COMBO II STUDY

Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial*.

Cannon CP, et al. Eur Heart J 2015; 36:1186–94.

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

Study objectives

The ODYSSEY COMBO II study evaluated the efficacy and safety of Praluent 75/150 mg compared with ezetimibe as add-on therapy to maximally tolerated dose (MTD) statin** in high cardiovascular (CV) risk patients with inadequately controlled hypercholesterolaemia.

Study design

This 104 week, multicentre, randomised, double-blind, double-dummy, active-controlled, parallel-group, phase III study involved 720 adult patients (≥18 years) who were receiving MTD statins ± other LLTs with:

• LDL-C ≥1.8 mmol/L and established coronary heart disease (CHD)†

OR

• LDL-C level ≥2.6 mmol/L and CHD risk equivalents†

Patients were randomised to subcutaneous Praluent 75 mg every 2 weeks (Q2W) plus oral placebo daily (n=479) or subcutaneous placebo Q2W plus oral ezetimibe 10mg daily (n=241) (Figure 1). Praluent dose was increased to 150 mg Q2W at Week 12 if Week 8 LDL-C was ≥1.8 mmol/L.

This study was ongoing at the time of publication and randomised treatment would be continued until Week 104, followed by an 8-week post treatment observation period. Results are presented from a pre-specified analysis, including final efficacy results up to Week 52 and safety data up to the date of the last patient Week 52 visit.

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 level target of <1.8 mmol/L at Week 24
Percentage change in LDL-C from baseline to Week 52
Safety profile including incidence of treatment-emergent adverse events (TEAEs), serious treatment-emergent AEs (SAEs), injection site reactions and adjudicated CV events.

Figure 1: ODYSSEY COMBO II: Study design - Adapted from Cannon CP, et al. Eur Heart J 2015;36:1186-941

^*Praluent dose was 75 mg administered SC every two weeks, but if LDL-C level was ≥1.8 mmol/L at Week 8, a pre-specified dose up-titration to 150 mg every two weeks was performed at Week 12¹

^†Statin therapy at the maximum-tolerated dose (40–80 mg atorvastatin, 20–40 mg rosuvastatin daily or 80 mg simvastatin [if on this dose for >1 year]) or a lower dose, provided a reason was documented

Baseline characteristics

Baseline characteristics were well balanced between the treatment groups (Table 1). The mean ± standard deviation (SD) duration of injection exposure was 58.0 ± 18.7 weeks (26.6 ± 8.8 injections) in the Praluent arm and 57.7 ± 19.0 weeks (26.6 ± 9.0 injections) in the ezetimibe arm.

Table 1: ODYSSEY COMBO II: Baseline characteristics - Adapted from Cannon CP, et al. Eur Heart J 2015;36:1186-941

CHD = coronary heart disease; CV = cardiovascular; LLT = lipid-lowering therapy, SD= standard deviation.
^§High-dose statin therapy defined as 40–80 mg atorvastatin, 20–40 mg rosuvastatin or 80 mg simvastatin¹

Key efficacy results

In high CV risk patients with inadequately controlled hypercholesterolaemia, Praluent 75/150 mg led to significantly greater reductions in LDL-C compared to ezetimibe (Figure 2), allowed a significantly greater proportion of patients to achieve the pre-specified LDL-C target compared to placebo and the LDL-C reductions were consistent and sustained over 52 weeks(Figure 3).

• At Week 24, mean percentage change in LDL-C from baseline was -50.5% (1.5 mmol/L) for Praluent versus -20.7% (0.6 mmol/L) for ezetimibe (p<0.0001) (Figure 2);
• At Week 24, 77% of Praluent versus 45.6% of ezetimibe patients achieved the pre-specified LDL-C target of <1.8 mmol/L (p<0.0001);

Figure 2: ODYSSEY COMBO II: Mean reduction in LDL-C from baseline to Week 24 - Adapted from Cannon CP, et al. Eur Heart J 2015;36:1186-94¹

^*Praluent dose was 75 mg administered subcutaneously every two weeks, but if LDL-C level was ≥1.8 mmol/L at Week 8, a pre-specified dose up-titration to 150 mg every two weeks was performed at Week 121
^†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 COMBO II: Mean reduction in LDL-C from baseline to Week 52 - Adapted from Cannon CP, et al. Eur Heart J 2015;36:1186-94¹

^*Praluent dose was 75 mg administered subcutaneously every two weeks, but if LDL-C level was ≥1.8 mmol/L at Week 8, a pre-specified dose up-titration to 150 mg every two weeks was performed at Week 121
^†This number refers to the number of patients receiving Praluent (ITT analysis)
^‡This number refers to the number of patients receiving ezetimibe (ITT analysis)

Key safety results

Frequency of TEAEs and SAEs were similar in Praluent and ezetimibe patients (Table 2) with the exception of nasopharyngitis TEAEs which was more frequent in the alirocumab group. Injection site reactions were reported by 2.5% of Praluent patients and 0.8% of ezetimibe patients. Reactions were of mild intensity, except for one of moderate intensity, and none were serious. Two events led to discontinuation in the Praluent group.

Table 2: ODYSSEY COMBO II: Treatment-emergent adverse events at Week 52 (safety population) - Adapted from Cannon CP, et al. Eur Heart J 2015;36:1186-941

Please refer to publication for full safety profile information

CV = cardiovascular ; SAE = serious adverse event ; TEAE = treatment-emergent adverse event

Conclusions

• Praluent 75/150 mg every two weeks significantly lowered calculated LDL-C level from baseline to Week 24 in high CV risk patients on the maximum-tolerated dose of statin therapy vs ezetimibe (-50.6% vs -20.7%; p<0.0001);
• Praluent demonstrated sustained LDL-C reduction from Week 4 to 52 Weeks;
  The frequency of TEAE and serious TEAE were similar between the treatment groups with the exception of nasopharyngitis TEAEs which was more frequent in the alirocumab group.