Dataset Information

Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

ABSTRACT:

Importance

Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.

Objective

To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.

Design, setting, and participants

Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017.

Interventions

One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo.

Main outcomes and measures

Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year.

Results

At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year.

Conclusions and relevance

Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing.

Trial registration

ClinicalTrials.gov identifier: NCT02597127.

SUBMITTER: Ray KK

PROVIDER: S-EPMC6763983 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

Ray Kausik K KK Stoekenbroek Robert M RM Kallend David D Nishikido Toshiyuki T Leiter Lawrence A LA Landmesser Ulf U Wright R Scott RS Wijngaard Peter L J PLJ Kastelein John J P JJP

JAMA cardiology 20191101 11

<h4>Importance</h4>Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.<h4>Objective</h4>To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.<h4>Design, setting, and participants</h4>Prespecified analysis of a randomized, double-blind, placebo-controlled multic ...[more]

PMID: 31553410

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Project description:AimsData describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials.Methods and resultsFollowing completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified.ConclusionIn the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile.Trial registration numberClinicalTrials.gov identifier: NCT03814187.

Project description:BackgroundTo determine the association between triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) for identifying subjects at risk of incident prediabetes and type 2 diabetes mellitus (T2DM).MethodsIn 5064 subjects (men = 2247) aged ≥ 20 years, using Cox proportional hazards regression analyses, the associations of TG/HDL-C with incident prediabetes and T2DM were examined among normoglycemic men and women. Furthermore, the association of this lipid ratio with incident T2DM was also assessed among prediabetic subjects (n = 1414). The multivariable analyses were adjusted for age, body mass index, waist-to-height ratio, wrist circumference, systolic blood pressure, family history of T2DM, education level, history of cardiovascular diseases, and fasting plasma glucose (FPG).ResultsDuring a median follow-up of 11.2 years, 2140 new cases of prediabetes (men = 1070) and 360 incident T2DM (men = 152) were identified among normoglycemic individuals. In the prediabetic population, 574 new cases of T2DM (men = 252) were developed. Among the whole population, compared to the first quartile (reference), higher quartiles of TG/HDL-C were significantly associated with higher risks of incident prediabetes and T2DM among normoglycemic individuals and incident T2DM in the prediabetic population (all P for trend < 0.001). The corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for the fourth quartiles were 1.37(1.20-1.58), 1.92(1.34-2.75), and 1.57(1.22-2.01), respectively. The sex-stratified analyses demonstrated similar significant associations in both sexes; however, TG/HDL-C lost its association with incident T2DM among prediabetic men. Among the normoglycemic population, 1 unit increase in TG/HDL-C was significantly associated with incident prediabetes and T2DM [1.02(1.00-1.03) and 1.06(1.03-1.08), respectively]. The corresponding value for incident T2DM in prediabetic individuals was 1.01(1.00-1.03). In a subgroup population having insulin data (n = 2897), the associations between TG/HDL-C and incident prediabetes and T2DM among normoglycemic individuals generally persisted even after replacing FPG with an index of insulin resistance (IR), i.e., homeostasis model assessment of IR (HOMA-IR) in the adjusted model.ConclusionsIn conclusion, in the normoglycemic population, the increasing value of TG/HDL-C was unfavorably associated with incident prediabetes and T2DM, especially among women. Similarly, TG/HDL-C was associated with incident T2DM in prediabetic individuals. Generally, we found that the correlation between TG/HDL-C and different states of dysglycemia is independent of HOMA-IR.

Project description:BackgroundInclisiran is a novel, cholesterol-lowering therapy, with a long duration of effect, administered every 6 months (subcutaneously by a healthcare professional). In the ORION-10 trial in US patients with atherosclerotic cardiovascular disease (ASCVD) in addition to maximum tolerated statins, with or without ezetimibe, inclisiran demonstrated statistically significant reductions in low-density lipoprotein cholesterol (LDL-C) of up to 51%. This is the first peer-reviewed publication to investigate the price at which inclisiran is cost effective in the US.ObjectiveThe aim of this study was to determine the maximum price at which inclisiran is cost effective in addition to standard of care, in US patients with ASCVD, versus standard of care alone, at different willingness-to-pay thresholds.Design, setting and participantsA lifetime Markov model from the US health system perspective, including 15 health states, was used to evaluate the cost effectiveness of inclisiran. The following states were separated by time from a previous cardiovascular event (0-1 years, 1-2 years, 2+ years ['stable']): initial, unstable angina, myocardial infarction, and stroke. Additional states included revascularization and death (cardiovascular or non-cardiovascular causes). Baseline risk of cardivoascular events were from US database sources or published literature. Reductions in LDL-C from inclisiran were from the ORION-10 trial. LDL-C reduction was used to adjust baseline risk of cardiovascular events, based on established relationships between 1 mmol/L reduction in LDL-C and decreases in cardiovascular events, from the Cholesterol Treatment Trialists studies. The population included adults with a history of ASCVD, and LDL-C ≥ 70 mg/dL, despite maximum tolerated doses of statin therapy.InterventionsInclisiran as an adjunct to standard of care, compared with standard of care alone.Main outcomes and measuresThe threshold price of inclisiran.ResultsInclisiran as an adjunct to standard of care resulted in threshold annual inclisiran prices of $6383, $9973, and $13,563 at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per quality-adjusted life-year, respectively. Probabilistic sensitivity analysis showed that at a threshold of $100,000 per QALY, inclisiran had a 100% probability of being cost effective, with an annual price below $9000. At the publicly available price of $3250 per dose, inclisiran was found to have an incremental cost-effectiveness ratio just above the $50,000 per QALY threshold, of $51,686.Conclusions and relevanceThis study identified the price at which inclisiran is cost effective for the US health system, at generally accepted willingness-to-pay thresholds.

Project description:AimsPatients often require combination therapies to achieve LDL cholesterol (LDL-C) targets for the primary prevention of atherosclerotic cardiovascular disease. This study investigates the effect of inclisiran, a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 production, in primary prevention patients with elevated LDL-C despite statins.Methods and resultsThis pre-specified analysis of the placebo-controlled, randomized ORION-11 trial included 203 individuals at risk of, but without prior, cardiovascular events and LDL-C ≥2.6 mmol/L, despite maximally tolerated statins. Inclisiran 284 mg or placebo was administered on Days 1, 90, and thereafter every 6 months up to 540 days. Co-primary endpoints were percentage LDL-C change from baseline to Day 510 and time-adjusted change from baseline after Day 90 and up to Day 540. Key secondary endpoints included percentage and absolute changes in atherogenic lipoproteins. Safety was assessed over 540 days. The mean baseline (SD) LDL-C was 3.6 (1.5) mmol/L. At Day 510, the placebo-corrected LDL-C change with inclisiran was -43.7% [95% confidence interval (CI): -52.8 to -34.6] with a corresponding time-adjusted change of -41.0% (95% CI: -47.8 to -34.2); (P < 0.0001). The placebo-corrected absolute change in LDL-C at Day 510 with inclisiran was -1.5 mmol/L (95% CI: -1.8 to -1.2), with a respective time-adjusted change of -1.3 mmol/L (95% CI: -1.6 to -1.1). Inclisiran significantly lowered non-HDL cholesterol and apolipoprotein B (apoB) at Day 510 vs. placebo (P < 0.0001 for both), with a greater likelihood of attaining lipoprotein and apoB goals, and was well-tolerated except for mainly mild, treatment-emergent adverse events at the injection site.ConclusionInclisiran was generally well-tolerated in primary prevention patients with elevated LDL-C, who derived significant reductions in atherogenic lipoprotein levels with twice-yearly maintenance dosing.

Dataset Information

Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

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