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Last update: February 2019

The usual starting dose for praluent is 75mg administered subcutaneously once every 2 weeks. Patients requiring larger LDL-C reduction (>60%) may be started on 150mg once every 2 weeks.

Efficacy and Safety of Alirocumab in Reducing Lipids*

Robinson J.G, et al. N Engl J Med 2015; 372:1489–99.

*All of the information and data within this section (unless noted) is a summary of this publication. 

Study objectives

The ODYSSEY LONG TERM study evaluated the long term efficacy and safety of Praluent 150mg versus placebo as an add-on to maximally tolerated dose (MTD) statin** ± other lipid-lowering therapy (LLT) in high cardiovascular (CV) risk patients with inadequately controlled hypercholesterolaemia.

Study design

This 78 week, multicentre, randomised, double-blind, placebo-controlled, parallel group, phase III study involved 2,341 adult patients (≥18 years) with heterozygous familial hypercholesterolaemia (HeFH) (as determined by genotyping or clinical criteria) or established coronary heart disease (CHD) or CHD risk equivalent†, a LDL-C level ≥1.8 mmol/L and all patients were receiving MTD statins* ± other LLTs.

Patients were randomised to subcutaneous Praluent 150 mg every 2 weeks (Q2W) (n=1,553) or placebo Q2W (n=788) (Figure 1).

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

  • Proportion of 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 78
  • Safety profile including incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious AEs (SAEs), injection site reactions and adjudicated CV events.

Figure 1: ODYSSEY LONG TERM: Study design - Adapted from Robinson J.G, et al. N Engl J Med 2015; 372:1489–991

Long Term Study Design

Baseline Characteristics

Baseline characteristics were well balanced between the treatment groups (Table 1).

Table 1: ODYSSEY LONG TERM: Baseline characteristics - Adapted from Robinson J.G, et al. N Engl J Med 2015; 372:1489–991

  Praluent 150 mg
(n=1553)
Placebo
(n=788)
Demographics
Age in years, mean ± SD 60.4 ± 10.4 60.6 ± 10.4
Male, % 63.3 60.2
CV history/risk factors
HeFH, % 17.8 17.6
CHD, % 67.9 70.1
CHD risk equivalent, % 41.1 41.0
Type 2 diabetes 34.9 33.9
Lipid medication
Any statin, % >99.9 99.9
High dose statin§, % 46.8 46.7
Other LLT, % 28.1 27.9
Ezetimibe, % 13.9 15.0
Lipid parameters
LDL-C, (calculated) mmol/L ± SD 3.18 ±1.1 3.16 ±1.1

CHD = coronary heart disease; CV = cardiovascular; HeFH = heterozygous familial hypercholesterolaemia, LLT = lipid-lowering therapy, SD= standard deviation.
†HeFH diagnosed by genotyping (40.2%) and by clinic criteria (World health organisation-Simon Broome diagnostic criteria) (59.8%)
‡CHD risk equivalent defined as Coronary heart disease risk equivalents were defined as peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to <60 ml per minute per 1.73 m2 of body-surface area), or diabetes mellitus plus two or more additional risk factors (hypertension; ankle–brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of >2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or a family history of premature coronary heart disease)
§High-dose statin therapy defined as 40–80 mg atorvastatin, 20–40 mg rosuvastatin or 80 mg simvastatin

Key efficacy results

In high CV risk patients with inadequately controlled hypercholesterolaemia, Praluent 150mg Q2W 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 and the LDL-C reductions were consistent and sustained over 78 weeks (Figure 4):

  • At Week 24, mean percentage change in LDL-C from baseline was -61.0% for Praluent versus +0.8% for placebo (p<0.001)
  • At Week 24, 79.3% of Praluent versus 8% of placebo patients achieved the pre-specified LDL-C target of ≤1.8 mmol/L (p<0.001)
  • At Week 78, mean percentage change in LDL-C from baseline was -52.4% for Praluent versus +3.6% for placebo (p<0.001)* and a consistent reduction in LDL-C level from baseline was observed from Week 4 to Week 78 in the Praluent group (Figure 4).

*This P value was not adjusted for multiplicity and is descriptive only.

Figure 2: ODYSSEY LONG TERM: Mean reduction in LDL-C from baseline to Week 24 - Adapted from Robinson J.G, et al. N Engl J Med 2015; 372:1489–991

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

 

Figure 3: ODYSSEY LONG TERM: Mean reduction in LDL-C from baseline to Week 24 by baseline LDL-C2 - Adapted from Robinson JG, et al. N Engl J Med 2015;372(16):Suppl.

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

 

Figure 4: ODYSSEY LONG TERM: Mean reduction in LDL-C from baseline to Week 78 - Adapted from Robinson JG, et al. N Engl J Med 2015;372(16):1489-99

Long Term Study Key Results 3

*This number refers to the number of patients receiving Praluent (ITT analysis)1
†This number refers to the number of patients receiving placebo (ITT analysis)1
‡P-value not adjusted for multiple testing and is provided for descriptive purposes only1

Key safety results

2,338 patients, 1,550 patients for Praluent and 788 for placebo, were included in the safety analysis.

  • Mean duration of follow-up - 80.9 weeks for Praluent and 80.1 weeks for placebo.
  • Mean study-drug exposure was 70 weeks, providing 2,061 patient-years of exposure to Praluent 150mg Q2W.

Frequency of any AEs and SAEs were comparable in Praluent and placebo patients (Table 2). Although compared with placebo, Praluent had higher rates of AEs leading to discontinuation, injection site reactions, myalgia, neurocognitive disorders and ophthalmologic events (Table 2), with the exception of myalgia, these differences were not statistically significant.

The number of cardiovascular events was relatively small, which limits the robustness of these data and the confidence that they are not simply a chance finding.

A post hoc analysis was performed that compared the rate of positively adjudicated major adverse cardiovascular events between the two study groups, using the composite end point of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalisation.

The effect of Praluent on cardiovascular morbidity and mortality has not yet been determined.

Table 2: ODYSSEY LONG TERM: Adverse events (safety population) - Adapted from Robinson J.G, et al. N Engl J Med 2015; 372:1489–991

  Praluent 150 mg
(n=1550)
Placebo
(n=788)
p*
Adverse events, n (%) 1255 (81) 650 (82.5) 0.40
Serious adverse events, n (%) 290 (18.7) 154 (19.5) 0.66
Adverse events leading to discontinuation, n (%) 111 (7.2) 46 (5.8) 0.26
Adverse events leading to death, n (%) 8 (0.5) 10 (1.3) 0.08
CV adverse events
All cardiovascular events, n (%) 72 (4.6) 40 (5.1) 0.68
Adjudicated major adverse cardiovascular events in post hoc analysis, n (%) 27 (1.7) 26 (3.3) 0.02
Death from CHD, n (%) 4 (0.3) 7 (0.9) 0.26
Non-fatal myocardial infarction, n (%) 14 (0.9) 18 (2.3) 0.01
Fatal or non-fatal ischemic stroke, n (%) 9 (0.6) 2 (0.3) 0.35
Unstable angina requiring hospitalisation, n (%) 0 1 (0.1) 0.34
Congestive heart failure requiring hospitalisation, n (%) 9 (0.6) 3 (0.4) 0.76
Ischemia-driven coronary revascularisation procedure, n (%) 48 (3.1) 24 (3.0) 1
Other adverse events of interest
Injection site reactions, n (%) 91 (5.9) 33 (4.2) 0.10
General allergic reactions, n (%) 156 (10.1) 75 (9.5) 0.71
Myalgia, n (%) 84 (5.4) 23 (2.9) 0.006
Neurological events, n (%) 65 (4.2) 35 (4.4) 0.83
Ophthalmologic events, n (%) 45 (2.9) 15 (1.9) 0.65
Neurocognitive disorder, n (%) 18 (1.2) 4 (0.5) 0.17
Amnesia , n (%) 5 (0.3) 0 0.17
Memory impairment , n (%) 4 (0.3) 1 (0.1) 0.67
Confusional state , n (%) 4 (0.3) 1 (0.1) 0.67
Hemolytic anemia, n (%) 0 0 NC
Diabetes in patients with no history of diabetes, n/total n (%) 18/994 (1.8) 10/509 (2.0) 0.84
Worsening of diabetes in patients with history of diabetes, n/total n (%) 72/556 (12.9) 38/279 (13.6) 0.83

*These P values were not adjusted for multiplicity and are descriptive only.

Please refer to publication for full safety profile information
CHD = coronary heart disease; CV = cardiovascular

 

 

Conclusions

  • Praluent 150 mg every two weeks achieved significantly lowered LDL-C from baseline to Week 24 in patients with high CV risk patients on the maximally tolerated dose of statin therapy in comparison to placebo (-61.0% vs +0.8%, p<0.001);
  • Praluent demonstrated sustained long-term LDL-C lowering in comparison to placebo from week 4 to week 78 (-52.4% vs +3.6%);
  • Praluent 150 mg every two weeks demonstrated significant LDL-C lowering compared to placebo regardless of baseline LDL-C (interaction p<0.0001)2;
  • The incidences of TAEAs and serious TEAEs were comparable between treatment groups.

References

  • Robinson J.G, et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events N Engl J Med 2015; 372:1489–99
  • Robinson J.G, et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events N Engl J Med 2015; 372:1489–99. Suppl. Appendix

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)