Helina Kassahun

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial

Importance Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. Objective To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. Design, Setting, and Participants The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Interventions Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. Main Outcomes and Measures The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV). Conclusions and Relevance Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. Trial Registration clinicaltrials.gov Identifier: NCT01813422.

Long-term Low-Density Lipoprotein Cholesterol–Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years From the Open-Label OSLER-1 Extension Study

Importance The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) evaluated the durability of long-term efficacy and safety during long-term therapy with evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9). Objective To determine whether LDL-C level reductions with evolocumab persist across different populations. Secondary objectives included assessment of adverse events, antidrug antibodies, and factors contributing to treatment discontinuation. Design, Setting, and Participants This ongoing, randomized open-label extension trial (OSLER-1) was conducted at 192 sites in 18 countries. A total of 1324 of 1666 patients randomized into 1 of 5 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1255 received 1 or more evolocumab doses. As of August 2016, 812 of 1324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016. Interventions During year 1, patients were randomized to evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received evolocumab, 420 mg, plus SOC. Main Outcomes and Measures Lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of evolocumab. Results At parent study baseline, the mean (SD) age of the population was 57.1 (11.6) years, with 52.9% being women. The median LDL-C level was 133 mg/dL (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% CI, −63% to −60%) vs 2% (95% CI, −5% to −0.2%) with SOC alone (P < .001). At approximately 2, 3, and 4 years of study follow-up, the median LDL-C level was reduced by 59% (95% CI, −60% to −57%), 59% (95% CI, −61% to −58%), and 57% (95% CI, −59% to −55%), respectively, from parent study baseline. For patients receiving statin therapy unchanged from baseline, at week 208, the median LDL-C level reduction was 58%. No neutralizing antibodies to evolocumab were detected. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and, adjusting for duration of evolocumab exposure, 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC). A total of 79% of patients persisted with evolocumab treatment, with a mean exposure duration of 44 months. Conclusions and Relevance In the longest clinical trial exposure to a PCSK9 inhibitor to date, evolocumab produced sustained reductions in LDL-C levels. The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation. Trial Registration clinicaltrials.gov Identifier: NCT01439880

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV)

BACKGROUND Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. AIMS To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. METHODS A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. CONCLUSIONS The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).

Relationship between changes in coronary atherosclerotic plaque burden measured by intravascular ultrasound and cardiovascular disease outcomes: a systematic literature review.

Abstract Objective Evidence from coronary imaging studies suggests an association between increased atherosclerotic plaque burden and cardiovascular disease (CVD) outcomes. A systematic review was performed to evaluate the relationship between coronary atherosclerotic plaque burden changes measured by intravascular ultrasound (IVUS) and CVD outcomes. Research design and methods Rigorous systematic review methodology was used to identify prospective studies of any design assessing the relationship between atherosclerotic plaque volume (percentage or total atheroma volume [PAV or TAV]) changes and CVD outcomes, using multivariable analyses. Main outcome measures CVD outcomes including major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). Results Literature searches from inception to February 2015 retrieved 6958 records after de-duplication. From these four studies (14 papers) were included. One study reported a significantly lower rate of CVD outcomes associated with a greater reduction in PAV (hazard ratio [HR] 0.26, 95% confidence interval [CI] 0.07–0.83). One study reported that large plaque volume was significantly associated with a greater risk of major adverse cardiac events (MACEs) (HR 1.73, 95% CI: 1.02–2.96). Similarly, a third study reported a significant increase in MACE with an increase in baseline PAV (HR 1.51, 95% CI: 1.06–2.51). Only one potentially inadequately powered Japanese study did not find a statistically significant relationship between PAV changes and MACE. Conclusions The current evidence suggests an independent and statistically significant association between increases in coronary atherosclerotic plaque burden measured by IVUS and greater long-term risk of future CVD outcomes. However, this evidence comes from a limited number of studies which mainly focus on Japanese populations and populations after PCI. Further large prospective studies are required to confirm these findings.

Evolocumab: Considerations for the Management of Hyperlipidemia

Purpose of ReviewTo review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.Recent FindingsPCSK9 inhibitors are a class of lipid-lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia. Data from these studies show that evolocumab significantly reduces LDL-C levels. Treatment with evolocumab also significantly improves levels of other lipid parameters (e.g., apolipoproteins A1 and B, lipoprotein(a), non–high-density lipoprotein cholesterol, and triglycerides). Recent results indicate that LDL-C reduction with evolocumab significantly reduces the risk of cardiovascular events and is also associated with atherosclerotic plaque regression. From a safety standpoint, rates of adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between evolocumab and controls in clinical trials, and no increase in AEs was observed when evolocumab was used in combination with statins.SummaryPatients with elevated LDL-C benefit from evolocumab treatment, suggesting that evolocumab could help meet an unmet medical need in high-risk patient populations with atherosclerotic cardiovascular disease and hyperlipidemia that are unable to reduce LDL-C levels sufficiently with statin therapy alone.

One-Year Efficacy and Safety of Evolocumab in Japanese Patients ― A Pooled Analysis From the Open-Label Extension OSLER Studies ―

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.

GREATER LIKELIHOOD OF REGRESSION OF CORONARY ATHEROSCLEROSIS WITH THE PCSK9 INHIBITOR, EVOLOCUMAB, IN PATIENTS WITH HIGHER LP(A) LEVELS

There is genetic and epidemiological evidence demonstrating the association between Lp(a) levels and cardiovascular disease. While evolocumab reduces Lp(a) by 25-30%, the impact of PCSK9 inhibition on plaque at different Lp(a) levels is unknown. GLAGOV compared the effects of the PCSK9 inhibitor,

ELEVATED CRP LEVELS DO NOT ADVERSELY MODULATE THE ABILITY OF EVOLOCUMAB TO REGRESS CORONARY ATHEROSCLEROSIS: INSIGHTS FROM GLAGOV

Achieved CRP levels associate with plaque progression and cardiovascular events in statin-treated patients. It is unknown whether CRP levels modulate the ability of the PCSK9 inhibitor, evolocumab, to regress coronary atherosclerosis. GLAGOV compared the effects of treatment for 78 weeks with

Consistent LDL-C response with evolocumab among patient subgroups in PROFICIO: A pooled analysis of 3146 patients from phase 3 studies

Evolocumab significantly lowers low‐density lipoprotein cholesterol (LDL‐C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously.