 study evaluating an unconjugated ASO in patients with end-stage renal disease; and (3) a phase 3 study evaluating an unconjugated ASO, which included patients with mild hepatic or renal impairment. Results showed that patients with end-stage renal disease had a mild increase (≈34%) in total plasma exposure, whereas mild or moderate renal impairment showed no effect on plasma PK. The effect of hepatic impairment on ASO PK could not be fully evaluated due to lack of data in moderate and severe hepatic impairment study participants. Nonetheless, available data suggest that mild hepatic impairment had no effect on ASO exposure.

Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia.

BACKGROUND: Olezarsen is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apolipoprotein C-III (apoC-III) and triglyceride-rich lipoproteins (TRLs). OBJECTIVE: To define the effect of olezarsen on NMR-derived lipoprotein particle size and concentration. METHODS: Patients (n=114) with or at risk for atherosclerotic cardiovascular disease and fasting triglycerides ≥200 and <500 mg/dL received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. NMR LipoProfile® analysis was performed in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. RESULTS: A dose-dependent relationship was generally noted with increasing cumulative doses of olezarsen in TRL particle (TRLP), LDL particle (LDL-P) and HDL (HDL-P) particle concentrations. In the 50 mg every 4 weeks dose, compared to placebo, olezarsen resulted in a significant reduction in total TRL-P (51%, P<0.0001) with largest reductions in large-size (68%, P<0.0001) and medium-size (63%, P<0.0001) TRL-P. Total LDL-P concentration was not changed, but large LDL-P increased by 186% (p=0.0034), and small LDL-P decreased by 39% (p=0.0713). Total HDL-P concentration increased by 15% (P=0.0006), driven primarily by a 32% increase in small HDL subspecies (diameters <8.3 nm) (P=0.0008). CONCLUSION: Olezarsen results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDL-P. These findings suggest that apoC-III inhibition improves the overall atherogenic risk profile.

Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol.

BACKGROUND: Laboratory methods that report low-density lipoprotein cholesterol (LDL-C) include both LDL-C and lipoprotein(a) cholesterol [Lp(a)-C] content. OBJECTIVES: The purpose of this study was to assess the effect of pelacarsen on directly measured Lp(a)-C and LDL-C corrected for its Lp(a)-C content. METHODS: The authors evaluated subjects with a history of cardiovascular disease and elevated Lp(a) randomized to 5 groups of cumulative monthly doses of 20-80 mg pelacarsen vs placebo. Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apolipoprotein(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-Ccorr = laboratory-reported LDL-C - direct Lp(a)-C; and 3) LDL-CcorrDahlén = laboratory LDL-C - [Lp(a) mass × 0.30] estimated by the Dahlén formula. RESULTS: The baseline median Lp(a)-C values in the groups ranged from 11.9 to 15.6 mg/dL. Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs -29% to -67%; P = 0.001-<0.0001). Baseline laboratory-reported mean LDL-C ranged from 68.5 to 89.5 mg/dL, whereas LDL-Ccorr ranged from 55 to 74 mg/dL. Pelacarsen resulted in mean percent/absolute changes of -2% to -19%/-0.7 to -8.0 mg/dL (P = 0.95-0.05) in LDL-Ccorr, -7% to -26%/-5.4 to -9.4 mg/dL (P = 0.44-<0.0001) in laboratory-reported LDL-C, and 3.1% to 28.3%/0.1 to 9.5 mg/dL (P = 0.006-0.50) increases in LDL-CcorrDahlén. Total apoB declined by 3%-16% (P = 0.40-<0.0001), but non-Lp(a) apoB was not significantly changed. CONCLUSIONS: Pelacarsen significantly lowers direct Lp(a)-C and has neutral to mild lowering of LDL-Ccorr. In patients with elevated Lp(a), LDL-Ccorr provides a more accurate reflection of changes in LDL-C than either laboratory-reported LDL-C or the Dahlén formula.

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk.

AIMS: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site. CONCLUSION: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. TRIAL REGISTRATION NUMBER: NCT03385239.

Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study.

BACKGROUND: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. METHODS: This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). RESULTS: Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. CONCLUSIONS: Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen.

BACKGROUND AND AIMS: Antisense oligonucleotides (ASOs) targeting LPA to lower lipoprotein(a) [Lp(a]] are in clinical trials. Patients have been recruited according to various Lp(a) thresholds, but the prevalence of LPA genetic variants and their effect on efficacy of these ASOs are not well described. METHODS: We analyzed data from 4 clinical trials of the ASO pelacarsen targeting apolipoprotein(a) that included 455 patients. Common LPA genetic variants rs10455872 and rs3798220, major and minor isoform size, and changes in Lp(a), LDL-C, apoB, OxPL-apoB and OxPL-apo(a) were analyzed according to categories of baseline Lp(a). RESULTS: The prevalence of carrier status for rs10455872 and rs3798220 combined ranged from 25.9% in patients with Lp(a) in the 75 - <125 nmol/L range to 77.1% at Lp(a) ≥375 nmol/L. The prevalence of homozygosity for rs3798220, rs10455872 and for double heterozygosity in category of Lp(a) ≥375 nmol/L was 6.3%, 14.6% and 12.5%, respectively. Isoform size decreased with increasing Lp(a) plasma levels, with 99.3% of patients with Lp(a) ≥175 nmol/L having ≤20 KIV repeats in the major isoform. The mean percent reduction from baseline in Lp(a), OxPL-apoB and OxPL-apo(a) in response to pelacarsen was not affected by the presence of rs10455872 and rs3798220, isoform size or baseline Lp(a) at all doses studied. CONCLUSIONS: In patients randomized to Lp(a) lowering trials, LPA genetic variants are common, but a sizable proportion do not carry common variants associated with elevated Lp(a). In contrast, the major isoform size was almost uniformly ≤20 KIV repeats in patients with Lp(a) ≥175 nmol/L. The Lp(a) and OxPL lowering effects of pelacarsen were independent of both LPA genetic variants and isoform size.

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia.

AIMS: Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis. METHODS AND RESULTS: This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild. CONCLUSION: Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.

Treatment with Volanesorsen, a 2'-O-Methoxyethyl-Modified Antisense Oligonucleotide Targeting APOC3 mRNA, Does Not Affect the QTc Interval in Healthy Volunteers.

The aim of this study was to assess the effect of volanesorsen on the corrected QT (QTc) interval. This thorough QT study enrolled 52 healthy male and female subjects who were randomized at a single site in a four-way crossover study. Subjects were randomly assigned to 1 of 12 treatment sequences and crossed over into four treatment periods over the course of which each subject was to receive a single therapeutic dose of volanesorsen as a 300 mg subcutaneous (SC) injection, a single supratherapeutic dose of volanesorsen as 300 mg intravenous (IV) infusion, a single oral (PO) dose of moxifloxacin (positive control), and placebo dose. The study demonstrated that volanesorsen 300 mg SC and 300 mg IV did not have a clinically relevant effect on ΔΔQTcF exceeding 10 ms. The largest mean effect at any postdose time point was 3.0 ms (90% confidence interval [CI]: 0.8-5.2) after SC dosing and 1.8 ms (90% CI -0.4 to 4.0) after IV dosing. Volanesorsen, at the studied therapeutic and supratherapeutic doses, does not have a clinically meaningful effect on the QTc.

Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS: The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS: APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).

Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder caused by mutations in lipoprotein lipase (LPL) or genes required for LPL functionality and is characterized by hyperchylomicronemia that results in recurrent episodes of acute pancreatitis. Owing to the rarity of FCS, there are few case series describing the phenotypic variability in FCS patients in detail. OBJECTIVE: To provide baseline characteristics in the largest study population to date of patients with FCS. METHODS: We analyzed baseline demographic and clinical characteristics of adult FCS patients in the phase 3 APPROACH study of volanesorsen sodium (antisense inhibitor of apolipoprotein C-III). RESULTS: Sixty-six patients were included in the analysis. Mean (SD) age was 46 (13) years; and mean body mass index was 24.9 (5.7) kg/m2. We identified causal mutations in 79% (52) of patients, with LPL mutations accounting for 62% (41) of cases. Median age at diagnosis was 24 years, 54% were females, and 81% were Caucasian. All patients followed a low-fat diet, 43% received fibrates, 27% fish oils, and 21% statins. Median fasting triglyceride levels (P25, P75) were 1985 (1179, 3047 mg/dL). Overall, 76% of patients reported ≥1 lifetime episode of acute pancreatitis; 23 patients reported a total of 53 pancreatitis events in the 5 years before enrollment. CONCLUSIONS: Our data emphasize the severe hypertriglyceridemia characteristic of FCS patients despite restrictive low-fat diets and frequent use of existing hypolipemic therapies. Acute pancreatitis and recurrent acute pancreatitis are frequent complications of FCS. Diagnosis at an older age suggests likely underdiagnosis and underappreciation of this rare disorder.

The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism.

BACKGROUND: Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety. METHODS AND RESULTS: HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone's negative inotropic effect-see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo (P=0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (P=0.072). Both combinations were well tolerated. CONCLUSIONS: HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Unique identifier: NCT01522651.

Effects of Ranolazine in Patients With Chronic Angina in Patients With and Without Percutaneous Coronary Intervention for Acute Coronary Syndrome: Observations From the MERLIN-TIMI 36 Trial.

BACKGROUND: Ranolazine, a piperazine derivative with anti-ischemic effects, reduces the frequency of angina and improves exercise performance in patients with chronic angina. The effects of ranolazine in patients with established ischemic heart disease and chronic angina undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) is not well described. We hypothesized that ranolazine would reduce ischemic events, regardless of revascularization. METHODS: We examined the 1-year incidence of recurrent cardiovascular (CV) events in the subgroup of patients with prior chronic angina (n = 3565) enrolled in the randomized, double-blind, placebo-controlled Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation ACS (MERLIN)-Thrombolysis In Myocardial Infarction (TIMI) 36 trial who did or did not have a PCI within 30 days of the index event. RESULTS: Ranolazine reduced the risk of recurrent ischemia following admission regardless of whether patients had (hazard ratio [HR], 0.69; 95% confidence interval [CI] 0.51-0.92] or did not have PCI (HR, 0.81; 95% CI, 0.66-0.99; P interaction = 0.39). CV death, myocardial infarction, and recurrent ischemia were similarly lower with ranolazine in the PCI group (HR, 0.71; 95% CI, 0.55-0.91) vs the non-PCI group (HR, 0.91; 95% CI, 0.78-1.06; P interaction = 0.10), with a nominally significant decrease in CV death (HR, 0.39; 95% CI, 0.16-0.93) in the PCI group vs no difference in the non-PCI group (HR, 1.19; 95% CI, 0.89-1.59; P interaction = 0.02). CONCLUSIONS: In patients with chronic angina, ranolazine reduced recurrent ischemic events, regardless of whether patients did or did not receive PCI within 30 days of a non-ST-segment ACS.

Effect of ranolazine on atrial fibrillation in patients with non-ST elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 trial.

AIMS: To determine the effect of ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether ranolazine reduces the long-term incidence of clinical AF after ACS. METHODS AND RESULTS: MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to ranolazine or placebo. Atrial fibrillation episodes detected on continuous electrocardiogram (cECG) monitoring were reviewed in 6351 patients (97% of trial). Atrial fibrillation burden was categorized according to the time in AF: clinically insignificant AF (<0.01% of time), paroxysmal AF (>0.01-98%), or predominantly persistent AF (>98%). Clinical AF events were identified through adverse event reporting for a median 1-year follow-up. Overall, patients assigned to ranolazine had a trend towards fewer episodes of AF [75 (2.4%) vs. 55 (1.7%) patients, P = 0.08] detected on cECG during the first 7 days after randomization. The pattern of new-onset AF differed between ranolazine vs. placebo: clinically insignificant AF (five patients in ranolazine vs. seven in placebo), paroxysmal AF (18 vs. 48 patients), and predominantly chronic AF (28 vs. 20 patients, three-way P < 0.01). Among patients with a paroxysmal AF pattern, the overall burden was lower with ranolazine than with placebo (median 4.4 vs.16.1%, P = 0.015). Over the median 1-year follow-up, fewer patients treated with ranolazine experienced an AF event compared with placebo (2.9 vs. 4.1%, RR 0.71, P = 0.01). CONCLUSION: Ranolazine, an anti-anginal agent with electrophysiological effects, may reduce the frequency of paroxysmal AF in patients with non-ST elevation ACS with a pattern of lower overall AF burden in this group. Ranolazine reduced the overall 1-year incidence of clinical AF events. These atrial-specific anti-arrhythmic properties of ranolazine may be of clinical interest and warrant additional investigation. CLINICAL TRIAL REGISTRATION: NCT00099788.