Efficacy and Safety of Alirocumab as Add‐on Therapy in High–Cardiovascular‐Risk Patients With Hypercholesterolemia Not Adequately Controlled With Atorvastatin (20 or 40 mg) or Rosuvastatin (10 or 20 mg): Design and Rationale of the ODYSSEY OPTIONS Studies

Abstract The phase 3 ODYSSEY OPTIONS studies (OPTIONS I, NCT01730040; OPTIONS II, NCT01730053) are multicenter, multinational, randomized, double‐blind, active‐comparator, 24‐week studies evaluating the efficacy and safety of alirocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, as add‐on therapy in ∼ 650 high‐cardiovascular (CV)‐risk patients whose low‐density lipoprotein cholesterol (LDL‐C) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV‐risk category, high and very high CV risk, respectively, with atorvastatin (20–40 mg/d) or rosuvastatin (10–20 mg/d). Patients are randomized to receive alirocumab 75 mg via a single, subcutaneous, 1‐mL injection by prefilled pen every 2 weeks (Q2W) as add‐on therapy to atorvastatin (20–40 mg) or rosuvastatin (10–20 mg); or to receive ezetimibe 10 mg/d as add‐on therapy to statin; or to receive statin up‐titration; or to switch from atorvastatin to rosuvastatin (OPTIONS I only). At week 12, based on week 8 LDL‐C levels, the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL‐C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk, respectively. The primary efficacy endpoint in both studies is difference in percent change in calculated LDL‐C from baseline to week 24 in the alirocumab vs control arms. The studies may provide guidance to inform clinical decision‐making when patients with CV risk require additional lipid‐lowering therapy to further reduce LDL‐C levels. The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL‐C reduction required to achieve the desired LDL‐C level.


Introduction
Statins are first-line therapy for reducing atherosclerotic cardiovascular disease (ASCVD) risk. 1 Several international guidelines recommend high-risk and very high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL and <70 mg/dL, respectively. 2 -4 However, many patients fail to reach expected or recommended LDL-C levels on statin therapy. For example, a 2012 cross-sectional survey reported that approximately twothirds of high-risk patients on statin monotherapy for >90 days did not achieve LDL-C levels <100 mg/dL, and only an estimated quarter of these high-risk patients had LDL-C levels <70 mg/dL. 5 Surveys from other countries show similar results. 6 -9 A European study found that of dyslipidemic patients receiving lipid-lowering drugs, fewer than half achieved LDL-C levels <100 mg/dL. 6 In addition, studies have shown that approximately 80% of patients with heterozygous familial hypercholesterolemia (heFH) do not achieve LDL-C levels <100 mg/dL from a statin. 10,11 In clinical practice, patients are typically started on a statin of moderate intensity, where the daily dose is expected to lower LDL-C levels by approximately 30% to <50%. 12,13 However, the recent 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommended high-intensity statin therapy that lowers LDL-C by ≥50% for higherrisk patients, such as those with clinical ASCVD, diabetes mellitus (with an estimated 10-year ASCVD risk ≥7.5%), and for LDL-C ≥190 mg/dL. 1 If patients fail to reach target LDL-C levels or achieve the expected therapeutic response on their initial statin therapy, the treating clinician currently has the options of increasing the statin dose or switching to a more effective LDL-Clowering statin; and for those unable to tolerate highintensity statins, nonstatin therapy may be added to further lower LDL-C (most commonly ezetimibe). 1 Given the degree to which hypercholesterolemia remains poorly controlled, even with statin therapy, high-CV-risk patients may benefit from more intensive cholesterol-lowering therapy options. 1,5,14 Alirocumab (formerly REGN727/SAR236553; Sanofi-Regeneron) is a fully human monoclonal antibody currently in phase 3 development for LDL-C lowering. In phase 2 trials in patients receiving concomitant statin or statin + ezetimibe therapy (NCT01288443, NCT01266876, and NCT01288469), alirocumab significantly reduced mean LDL-C levels by up to 72.4% and also reduced levels of apolipoprotein B, total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a), and triglycerides (TG), and moderately increased HDL-C and apolipoprotein A-1 levels. 15 -17 The most common treatment-emergent adverse event (TEAE; defined as an adverse event (AE) occurring in the time period from first study treatment dosing to 70 days following the last study treatment dosing) in phase 2 trials was injection-site reaction, which was generally of mild intensity and short duration. 15 -17 The OPTIONS I and II studies (NCT01730040 and NCT01730053, respectively) will compare the lipid-lowering efficacy and safety of alirocumab with various therapeutic choices in patients at high CV risk on atorvastatin 20 mg or 40 mg daily or rosuvastatin 10 mg or 20 mg daily and who had LDL-C levels above prespecified levels of ≥70 mg/dL or ≥100 mg/dL. The OPTIONS studies are part of the 14study ODYSSEY alirocumab phase 3 program that includes more than 23 500 patients in >2000 centers globally; this also comprises a large CV outcomes trial evaluating the long-term impact of alirocumab and lower levels of LDL-C on the occurrence of CV events in 18 000 patients after a recent (<52 weeks) acute coronary syndrome event. Here we describe the OPTIONS I and II study designs and discuss how these studies may inform clinical management.

Methods Overview
The OPTIONS I and OPTIONS II clinical trials are phase 3, multinational, multicenter, randomized, double-blind, activecomparator, and parallel-group studies that were conducted across North America, Europe, and Australia. OPTIONS I commenced October 2012, was conducted at 91 sites, and completed in June 2014. OPTIONS II commenced November 2012, was conducted at 90 sites, and also completed in June 2014.
The trials were performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference on Harmonisation Good Clinical Practice Guidelines. Institutional review board or independent ethics committee approval of the protocols and informed consent forms were obtained from each study site, and written informed consent was obtained from all patients.

Study Objectives
The primary objective of OPTIONS I is to compare the LDL-C-lowering efficacy and safety of adding alirocumab to the most commonly used doses of atorvastatin (20 mg or 40 mg) with the strategies of adding ezetimibe, doubling the atorvastatin dose, or switching from atorvastatin 40 mg to rosuvastatin 40 mg. Patients were receiving either atorvastatin 20 mg or 40 mg at baseline and had received this stable dose for ≥4 weeks.
OPTIONS II focuses on patients receiving rosuvastatin. Here, the LDL-C-lowering efficacy and safety of adding alirocumab to rosuvastatin will be compared with adding ezetimibe or doubling the rosuvastatin dose. Patients were receiving either rosuvastatin 10 mg or 20 mg at baseline and had received the same dose for ≥4 weeks.
Both studies are evaluating these treatment options in high-CV-risk patients whose LDL-C levels were greater than or equal to the prespecified levels of 70 mg/dL or 100 mg/dL on their existing statin dose ( Table 1). The levels were based on guidelines current at the time the protocols were finalized. 12,13 In both studies, patients could have been on other lipid-lowering therapies (LLTs), except for ezetimibe or statins other than atorvastatin (for OPTIONS I) and rosuvastatin (OPTIONS II).

Randomization
In OPTIONS I, depending on whether they were receiving 20 mg or 40 mg atorvastatin daily at baseline, patients were 598 Clin. Cardiol. 37, 10, 597-604 (2014) randomized to 1 of 3 (20 mg atorvastatin daily at baseline) or 1 of 4 (40 mg atorvastatin daily at baseline) treatment arms ( Figure 1). In OPTIONS II, patients receiving 10 mg or 20 mg rosuvastatin daily at baseline were randomized to 1 of 3 treatment arms ( Figure 1). Screening was stopped once approximately 5% to 10% more patients than specified by the protocol were projected to be randomized for a given baseline statin regimen. For each study, and within each baseline statin regimen, randomization was stratified according to whether or not the patient has a history of either myocardial infarction or ischemic stroke. This stratification contributes to balance patient history of these major atherosclerosis-associated CV events in treatment arms across the clinical trials program.

Study Endpoints and Assessments
The primary endpoint for both OPTIONS I and II is the difference in percent change in calculated LDL-C from baseline to week 24 (Table 2) in the alirocumab arm vs control arms. The LDL-C was calculated using the Friedewald formula at screening and at all time points during the double-blind treatment periods. If TGs exceeded 400 mg/dL (4.52 mmol/L), then the central laboratory reflexively measured LDL-C (via the β quantification method) rather than calculating it. The LDL-C was measured (via the β quantification method) at week 0 and week 24.
For both studies, there are 2 baseline statin regimens (atorvastatin 20 mg or 40 mg in OPTIONS I, rosuvastatin 10 mg or 20 mg in OPTIONS II), and there are 3 or 4 treatment arms within each regimen ( Figure 1). The primary analysis will compare the difference in percent change in LDL-C between the alirocumab arm and each of the comparator arms. For example, in OPTIONS I, for the atorvastatin 20-mg regimen, there will be 2 pairs of comparisons: The alirocumab arm will be compared with the ezetimibe arm, and the alirocumab arm will also be compared with the arm doubling the atorvastatin dose to 40 mg. Key secondary endpoints are summarized in Table 2.
On-site patient assessments took place at randomization and then at weeks 4, 8, 12, 16, and 24, and at the end-of-study visit, week 32.

Safety
Safety events (AEs [including adjudicated CV events categorized as coronary heart disease, death, nonfatal myocardial infarction, fatal and nonfatal ischemic stroke, unstable angina requiring hospitalization, and congestive heart failure requiring hospitalization], injection-site reactions, laboratory data [blood biochemistry, hematology, and urinalysis], vital signs and electrocardiogram) were assessed throughout the study. The development of anti-alirocumab antibodies was also monitored.

Inclusion Criteria
In both studies, entry criteria included a lower limit for baseline LDL-C levels depending on risk category for CVD (Table 1). For patients with heFH, the diagnosis must have been made either by genotyping or clinical criteria. For those patients not genotyped, the clinical criteria were based on either the Simon Broome criteria with criteria for definite heFH 18 or the World Health Organization/Dutch Lipid Network criteria with a score of >8 points. 19

Exclusion Criteria
The key exclusion criteria were age <18 years; fasting serum TG    (10 mg or 20 mg; OPTIONS II) for a 4-week run-in period between the prescreening visit 1a (day −42) and visit 1. The run-in dose of atorvastatin or rosuvastatin was based on the judgment of the study physician. At randomization, treatment kit numbers were allocated using a centralized treatment allocation system, either an interactive voice-response system or an interactive Webresponse system, depending on the site preference. Study patients, principal investigators, and study-site personnel were blinded to all randomization assignments throughout the duration of the study. All lipid and antidrug antibody results collected after randomization were masked.
Each eligible patient received a single, subcutaneous, 1-mL injection by prefilled pen every 2 weeks (Q2W) (alirocumab or placebo-alirocumab) and 2 oral-blinded medications daily (a statin [atorvastatin or rosuvastatin] and ezetimibe or placebo-ezetimibe). The first injection of alirocumab or placebo-alirocumab was administered at the clinical site (week 0), after study assessments were completed, and as soon as possible after the patient was randomized into the study. The patient/caregiver administered subsequent autoinjections outside of the clinic, at a patient-preferred location, on weeks 2, 4, 6, 8, and 10.
At week 12, based on their week 8 LDL-C level and baseline CV risk, patients randomized to alirocumab may, in a blinded manner, have had their dose increased from 75 mg Q2W to 150 mg Q2W. To maintain blinding, lipid values obtained at week 8 for the purpose of up-titration occurred in an automated process and were not communicated to investigators or patients. Patients with baseline LDL-C levels ≥70 mg/dL and documented CVD continued to receive alirocumab 75 mg Q2W if their week 8 LDL-C level was <70 mg/dL (1.81 mmol/L); otherwise, they were dose up-titrated to receive alirocumab 150 mg Q2W (also via a 1-mL autoinjection) if their week 8 LDL-C level was ≥70 mg/dL (1.81 mmol/L). Patients with baseline LDL-C levels ≥100 mg/dL without documented CVD continued to receive alirocumab 75 mg Q2W if their week 8 LDL-C level was <100 mg/dL (2.59 mmol/L); otherwise, they were dose up-titrated to alirocumab 150 mg Q2W if their week 8 LDL-C level was ≥100 mg/dL (2.59 mmol/L). Autoinjections continued to be administered at weeks 12, 14, 16, 18, 20, and 22; the last dose of daily oral study drugs was administered at week 24.
So as not to interfere with the study drug or serum lipids, the following concomitant LLTs were prohibited from the initial screening visit until the end of the study visit: statins other than atorvastatin and rosuvastatin (provided as blinded medications), ezetimibe (other than that provided as blinded medication), fibrates other than fenofibrate, and red yeast rice products. Lipid-lowering therapies that were allowed as background therapy throughout the study included fish oils with omega-3 fatty acids, fenofibrate, bile acid-binding sequestrants, and niacin. Doses of these medications were stable for ≥4 weeks before screening (≥6 weeks for fenofibrate) and were to remain stable for the duration of the study.
Throughout the studies, patients were asked to follow a stable, National Cholesterol Education Program-Adult Treatment Panel III Therapeutic Lifestyle Changes (NCEP-ATP III TLC) diet or equivalent diet from screening to the end-of-study visit. At the end of the 24-week treatment period, patients entered an 8-week follow-up period.

Statistical Design and Analysis
The planned patient populations were 350 and 300 for OPTIONS I and OPTIONS II, respectively. For efficacy comparisons, it was estimated that a total sample size of 50 patients (OPTIONS I) or 47 patients (OPTIONS II) per arm would have 90% power to detect a difference in means of ≥20% in any one pairwise comparison (ie, alirocumab mean = 50% and control mean = 30%), assuming that the common standard deviation (SD) is 25 and that all 50 or 47 patients, respectively, are evaluable (for full statistical methods, see Supporting Information, Supplementary Methods, in the online version of this article).
In both OPTIONS I and II, the primary efficacy analysis population is the intent-to-treat population comprising all randomized patients with ≥1 baseline calculated LDL-C value available and ≥1 calculated LDL-C value available at one of the planned time points from weeks 4 and 24, regardless of treatment adherence.
The percent change in calculated LDL-C from baseline to week 24 will be analyzed using a mixed-effect model with repeated measures (MMRM) approach to account for missing data (see Supporting Information, Supplementary Methods, in the online version of this article). 20,21 Treatment differences between alirocumab-treated patients and patients treated with active comparators will be estimated and tested through pairwise comparisons within each baseline statin regimen (see Supporting Information, Supplementary Methods, in the online version of this article). Secondary endpoints will be tested with a similar approach (see Supporting Information, Supplementary Methods, in the online version of this article).
Safety events will be reported using descriptive statistics, based on the safety population (all randomized patients who received ≥1 dose or partial dose of study treatment). The safety analysis will focus on the TEAE period, defined as the time from the first double-blind dose to 70 days after the last double-blind dose of the investigational drug.

Results
Three hundred and fifty-five patients were randomized into OPTIONS I, and 305 patients were randomized into OPTIONS II. Baseline characteristics and lipid parameters are reported in Table 3. Briefly, 65.1% and 61.3% of patients were male in the OPTIONS I and OPTIONS II studies, respectively. The average age was 63 years in OPTIONS I and 61 years in OPTIONS II, and patients had CV risk factors such as coronary heart disease (59.4% and 63.0%), diabetes mellitus (50.1% and 42.0%), and hypertension (78.3% and 72.5%) in OPTIONS I and II, respectively. In OPTIONS I, the average baseline LDL-C level was 105.1 mg/dL, and in OPTIONS II it was 111.3 mg/dL.

Discussion
Evidence from meta-analyses and well-controlled randomized trials of statin therapy show that reducing LDL-C is associated with a significant reduction in risk of CV events 602 Clin. Cardiol. 37, 10, 597-604 (2014)   In clinical practice, patients tend to be initiated on low-to moderate-intensity statin therapy (a daily dose that provides an approximate <30% to 30% to 50% LDL-C reduction, respectively), with up-titration or switching to a higher-intensity statin regimen (a daily dose that provides an approximate ≥50% LDL-C reduction) as necessary for individuals not achieving LDL-C targets or the expected therapeutic response from the initial dose of statin. 12,13 For high-risk individuals who require greater LDL-C lowering than that achieved with statin therapy alone, some guidelines recommend combination of statin therapy with ≥1 other LLT. Guidelines also recommend the use of other LLTs for individuals who are unable to tolerate a statin dose sufficient to reduce LDL-C to target levels or who are unable to tolerate high-intensity statin therapy or achieve the desired percent reduction in LDL-C. 1,12,13 Despite these guidelines, however, studies conducted in real-world settings suggest that the percentage of patients achieving recommended LDL-C levels is not optimal and can be improved. 6 -8,28 For example, an observational study assessing treatment practice patterns in high-CVrisk patients on statin monotherapy found that although greater LDL-C reductions were seen in patients who received add-on ezetimibe therapy or underwent a statin dose up-titration, approximately 30% of these patients were not achieving LDL-C levels <70 mg/dL, 29 suggesting that currently available treatment options are not sufficient for some higher-risk patients. Furthermore, recent evidence also suggests doubling the dose to that of a high-intensity statin may provide minimal benefit from additional LDL-C lowering. 30 For example, it was calculated that increasing the dose from 40 mg to 80 mg of atorvastatin may result in only an approximate 2% reduction in the risk of clinical events. 30 Overall, whereas statins have been shown to be efficacious in lowering LDL-C, patients at high CV risk may benefit from additional, more intensive LLTs to help them achieve their LDL-C goals.
A recent study conducted with another proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with hypercholesterolemia and on stable, daily, moderate-intensity (10 mg atorvastatin, 40 mg simvastatin, or 5 mg rosuvastatin) or high-intensity (80 mg atorvastatin or 40 mg rosuvastatin) statin therapy, assessed the LDL-C-lowering effect of added evolocumab or ezetimibe. 31 Findings showed that the addition of evolocumab resulted in additional LDL-C lowering. 31 The ODYSSEY OPTIONS studies assess the lipid-lowering efficacy and safety of alirocumab as add-on therapy in comparison with the current clinical strategies that exist for high-CV-risk patients whose LDL-C levels are not sufficiently reduced with the most commonly used atorvastatin or rosuvastatin doses. The studies are designed to answer practical questions facing the clinician: Which clinical strategy provides the best combination of LDL-C-lowering efficacy and safety/tolerability? Add alirocumab? Increase the statin dose or switch to another statin, or add ezetimibe? The study design also provides flexibility in the alirocumab dosing regimen, which in turn allows for individualized therapy based on the degree of LDL-C reduction required to achieve the desired treatment response.
Whether additional LDL-C lowering in patients optimally treated with statins will further reduce CV events is under evaluation in ongoing trials of ezetimibe as well as a number of PCSK9 monoclonal antibodies. The ODYSSEY OUTCOMES trial is evaluating alirocumab in patients with acute coronary syndromes.
In conclusion, the ODYSSEY OPTIONS studies aim to provide further data regarding the efficacy of alirocumab to reduce LDL-C levels in patients with hypercholesterolemia at high CV risk, in particular those patients who are not achieving specific LDL-C levels with the most commonly used atorvastatin or rosuvastatin doses. This trial will also evaluate the safety and tolerability of alirocumab in a larger patient population over 24 weeks.