FH I & FH II Studies Praluent® (alirocumab)

ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.

Kastelein JJP, et al. Eur Heart J 2015; 36:2996–3003.

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

Study objectives

The ODYSSEY FHI and FH II studies evaluated the long-term efficacy and safety of Praluent^® 75/150 mg in heterozygous familial hypercholesterolaemia‡ (HeFH) patients with inadequately controlled low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated dose (MTD) statins** ± other lipid-lowering therapies (LLTs).

Study design

ODYSSEY FH I and FH II studies had similar study designs with FH I performed at 89 sites across North America, Europe and South Africa whilst FH II was performed across 26 sites in Europe.

Both FH I and FH II were 78 week, multicentre, double-blind, placebo-controlled, parallel group, phase III studies involving 735 adult HeFH‡ patients (FH I, n=486; FH II, n=249) who were receiving MTD statins** ± other LLTs with:

• LDL-C ≥1.8 mmol/L in patients with prior cardiovascular events^†

or

• LDL-C ≥2.6 mmol/L in patients without a history of CV events

Patients were randomised to subcutaneous Praluent^® 75 mg every 2 weeks (Q2W) (FH I, n=323; FH II, n=167) or placebo Q2W (FH I, n=163; FH II, n=82) (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 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 - including incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious AEs (SAEs), injection site reactions and adjudicated CV events.

Figure 1: ODYSSEY FHI and FH II: Study design - Adapted from Kastelein JJP, et al. Eur Heart J 2015; 36:2996–3003¹

Baseline characteristics

Baseline characteristics were well balanced between the treatment groups (Table 1). In FH I and FH II, 85.8% and 91.6% of Praluent patients received study treatment for ≥76 weeks versus 87.7% and 90.1% of placebo.

HD = coronary heart disease; CV = cardiovascular; LLT = lipid-lowering therapy, SD= standard deviation.
^*CHD history defined as acute myocardial infarction, silent myocardial infarction, unstable angina, or coronary revascularization.
^†CHD risk equivalent; Ischaemic stroke, peripheral arterial disease, moderate chronic kidney disease (estimated glomerular filtration rate of ≥30 and ≤60 mL/min/1.73 m2), and diabetes with two or more risk factors.
^§High-dose statin therapy defined as daily doses of 40–80 mg atorvastatin, 20–40 mg rosuvastatin or 80 mg simvastatin.

Key efficacy results

In adults with HeFH, Praluent75/150 mg 2QW led to significantly greater reductions in LDL-C compared to placebo (Figure 2), allowed a significantly greater proportion of patients to achieve a pre-specified LDL-C target compared to placebo (Figure 3) and LDL-C reductions were consistent and sustained over 78 weeks (Figure 4):

• At Week 24, mean percentage change in LDL-C was -48.8% (1.9mmol/L) (FH I) and -48.7% (1.74mmol/L) (FH II) for Praluent versus 9.1% (0.29mmol/L) (FH I) and 2.8% (0.07mmol/L) (FH II) for placebo (p<0.0001 for both studies) (Figure 2)
• At Week 24, regardless of prior CV status, 59.8% (FH I) and 68.2% (FH II) of Praluent patients achieved pre-specified LDL-C target of <1.8 mmol/L versus 0.8% (FH I) and 1.2% (FH II) of placebo patients (p<0.0001 for both studies) (Figure 3)
• At Week 78, the mean reduction in LDL-C level with Praluent compared with placebo was -51.8% (1.9mmol/L) (FH I)  and -52.1% (1.76 mmol/L) (FH II) (Figure 4).

Amongst Praluent patients who received double-blind treatment for at least 12 weeks, 56.6% (FH I) and 61.4% (FH II) had LDL-C levels <1.8 mmol/L at Week 8 and therefore remained on Praluent 75 mg Q2W for the duration of the study. LDL-C responses were durable and were maintained (up to 78 weeks) in Praluent treated patients.

Figure 2: ODYSSEY FH I and FH II: Mean reduction in LDL-C from baseline to Week 52 - Adapted from Kastelein JJP, et al. Eur Heart J 2015; 36:2996–3003¹

Placebo + MTD statin therapy ± other LLT
Praluent + MTD statin therapy ± other LLT
^*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 12
^†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 FH I and FH II: Proportion of patients achieving LDL-C target at Week 24 - (Adapted from Kastelein JJP, et al. Eur Heart J 2015; 36:2996–3003¹)

Placebo + MTD statin therapy ± other LLT
Praluent + MTD statin therapy ± other LLT
^*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 12
^†This number refers to the number of patients receiving Praluent (ITT analysis)^1
‡Intention to treat (ITT) analysis
 

Figure 4: ODYSSEY FH I and FH II: Mean reduction in LDL-C from baseline to Week 78^1,2 - (Adapted from Kastelein JJP, et al. Eur Heart J 2015;36:2996-3003)

Placebo + MTD statin therapy ± other LLT
Praluent + MTD statin therapy ± other LLT
^‡Intention to treat (ITT) analysis

*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

Key safety results

Frequency of TEAEs and SAEs were similar in Praluent and placebo patients (Table 2). Although a higher proportion of Praluent than placebo patients experienced injection site reactions, these differences were non-significant (FH I, p=0.77; FH II, p=0.38); most reactions were mild and none lead to discontinuation (Table 2).

Table 2: ODYSSEY FH I and FH II: Treatment-emergent adverse events (safety population) - Adapted from Kastelein JJP, et al. Eur Heart J 2015; 36:2996–3003¹

Please refer to publication for full safety profile information

CV = cardiovascular; SAEs, serious adverse events; TEAE = treatment-emergent adverse events

Conclusions

• Praluent 75/150 mg every 2 weeks significantly lowered calculated LDL-C from baseline to Week 24 in patients with HeFH on top of the maximum-tolerated dose of statin compared to placebo (-48.8% (1.9mmol/L) (FH I) and -48.7% (1.74mmol/L) (FH II) for Praluent versus 9.1% (0.29mmol/L) (FH I) and 2.8% (0.07mmol/L) (FH II) p <0.0001 for both studies)
• At Week 24, 59.8% of patients in the FHI study and 68.2% in the FHII study achieved the pre-specified target LDL-C level of <1.8 mmol/L compared to 0.8% (FHI) and 1.2% (FHII) patients on placebo (p<0.0001 for both studies)
• At week 8, over 50% of patients achieved pre-specified LDL-C target of <1.8 mmol/L and were maintained on the 75mg dose
• The incidences of TEAEs and treatment-emergent SAEs were similar between treatment groups over 78 weeks of treatment
   

^‡HeFH diagnosed by either genotyping or clinical criteria (Simon Broome or World Health Organization/Dutch Lipid clinic network score of >8)

^**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)

^§High-dose statin therapy defined as 40–80 mg atorvastatin, 20–40 mg rosuvastatin or 80 mg simvastatin

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