Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report ...the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.
Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver.
We conducted a ...randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed.
Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain.
Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEANa-DOSE ClinicalTrials.gov number, NCT04270760.).
Data support lipoprotein(a) (LpLp(a)) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in ...hepatocytes.
The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing.
OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial.
Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated ...patients.
The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition.
A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal.
Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (−1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (−3.6 mm3 vs. −0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (−3.0 ± 0.6 mm3 vs. −2.4 ± 0.6 mm3; p = 0.49), fibrofatty (−5.0 ± 1.0 mm3 vs. −3.0 ± 1.0 mm3; p = 0.49), and necrotic (−0.6 ± 0.5 mm3 vs. −0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = −0.15; p < 0.001).
The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound GLAGOV; NCT01813422)
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Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) ...(lipoproteina) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years interquartile range: 51-66 years). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.
Background:Evolocumab, a fully human monoclonal antibody against PCSK9, significantly reduced low-density lipoprotein-cholesterol (LDL-C) levels in Japanese patients by up to 76% when administered ...with a statin. We evaluated the efficacy and safety of 1 year of evolocumab in a pooled analysis of patients from the 12-week YUKAWA studies who continued into the open-label extension (OLE) OSLER studies.Methods and Results:YUKAWA-1 and YUKAWA-2 were conducted in hypercholesterolemic, high-cardiovascular-risk Japanese patients who were receiving statin therapy. Patients completing these studies were eligible for an OLE study. At OLE entry, patients were re-randomized 2:1 to evolocumab+standard of care (SOC) or SOC alone (OSLER-1: evolocumab 420 mg monthly; OSLER-2: evolocumab 140 mg biweekly or 420 mg monthly). A 1-year analysis was performed on patients enrolled from the YUKAWA studies into OSLER. At parent-study baseline (YUKAWA-1 or YUKAWA-2 patients continuing into OSLER), mean (SD) age was 61 (10) years; 39% were female; mean (SD) baseline LDL-C (on statin) was 119.7 (33.0) mg/dL. Overall rates of adverse events were comparable between evolocumab+SOC and SOC alone. In YUKAWA patients receiving evolocumab+SOC, mean (SE) reductions in LDL-C from parent-study baseline to OLE 1 year were 69.1% (1.2%; OSLER-1) and 65.1% (2.2%; OSLER-2).Conclusions:In a pooled 1-year analysis of Japanese patients in the ongoing OSLER studies, treatment with evolocumab+SOC was well tolerated and resulted in sustained LDL-C reductions at 1 year.
Background
Evolocumab significantly lowers low‐density lipoprotein cholesterol (LDL‐C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously.
Hypothesis
LDL‐C changes are ...comparable among different patient subgroups in a pooled analysis of data from phase 3 trials.
Methods
A total of 3146 patients received ≥1 dose of evolocumab or control in four 12‐week phase 3 studies. Percent change from baseline in LDL‐C for evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested.
Results
In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non‐Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low‐magnitude variations in LDL‐C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each evolocumab dosing regimen or control.
Conclusions
Consistent reductions in LDL‐C were observed in the evolocumab group regardless of demographic and disease characteristics.
Methods GLAGOV compared the effects of the PCSK9 inhibitor, evolocumab, and placebo on plaque progression in statin-treated patients with coronary artery disease. Evolocumab treated patients with ...baseline Lp(a) >11.8 mg/dL were less likely to have diabetes (16.1% vs 25.5%, P=0.02), hypertension (75.4% vs 86.5%, P=0.001), had lower baseline CRP levels (1.3 vs 1.77 mg/L, P=0.02) and higher on-treatment LDL-C levels (33.9 vs 32.6 mg/dL, P=0.02).
Methods GLAGOV compared the effects of treatment for 78 weeks with evolocumab or placebo on progression of coronary atherosclerosis, measured by serial intravascular ultrasonography, in ...statin-treated patients with coronary artery disease. Results Female patients were older (61.7 vs 58.8 years, P<0.001), more likely to have hypertension (89.2 vs 79.5%, P=0.001), two or more risk factors at baseline (77.2 vs 66.4%, P=0.003) and low HDL-C (females <50mg/dL, males <40mg/dL) at baseline (49.6 vs 39.1%, P=0.006).
Primary cardiac tumors are far rarer than tumors metastatic to the heart. Angiosarcoma is the primary cardiac neoplasm most frequently detected; lymphomas constitute only 1% of primary cardiac ...tumors. We present the case of a 55-year-old woman with a recently diagnosed intracardiac mass who was referred to our institution for consideration of urgent orthotopic heart transplantation. Initial images suggested an angiosarcoma; however, a biopsy specimen of the mass was diagnostic for diffuse large B-cell lymphoma. The patient underwent chemotherapy rather than surgery, and she was asymptomatic 34 months later. We use our patient's case to discuss the benefits and limitations of multiple imaging methods in the evaluation of cardiac masses. Certain features revealed by computed tomography, cardiac magnetic resonance, and positron emission tomography can suggest a diagnosis of angiosarcoma rather than lymphoma. Cardiac magnetic resonance and positron emission tomography enable reliable distinction between benign and malignant tumors; however, the characteristics of different malignant tumors can overlap. Despite the great usefulness of multiple imaging methods for timely diagnosis, defining the extent of spread and the hemodynamic impact, and monitoring responses to treatment, we think that biopsy analysis is still warranted in order to obtain a correct histologic diagnosis in cases of suspected malignant cardiac tumors.
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