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Last update: July 2019

REDUCE RISK OF MACE†
Significantly reduced the risk of MACE versus placebo2
HR = 0.85 (95% CI 0.78, 0.93) P <0.001

LDL-C ≥2.6mmol/L
A greater benefit in MACE was observed in patients with baseline LDL-C ≥2.6mmol/L2

SAFETY PROFILE
The safety profile in ODYSSEY OUTCOMES was consistent with the overall safety profile described in the phase 3 controlled trials

† MACE defined as a composite of CHD death, nonfatal MI, fatal or nonfatal ischaemic stroke, or unstable angina requiring hospitalisation2

PCSK9i outcomes study with a median time from index event to randomisation of 2.6 months

Designed to evaluate the long-term efficacy and safety profile of PRALUENT in post-ACS patients1,2
  • 2-5 years double-blind treatment period2
  • 2.6 months median time post index event to randomisation2
  • ~19,000 patients were randomised2
  • 2.8 years median follow-up; more than 42% were eligible to be followed for 3-5 years; ~34% of patients received treatment for at least 3 years2

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STUDY Design Patient Characteristics MACE Results LDL-C Results Safety

Study Design

ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled phase 3 study. Patients with a recent MI or unstable angina 1-12 months earlier, and on high-intensity statin (40 or 80 mg atorvastatin or 20 or 40 mg rosuvastatin, or maximally tolerated dose of one of these agents) +/- other lipid-lowering therapy but not at predefined target LDL-C were enrolled.1,2

ODYSSEY Study Design

*Background therapy: 96% aspirin; 87% P2Y12 inhibitor; 85% beta blocker; ACE/ARB 78%.2
† Dose was up-titrated at month 2 from 75 mg Q2W to 150 mg Q2W if LDL-C was ≥1.29 mmol/L. Dose down-titrated from 150 mg Q2W to 75 mg Q2W occurred if LDL-C was <0.65 mmol/L on 2 consecutive measures. Patients on the 75 mg Q2W dose were blindly switched to placebo if LDL-C was <0.39 mmol/L on 2 consecutive measures.


Primary endpoint2 (time to first occurrence of)

  • MACE composite defined as:
    • CHD death, or
    • Nonfatal MI, or
    • Fatal or nonfatal ischaemic stroke, or
    • Unstable angina requiring hospitalisation

Major secondary endpoints (in order of hierarchical testing)2

  • CHD event (including CHD death, nonfatal MI, UA requiring hospitalisation or an ischaemia-driven coronary revascularisation procedure)
  • Major CHD event (including death from CHD or nonfatal MI)
  • CV event (including CV death, nonfatal ischaemic stroke, nonfatal MI, UA requiring hospitalisation, or an ischaemia-driven coronary revascularisation procedure)
  • The composite of all-cause mortality, nonfatal MI, nonfatal ischaemic stroke
  • CHD death
  • CV death
  • All-cause death

ODYSSEY OUTCOMES: A CV outcomes trial** including ~19,000 ACS patients2 similar to those you see in your daily practice

Praluent was studied:

ODYSSEY Patient Types

 

Patient Characteristics:

ODYSSEY Patient Characteristics

† Dose was up-titrated at month 2 from 75 mg Q2W to 150 mg Q2W if LDL-C was ≥1.29 mmol/L. Dose down-titrated from 150 mg Q2W to 75 mg Q2W occurred if LDL-C was <0.65 mmol/L on 2 consecutive measures. Patients on the 75 mg Q2W dose were blindly switched to placebo if LDL-C was <0.39 mmol/L on 2 consecutive measures.
** A double-blind, randomised PCSK9i treat-to-target LDL-C CV outcomes study, 2.8 years median follow-up, and more than 42% were eligible to be followed for 3-5 years.
¥ The Myocardial Ischaemia National Audit Project Annual Public Report published in 2017 found that 97.4% of ACS patients were taking statins at discharge.
‡ Included patients had a recent (1-12 months prior) acute coronary syndrome and had an LDL-C ≥1.8 mmol/L or non-HDL-C ≥2.6 mmol/L, or an ApoB of ≥1.6 μmol/L


Figure 1: On top of high-intensity/maximally tolerated statins, PRALUENT significantly reduces the risk of MACE (primary endpoint) in patients already on high intensity statins - Adapted from Schwartz et al. 20182

ODYSSEY Primary Endpoint

MACE defined as a composite of CHD death, nonfatal MI, fatal or nonfatal ischaemic stroke, or unstable angina requiring hospitalisation.
*Observed cumulative incidence of events over 4 years.


Table 1: On top of high-intensity/maximally tolerated statins, MACE risk reduction by baseline LDL-C2

ODYSSEY Table 1

*Baseline LDL-C by treatment interaction on relative risk reduction (RRR) was prespecified for the primary endpoint. Baseline LDL-C by treatment interaction on RRR for outcomes other than the primary endpoint, and on absolute risk reduction for all end points, was non-prespecified. Interaction of baseline LDL-C and treatment on absolute risk reduction (ARR) was assessed using the Gail-Simon test. The main secondary end points were tested in a hierarchical sequence. Endpoints up to CHD death were significantly reduced with PRALUENT. CHD death was the first endpoint that was not significantly modified by PRALUENT.


Figure 2: On top of high-intensity/maximally tolerated statins, PRALUENT was associated with the greatest MACE benefit in patients with baseline LDL-C ≥2.6mmol/L*2 - Adapted from Schwartz et al. 20182

ODYSSEY Figure 2

* The effect of PRALUENT on the relative risk of the composite endpoint did not differ significantly between pre-specified LDL-C subgroups.
† The NNT of 16 is calculated in accordance with the formula NNT = 1/ARR, with a 4 years Kaplan Meier estimate ARR of 6.1%.
‡ Observed cumulative incidence of events over a median of 2.8 years (post hoc analysis).


Figure 3: On top of high-intensity/maximally tolerated statins, PRALUENT provides rapid* and sustained LDL-C reduction - Adapted from Schwartz et al. 20182

ODYSSEY Figure 3

* Lipid levels can be assessed 4 to 8 weeks after treatment initiation or titration1
† Excluded LDL-C levels measured after premature discontinuation or after blinded substitution of placebo but included LDL-C levels measured after dose adjustments of PRALUENT were made under blinded conditions between 75 mg and 150 mg doses.


Figure 4: Efficacy of PRALUENT in ODYSSEY OUTCOMES (overall population)

ODYSSEY Figure 4

* MACE-plus defined as a composite of: coronary heart disease (CHD) death, nonfatal myocardial infarction (MI), fatal and nonfatal ischaemic stroke, or unstable angina (UA) requiring hospitalisation.
† Unstable angina requiring hospitalisation.
‡ CHD event defined as: major CHD event.
§ UA requiring hospitalisation, ischaemia-driven coronary revascularisation procedure.
§ Major CHD event defined as: CHD death, nonfatal MI.
|| Cardiovascular event defined as follows: CV death, any nonfatal CHD event, and nonfatal ischaemic stroke.


The safety profile in ODYSSEY OUTCOMES was consistent with the overall safety profile described in the phase 3 controlled trials.1 The only significant difference in adverse events identified in ODYSSEY OUTCOMES were injection site reactions (P<0.001).1

Table 2: PRALUENT safety and tolerability profile

Treatment-emergent AEs2 Praluent
(N=9451)
Placebo
(n=9443)
Any (n/N) 75.8% (7156) 77.1% (7282)
Serious (n/N) 23.3% (2202) 24.9% (2350)
Adverse Events2
General allergic reaction 7.9% (748) 7.8% (736)
Hepatic disorder 5.3% (500) 5.7% (534)
Local injection site reaction 3.8% (360) 2.1% (203)
Neurocognitive disorder 1.5% (143) 1.8% (167)
Cataracts 1.3% (120) 1.4% (134)
Haemorrhagic stroke, adjudicated <0.1% (9) 0.2% (16)
Adverse event that led to death 1.9% (181) 2.4% (222)
Adverse event that led to treatment discontinuation 3.6% (343) 3.4% (324)
Antidrug antibodies* 0.7% (67/9091) 0.4% (*32/9097)
Neutralising antidrug antibodies 0.5% (43/9091) <0.1% (6/9097)
Diabetic-related AEs2
Diabetes worsening or diabetic complications
Patients with DM at baseline (n/N)
18.8% (506/2688) 21.2% (583/2747)
New onset diabetes,† no baseline DM (n/N) 9.6% (648/6763) 10.1% (676/6696)

* Antidrug antibodies were defined by the presence of positive responses detected after the start of administration of the trial regimen in at least 2 consecutive post-baseline serum samples, separated by at least a 16-week period.
† New-onset diabetes was defined according to the presence of one or more of the following, with confirmation of the diagnosis by blinded external review by experts in the field of diabetes: an adverse event report, a new prescription for diabetes medication, a glycated hemoglobin level of at least 48 mmol/mol (6.5%) on 2 occasions (and a baseline level of <6.5%), or a fasting serum glucose level of at least 7.0 mmol/L on 2 occasions (and a baseline level of <7.0 mmol/L).

 

References