• Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial*

    Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-69.

    *All of the information and data within this section is a summary of this publication.

    STUDY OBJECTIVES

    The ODYSSEY ALTERNATIVE study evaluated the efficacy and safety of Praluent 75/150 mg compared to ezetimibe in patients at moderate to high cardiovascular (CV) risk**, statin intolerance† and had primary hypercholesterolaemia.

    STUDY DESIGN

    This 24 week, multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group, phase III study involved 314 adult patients (≥18 years) at moderate/high CV risk** (LDL-C level ≥2.6 mmol/L) or very high CV risk (LDL-C level ≥1.8 mmol/L) and statin intolerance (unable to tolerate ≥2 statins including one at the lowest approved starting dose) due to skeletal muscle-related symptoms†, and had primary hypercholesterolaemia.

    Patients were randomised to subcutaneous Praluent 75 mg every 2 weeks (Q2W) plus oral placebo daily (n=126), subcutaneous placebo Q2W plus oral ezetimibe 10mg daily (n=125) or subcutaneous placebo Q2W plus oral atorvastatin 20mg daily (statin re-challenge arm, n=63) (Figure 1).

    The study included a placebo run-in and statin re-challenge arm to confirm intolerance and Praluent dose was increased to 150 mg Q2W at Week 12 if Week 8 LDL-C was ≥1.8 mmol/L.

    The primary efficacy endpoint was the percentage change in LDL-C from baseline to Week 24. Secondary endpoints included:

    • Proportion patients achieving the pre-specified LDL-C target (<2.6 mmol/L for moderate/high CV risk and <1.8 mmol/L for very high CV risk) at Week 24
    • Safety analysis included incidence of all adverse events (AEs) and serious adverse events (SAEs), irrespective of their possible relationship to the study drug. Injection site reactions, adjudicated CV events and skeletal muscle AEs closely related to statin intolerance (myalgia or myositis, muscle spasms, muscular weakness, musculoskeletal stiffness, and muscle fatigue) were included.

    Efficacy comparisons versus atorvastatin were not assessed as this treatment arm was only included as an essential control to define the appropriate patient population.

    Figure 1: ODYSSEY ALTERNATIVE: Study design - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691

    ODYSSEY ALTERNATIVE: Study design

    *Praluent dose was 75 mg administered SC every two weeks, but at week 8, if LDL-C level was ≥1.8 mmol/L in very high risk patients or ≥2.6 mmol/L in moderate/high risk CV patients, a pre-specified dose up-titration to 150 mg every two weeks was performed at Week 12
    Statin intolerance defined as the inability to tolerate ≥2 statins because of unexplained skeletal muscle-related symptoms associated with statin use

    BASELINE CHARACTERISTICS

    Baseline characteristics were well balanced between treatment groups with high rates of conorary heart disease (CHD) and CV risk factors (Table 1).

    Table 1: ODYSSEY ALTERNATIVE: Baseline characteristics - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691


    Praluent
    75/150mg
    (n=126)
    Ezetimibe
    (n=125)
    Atorvastatin
    (n=63)
    Demographics
    Age in years, mean ± SD 64.1 ± 9.0 62.8 ± 10.1 63.4 ± 8.9
    Male, % 55.6 53.6 55.6
    CV risk level
    Moderate*, % 15.1 11.2 15.9
    High#, % 23.0 37.6 20.6
    Very high, % 57.9 49.6 55.6

    LLT other than statin % 37.3 44.0 54.0
    Lipid parameters
    LDL-C, mmol/L ± SD 4.9 ± 1.9 5.0 ± 1.98 4.8 ± 1.5

    CV = cardiovascular; LLT = lipid-lowering therapy; SD = standard deviation
    * 10-year fatal CV risk Systematic Coronary Risk Evaluation (SCORE) ≥1%–5%
    # 10-year fatal CV risk SCORE ≥5%; moderate chronic kidney disease; diabetes mellitus without target organ damage; or familial hypercholesterolaemia
    Documented history of CHD, ischemic stroke, peripheral artery disease, transient ischemic attack, abdominal aortic aneurysm, or carotid artery occlusion >50% without symptoms; carotid endarterectomy or carotid artery stent procedure; renal artery stenosis or renal artery stent procedure; or diabetes mellitus with target organ damage

    KEY EFFICACY RESULTS

    In statin intolerant adults, Praluent 75/150 mg 2QW led to significantly greater reductions in LDL-C compared to placebo (Figure 2) with sustained reductions from Week 4 to Week 24 (Figure 3). A significantly greater proportion of patients achieved a pre-specified LDL-C targets compared to placebo (Figure 4):

    • At Week 24, mean percentage change in LDL-C from baseline was -45.0% (97mg/dL) for Praluent versus -14.6% (38.3mg/dL) for ezetimibe (p<0.0001) (Figure 2)
    • Reductions in LDL-C concentration occurred within the first 4 weeks and persisted throughout the 24-week treatment period (Figure 3)
    • At Week 24, 41.9% of Praluent versus 4.4% of ezetimibe patients achieved the pre-specified LDL-C targets (<2.6 mmol/L for moderate/high CV risk and <1.8 mmol/L for very high CV risk) (p<0.0001) (Figure 4)

    Figure 2: ODYSSEY ALTERNATIVE: Mean reduction in LDL-C from baseline to Week 24 - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691

    ODYSSEY ALTERNATIVE: Mean reduction in LDL-C from baseline to Week 24

    *Praluent dose was 75 mg administered subcutaneously every two weeks, but if LDL-C level was above the pre-specified target (≥1.8 mmol/L for patients at very high CV risk and ≥2.6 mmol/L for patients at moderate to high CV risk) at Week 8, a pre-specified dose up-titration to 150 mg every two weeks was performed at Week 12
    This number refers to the number of patients receiving Praluent (ITT analysis)
    This number refers to the number of patients receiving ezetimibe (ITT analysis)

    Figure 3: ODYSSEY ALTERNATIVE: Mean LDL-C from baseline to Week 24. In a post-hoc ITT analysis, the mean (SD) change in LDL-C concentration in the atorvastatin arm was −31.9% (25.1%) at week 24 - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015;9:758-691

    ODYSSEY ALTERNATIVE: Mean LDL-C from baseline to Week 24

    LDL-C concentrations vs study time points for on–treatment analysis. Values indicate achieved LDL-C concentration and least squares mean (SE) percent change from baseline.

    Figure 4: ODYSSEY ALTERNATIVE: Proportion of patients achieving LDL-C** target at Week 24 - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691

    ODYSSEY ALTERNATIVE: Proportion of patients achieving LDL-C** target at Week 24

    ITT analysis
    *Praluent dose was 75 mg administered subcutaneously every two weeks, but if LDL-C level was above the pre-specified target (≥1.8 mmol/L for patients at very high CV risk and ≥2.6 mmol/L for patients at moderate to high CV risk) at Week 8, a pre-specified dose up-titration to 150 mg every two weeks was performed at Week 12
    **Pre-specified LDL-C level target for moderate to high risk patients was <2.6 mmol/L and for very high risk patients was <1.8 mmol/L

    KEY SAFETY RESULTS

    Although the frequency of treatment-emergent and serious AEs were similar between treatment groups, treatment-emergent AEs (TEAEs) leading to discontinuations tended to be lower with the Praluent group (Table 2).

    The incidence of skeletal muscular-related AEs was significantly lower in Praluent than in atorvastatin patients (32.5% versus 46.0%, respectively; HR=0.61; 95% CI: 0.38 –to 0.99; p=0.042) with a similar but non-significant trend for Praluent versus ezetimibe (HR=0.71; 95% CI: 0.47–1.06; p=0.096). Discontinuations due to skeletal muscular-related AEs were also lower in with Praluent versus atorvastatin (HR=0.67; 95% CI: 0.34–1.32; p=0.24) or ezetimibe (HR=0.78; 95%: CI 0.43–1.41; p=0.41), however these differences were not significant.

    Table 2: ODYSSEY ALTERNATIVE: Treatment-emergent adverse events at Week 24 (safety population) - Adapted from Moriarty P.M, et al. J Clin Lipidol 2015; 9:758-691


    Praluent (n=126) Ezetimibe (n=124) Atrovastatin (n=63)
    Any AE, n (%) 104 (82.5) 100 (80.6) 54 (85.7)
    Serious AE, n (%) 12 (9.5) 10 (8.1) 7 (11.1)
    AEs leading to discontinuation, n (%) 23 (18.3) 31 (25.0) 16 (25.4)
    Musculoskeletal† AEs, n (%) 41 (32.5) 51 (41.1) 29 (46.0)
    Musculoskeletal† AEs leading to discontinuation, n (%) 20 (15.9) 25 (20.2) 14 (22.2)
    Injection site reactions, n (%) 6 (4.8) 6 (4.8) 1 (1.6)
    Adjudicated CV adverse events‡, n (%) 4 (3.2) 1 (0.8) 1 (1.6)

    Please refer to publication for full safety profile information

    AE = adverse event; CV = cardiovascular
    Predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue
    Including coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalization, and ischemia-driven coronary revascularisation

    Conclusions

    • Praluent 75/150 mg every two weeks, administered to patients with primary hypercholesterolaemia and statin intolerance with moderate to very high CV risk achieved a significantly greater reductions from baseline in LDL-C in comparison to ezetimibe (-45.0% (97mg/dL) for Praluent versus -14.6% (38.3mg/dL) for ezetimibe; p<0.0001);
    • Significantly more patients achieved their pre-specified LDL-C target at Week 24 with Praluent vs placebo (41.9% vs 4.4%, respectively; p<0.0001)
    • Overall rates of TEAEs and SAEs were similar between Praluent, ezetimibe and atorvastatin-treated patients
    • Patients treated with Praluent 75/150 mg every two weeks demonstrated significantly lower rates of musculoskeletal AEs compared with atorvastatin treated patients (32.5% vs 46.0%, respectively; p=0.042)

    PRALUENT FHI & FHII STUDIES

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    PRALUENT ADDITIONAL STUDIES

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    **Moderate CV risk was defined as 10-year fatal cardiovascular risk SCORE between ≥1% and <5%. High CV risk was defined as 10-year fatal cardiovascular risk SCORE ≥5%; moderate chronic kidney disease; diabetes mellitus without organ damage; or familial hypercholesterolaemia. Very high CV risk was defined as documented history of CHD, ischaemic stroke, peripheral artery disease, transient ischaemic attack, abdominal aortic aneurysm, or carotid artery occlusion >50% without symptoms; carotid endarterectomy or carotid artery stent procedure; renal artery stenosis or renal stent procedure; or diabetes mellitus with target organ damage.

    Statin intolerance defined as the inability to tolerate ≥2 statins because of unexplained skeletal muscle-related symptoms associated with statin use

    §Myalgia or myositis, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue

    1. Moriarty P.M, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol 2015; 9:758-69.
    2. Praluent Summary of Product Characteristics. Available at https://www.medicines.org.uk/emc/medicine/30956. Accessed June 2020.