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Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study*. 

Kereiakes DJ, et al. Am Heart J 2015; 169:906–15.

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

Study objectives

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

Study design

This 52 week, multicentre, randomised, double-blind, placebo-controlled, parallel group, phase III study involved 316 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 (e.g., diabetes mellitus with other risk factors or chronic kidney disease).

Patients were randomised to subcutaneous Praluent 75 mg every 2 weeks (Q2W) (n=209) or placebo Q2W (n=107) (Figure 1). 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 of patients achieving a 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 adverse events (SAEs), injection site reactions and adjudicated CV events.

Figure 1: ODYSSEY COMBO I: Study designAdapted from Kereiakes DJ, et al. Am Heart J 2015;169(6):906-151

COMBO I Study Design

*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
‡Maximum-tolerated statin dose defined as 40–80 mg atorvastatin, 20–40 mg rosuvastatin or 80 mg simvastatin, or lower dose if documented reason provided e.g. intolerance or local practice1

 

Baseline characteristics

Baseline characteristics were well balanced between the treatment groups (Table 1). Over the 52-week double-blind period, adherence was similar between treatment groups (98% Praluent; 99% placebo). Based on Week 8 LDL-C levels ≥1.8 mmol/L, 16.8% of Praluent patients underwent ‘up-titration’ to 150 mg dose at Week 12.

Table 1: ODYSSEY COMBO I: Baseline characteristicsAdapted from Kereiakes DJ, et al. Am Heart J 2015;169(6):906-151


Praluent
75/150 mg
(n=209)
Placebo
(n=107)
Demographics
Age in years, mean ± SD 63 ± 9.5 63 ± 8.8
Male, % 62.7 72.0
CV history/risk factors
Any CV history/risk factors, % 98.6 99.1
CHD history, % 78.5 77.6
CHD risk equivalent, % 40.7 47.7
Type 2 diabetes 45.0 39.3
Lipid medication
Any statin, % 99.5 100
High dose statin§ 61.7 64.5
Other LLT, % 38.3 49.5
Ezetimibe, % 7.2 10.3
Lipid parameters
LDL-C, (calculated) mmol/L ± SD 2.59 ± 0.76
2.74 ± 0.91

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 adults at high CV risk, Praluent 75/150 mg led to significantly greater reductions in LDL-C compared to placebo (Figure 2), allowed a significantly greater proportion of patients to achieve the pre-specified LDL-C target compared to placebo (Figure 3) and the LDL-C reductions were consistent and sustained over 52 weeks (Figure 4):

  • At Week 24, mean percentage change in LDL-C from baseline was -48.2% for Praluent versus -2.3% for placebo (p<0.0001) (figure 2)
  • At Week 24, 75% of Praluent versus 9% of placebo patients achieved the pre-specified LDL-C target of <1.8 mmol/L (p<0.0001) (figure 3)
  • At Week 8, 83.2% of patients treated with Praluent achieved the pre-specified LDL-C of <1.8 mmol/L

Among the 16.8% of patients with Praluent up-titration at Week 12, reductions in LDL-C at Weeks 24, 36, and 52 were comparable with that observed among patients in whom no dose increase was performed.

Figure 2: ODYSSEY COMBO I: Mean reduction in LDL-C from baseline to Week 24Adapted from Kereiakes DJ, et al. Am Heart J 2015;169(6):906-151

48% Mean reduction in LDL-C
 

 

*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
‡This number refers to the number of patients receiving placebo (ITT analysis)1

 

Figure 3: ODYSSEY COMBO I: Proportion of patients achieving LDL-C target at Week 24Adapted from Kereiakes DJ, et al. Am Heart J 2015;169(6):906-151

 

 

 

*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

Figure 4: ODYSSEY COMBO I: Mean reduction in LDL-C from baseline to Week 52Adapted from Kereiakes DJ, et al. Am Heart J 2015;169(6):906-151

Estimated mean (95% CI) calculated LDL-C level, mmol/L
 

 

*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

Key safety results

Frequency of TEAEs and treatment-emergent SAEs were comparable in Praluent and placebo patients and AEs leading to study medicine discontinuation were uncommon (Table 2). Injection site reactions reported by 5.3% of Praluent and 2.8% of placebo patients were mild and did not lead to discontinuation (Table 2).

Table 2: ODYSSEY COMBO I: Treatment-emergent adverse events (safety population)Adapted from Kereiakes DJ, et al. Am Heart J 2015;169(6):906-151


Praluent
75/150 mg
(n=207)
Placebo
(n=107)
TEAE, n (%) 157 (75.8) 81 (75.7)
Treatment-emergent SAEs, n (%) 26 (12.6) 14 (13.1)
TEAE leading to discontinuation, n (%) 13 (6.3) 8 (7.5)
Safety terms of interest*
  Injection site reactions, n (%) 11 (5.3) 3 (2.8)
  Potential general allergic reaction events, n (%) 18 (8.7) 7 (6.5)
  Neurologic events 5 (2.4) 2 (1.9)
  Neurocognitive disorders 0 (0) 1 (0.9)
CV adverse events, n (%) 6 (2.9) 3 (2.8)
TEAE leading to death, n (%) 2 (1.0) 3 (2.8)

Please refer to publication for full safety profile information

CV = cardiovascular; TEAE = treatment-emergent adverse events; SAE = serious adverse events
*Neurocognitive events were selected using a company Medical Dictionary for Regulatory Activities query based on the following 5 high-level group terms: deliria (including confusion), cognitive and attention disorders and disturbances, dementia and amnestic conditions, disturbances in thinking and perception, and mental impairment disorders.

Conclusions

  1. Praluent 75/150mg every 2 weeks significantly lowered calculated LDL-C from baseline to Week 24 in high risk CV patients on the maximum tolerated dose of statin therapy in comparison to placebo (-48.2% vs -2.3%, respectively; p <0.0001)
  2. At Week 24, 75.0% of patients treated with Praluent achieved the pre-specified target LDL-C level of <1.8 mmol/L (vs 9.0% on placebo; p<0.0001)
  3. The frequency of TEAEs and serious TEAEs were comparable between the treatment groups

References

  • Kereiakes DJ, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J 2015; 169:906–15.

Footnotes

**Maximum-tolerated statin dose defined as 40–80 mg atorvastatin, 20–40 mg rosuvastatin or 80 mg simvastatin, or lower dose if documented reason provided e.g., intolerance or local practice

†Established CHD defined as acute myocardial infarction, silent myocardial infarction, unstable angina, coronary revascularisation, or clinically significant CHD diagnosed by invasive or non-invasive testing. CHD risk equivalents defined as ischaemic stroke, peripheral artery disease, moderate chronic kidney disease, or diabetes (only if ≥2 risk factors present)