Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.

BACKGROUND: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS: The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).

Effect of Alirocumab on Mortality After Acute Coronary Syndromes.

BACKGROUND: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. METHODS: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. RESULTS: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). CONCLUSIONS: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.

Lipid-lowering efficacy and safety of alirocumab in patients with or without diabetes: A sub-analysis of ODYSSEY COMBO II.

AIM: This sub-analysis of the ODYSSEY COMBO II study compared the effects of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in high cardiovascular risk patients with or without diabetes mellitus (DM) receiving maximally tolerated statin therapy. METHODS: COMBO II was a 104-week, double-blind study (n = 720) enrolling patients with documented atherosclerotic cardiovascular disease (ASCVD) and baseline LDL-C ≥70 mg/dL (1.8 mmol/L), and patients without documented ASCVD at high cardiovascular risk with LDL-C ≥100 mg/dL (2.6 mmol/L). Patients receiving maximally tolerated statin therapy were randomized (2:1) to alirocumab 75 mg every 2 weeks (Q2W; 1 mL subcutaneous injection) or oral ezetimibe 10 mg daily. Alirocumab dose was increased to 150 mg Q2W (also 1 mL) at Week 12 if Week 8 LDL-C was ≥70 mg/dL. RESULTS: History of DM was reported in 31% (n = 148) of patients on alirocumab and 32% (n = 77) of patients on ezetimibe. At Week 24, alirocumab consistently reduced LDL-C from baseline in patients with (-49.1%) or without DM (-51.2%) to a significantly greater extent than ezetimibe (-18.4% and -21.8%, respectively). Occurrence of treatment-emergent adverse events was similar between groups. Efficacy results at 104 weeks were similar to those at 24 weeks. CONCLUSIONS: Over a 104-week double-blind study period, alirocumab provided consistently greater LDL-C reductions than ezetimibe, with similar LDL-C results in patients with or without DM. Safety of alirocumab was similar regardless of baseline DM status.

Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses.

BACKGROUND: Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). METHODS: Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W. RESULTS: Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. CONCLUSIONS: Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production.

Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial.

BACKGROUND: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. OBJECTIVES: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. METHODS: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. RESULTS: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. CONCLUSIONS: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.

Efficacy and Safety of Alirocumab Versus Ezetimibe Over 2 Years (from ODYSSEY COMBO II).

The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to substantially reduce low-density lipoprotein cholesterol (LDL-C). Demonstrating whether efficacy and safety are maintained over a long duration of exposure is vital for clinical decision-making. The COMBO II trial compared the efficacy and safety of alirocumab versus ezetimibe over 2 years. A prespecified first analysis was reported at 52 weeks. Here we report the final end-of-study data (on-treatment) and evaluate post hoc the safety profile with longer versus shorter duration of alirocumab exposure. Patients (n = 720) on maximally tolerated statin dose were treated with alirocumab (75/150 mg every 2 weeks) or ezetimibe (10 mg/day). Overall mean adherence for both treatment groups during the first and second year was >97%. At 2 years, LDL-C was reduced by 49% (alirocumab) versus 17% (ezetimibe; p <0.0001), and LDL-C <70 mg/dl was achieved by 73% of alirocumab-treated versus 40% of ezetimibe-treated patients. Overall safety was similar in both treatment groups at 2 years and during the first versus the second year. Local injection-site reactions were reported by 2.5% (alirocumab) versus 0.8% (ezetimibe) during the first year, and 0.2% versus 0.5% during the second year, indicating early occurrence during prolonged alirocumab exposure. Two consecutive calculated LDL-C values <25 mg/dl were observed in 28% of alirocumab-treated patients (vs 0.4% with ezetimibe). Persistent anti-drug antibody responses were observed in 1.3% (6 of 454) of alirocumab-treated versus 0.4% (1 of 231) of ezetimibe-treated patients. Neutralizing antibodies (that inhibit binding in vitro) were observed in 1.5% (7 of 454) of alirocumab-treated patients (0 with ezetimibe), mostly at isolated time points. Alirocumab sustained substantial LDL-C reductions and was well tolerated up to 2 years in the COMBO II trial.

Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study.

BACKGROUND: The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone. METHODS AND RESULTS: Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events. CONCLUSIONS: Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879.