Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study.

AIMS/HYPOTHESIS: The study aimed to examine the efficacy of 12 weeks of monthly evolocumab or placebo in lowering LDL-cholesterol (LDL-C) in individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia and on a maximum-tolerated statin of at least moderate intensity. METHODS: For this randomised, placebo-controlled outpatient study, eligible individuals were ≥18 years old with type 2 diabetes, HbA1c <10% (86 mmol/mol), had been on stable pharmacological therapy for diabetes for ≥6 months and were taking a maximum-tolerated statin dose of at least moderate intensity. Lipid eligibility criteria varied by history of clinical cardiovascular disease. Participants were randomised 2:1 to evolocumab 420 mg s.c. or placebo. Randomisation was performed centrally via an interactive web-based or voice recognition system. Allocation was concealed using the centralised randomisation process. Treatment assignment was blinded to the sponsor study team, investigators, site staff and patients throughout the study. Co-primary endpoints were mean percentage change in LDL-C from baseline to week 12 and to the mean of weeks 10 and 12. Additional endpoints included LDL-C <1.81 mmol/l, LDL-C reduction ≥50% and other lipids. Exploratory analyses included percentage changes in fasting and post mixed-meal tolerance test (MMTT) lipoproteins and lipids, glucose metabolism variables and inflammatory biomarkers. RESULTS: In total, 421 individuals were randomised and analysed, having received evolocumab (280 participants) or placebo (141 participants) (mean [SD] age 62 [8] years; 44% women; 77% white). Evolocumab decreased LDL-C by 54.3% (1.4%) at week 12 (vs 1.1% [1.9%] decrease with placebo; p < 0.0001) and by 65.0% (1.3%) at the mean of weeks 10 and 12 (vs 0.8% [1.8%] decrease with placebo; p < 0.0001); it also decreased non-HDL-cholesterol (HDL-C) by 46.9% (1.3%) at week 12 (vs 0.6% [1.8%] decrease with placebo) and by 56.6% (1.2%) at the mean of weeks 10 and 12 (vs 0.1% [1.6%] decrease with placebo). Evolocumab significantly improved levels of other lipids and allowed more participants to reach LDL-C <1.81 mmol/l or a reduction in LDL-C levels ≥50%. After an MMTT (120 min), there were favourable changes (p < 0.05; nominal, post hoc, no multiplicity adjustment) in chylomicron triacylglycerol (triglycerides), chylomicron cholesterol, VLDL-C and LDL-C. Evolocumab had no effect on glycaemic variables and was well tolerated. CONCLUSIONS/INTERPRETATION: In statin-treated individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia, evolocumab significantly reduced LDL-C and non-HDL-C. Favourable changes (p < 0.05) were observed in postprandial levels of chylomicrons, VLDL-C and LDL-C. TRIAL REGISTRATION: ClinicalTrials.gov NCT02739984 FUNDING: This study was funded by Amgen Inc. DATA AVAILABILITY: Qualified researchers may request data from Amgen clinical studies. Complete details are available at www.amgen.com/datasharing .

PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS).

BACKGROUND: Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline. METHODS: We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10 454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests. RESULTS: The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58-2.13) using the CERAD battery and 0.89 (95% CI, 0.61-1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1-9.1) study period ranged between 0.07 (95% CI, -0.06 to 0.20) and -0.07 (95% CI, -0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P>0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96-1.08) and 0.99 (95% CI, 0.95-1.02) for the CERAD and SIS definitions of impairment, respectively. CONCLUSIONS: These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.

Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk).

BACKGROUND: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. METHODS: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. RESULTS: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. CONCLUSIONS: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.

Comparative Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition and Statins on Postprandial Triglyceride-Rich Lipoprotein Metabolism.

OBJECTIVE: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated. APPROACH AND RESULTS: We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load. We evaluated plasma total and incremental area under the curves for triglycerides, apo (apolipoprotein)B-48, and VLDL (very-LDL)-apoB-100. We also examined the kinetics of apoB-48 using intravenous D3-leucine administration, mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently lowered postprandial VLDL-apoB-100 total area under the curves (P<0.001). Atorvastatin, but not evolocumab, reduced fasting plasma apoB-48, apoC-III, and angiopoietin-like 3 concentrations (P<0.01), as well as postprandial triglyceride and apoB-48 total area under the curves (P<0.001) and the incremental area under the curves for plasma triglycerides, apoB-48, and VLDL-apoB-100 (P<0.01). Atorvastatin also independently increased TRL apoB-48 fractional catabolic rate (P<0.001) and reduced the number of apoB-48-containing particles secreted in response to the fat load (P<0.01). In contrast, evolocumab did not significantly alter the kinetics of apoB-48. CONCLUSIONS: In healthy, normolipidemic men, atorvastatin decreased fasting and postprandial apoB-48 concentration by accelerating the catabolism of apoB-48 particles and reducing apoB-48 particle secretion in response to a fat load. Inhibition of PCSK9 with evolocumab had no significant effect on apoB-48 metabolism.

Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics.

Aims: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results: We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P < 0.001 for main effect). As monotherapy, evolocumab significantly decreased the production of Lp(a)-apo(a) (-36%, P < 0.001). In contrast, in combination with atorvastatin, evolocumab significantly increased the fractional catabolism of Lp(a)-apo(a) (+59%, P < 0.001), but had no effect on the production of Lp(a)-apo(a). There was a highly significant association between the changes in the fractional catabolism of Lp(a)-apo(a) and Lp(a)-apoB in the substudy of 16 subjects (r = 0.966, P < 0.001). Conclusions: Evolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance. Clinical Trial Registration Information: NCT02189837.

Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies.

BACKGROUND: Evolocumab, a fully human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), markedly reduces low-density lipoprotein cholesterol across diverse patient populations. The objective of this study was to assess the safety and tolerability of evolocumab in a pooled safety analysis from phase 2 or 3 randomized and placebo or comparator-controlled trials (integrated parent trials) and the first year of open-label extension (OLE) trials that included a standard-of-care control group. METHODS: This analysis included adverse event (AE) data from 6026 patients in 12 phase 2 and 3 parent trials, with a median exposure of 2.8 months, and, of those patients, from 4465 patients who continued with a median follow-up of 11.1 months in 2 OLE trials. AEs were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs, laboratory assessments, and AEs of interest were evaluated. RESULTS: Overall AE rates were similar between evolocumab and control in the parent trials (51.1% versus 49.6%) and in year 1 of OLE trials (70.0% versus 66.0%), as were those for serious AEs. Elevations of serum transaminases, bilirubin, and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive AEs were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups versus 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing antievolocumab antibodies were detected. CONCLUSIONS: Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in OLE trials for 1 year supports a favorable benefit-risk profile for evolocumab.

Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism.

BACKGROUND: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. METHODS: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. RESULTS: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance. CONCLUSIONS: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.

BACKGROUND: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). METHODS: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. FINDINGS: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. INTERPRETATION: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. FUNDING: Amgen.

Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.

BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data. METHODS: In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. RESULTS: As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003). CONCLUSIONS: During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.).

Evolocumab: Considerations for the Management of Hyperlipidemia.

PURPOSE OF REVIEW: To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. RECENT FINDINGS: PCSK9 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. Patients 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.

Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies.

PURPOSE: Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients. METHODS: Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC. RESULTS: A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97-5.02 mmol/L (192-194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events. CONCLUSION: Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.

Population pharmacokinetics and exposure-response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia.

Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure-response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7-420 mg at various frequencies, either intravenously or subcutaneously. Evolocumab area under concentration-time curve from 8 to 12 weeks (AUCwk8-12) was simulated for individuals using the popPK model and was used to predict the LDL-C response in relation to AUCwk8-12. Evolocumab was eliminated through nonspecific (linear) and target-mediated (nonlinear) clearance. PopPK parameters and associated variabilities of evolocumab were similar to those of other monoclonal antibodies. The exposure-response model predicted a maximal 66% reduction in LDL-C from baseline to the mean of weeks 10 and 12 for doses of evolocumab 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. After inclusion of statistically significant covariates in an uncertainty-based simulation, LDL-C reduction from baseline at the mean of weeks 10 and 12 was predicted to be within 74% to 126% of the reference patient for all simulated patient groups. Evolocumab had nonlinear pharmacokinetics. The range of responses based on intrinsic and extrinsic factors was not predicted to be sufficiently different from the reference patient to warrant evolocumab dose adjustment.

Effect of evolocumab on cholesterol synthesis and absorption.

The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-cholesterol (LDL-C), but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an evolocumab clinical trial. At 2 weeks, changes in ß-sitosterol/total cholesterol (TC) from baseline were 4% for placebo, 10% for evolocumab 140 mg (nonsignificant vs. placebo), and 26% for evolocumab 420 mg (P < 0.001 vs. placebo). Changes in campesterol/TC at week 2, relative to baseline between placebo and evolocumab, were all nonsignificant. Evolocumab had a modest effect on markers of cholesterol synthesis. At 2 weeks, changes in desmosterol/TC were 1% for placebo, 7% for evolocumab 140 mg (nonsignificant vs. placebo), and 15% for evolocumab 420 mg (P < 0.01 vs. placebo). Changes from baseline in lathosterol/TC at week 2 between placebo and evolocumab were nonsignificant. These results suggest that evolocumab has a modest effect on cholesterol synthesis and absorption despite significant LDL-C lowering.

PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role.

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.

PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc.

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).

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.

IMPORTANCE: Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984424.

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.

Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial.

BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. METHODS AND RESULTS: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. CONCLUSION: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT01439880.