PRALUENT ALTERNATIVE STUDY

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

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

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

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

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

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

Please refer to publication for full safety profile information

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)