Anti-PCSK9 antibodies for the treatment of heterozygous familial hypercholesterolemia: patient selection and perspectives

Figures & data

Table 1 Clinical criteria for the diagnosis of familial hypercholesterolemia

A
Dutch lipid clinic network criteria
Criteria	Points
LDL-C values
>330 mg/dL	8
250–330 mg/dL	5
190–250 mg/dL	3
150–190 mg/dL	1
Personal history
Premature coronary heart disease	2
Premature cerebral or peripheral vascular disease	1
Family history
First-degree relation with premature coronary heart disease	1
Disease
First-degree relation with LDL-C >95th percentile	1
Children <18 years with LDL-C >95th percentile	2
Physical examination
Presence of xanthomas	6
Presence of corneal arcus (<45 years)	4
Genetic tests
Mutation of the LDLR gene	8

B
Simon Broome criteria
Criteria	Description
a	TC >7.5 mmol/L or LDL-C >4.9 mmol/L in adults, or TC >6.7 mmol/L or LDL-C >4.0 mmol/L in children <16 year
b	Tendinous xanthomata in the patient or a first-degree relative
c	DNA-based evidence of mutation in the LDLR, APOB, or PCSK9 gene
d	Family history of myocardial infarction before age of 50 year in a second-degree relative or before age 60 year in a first-degree relative
e	Family history of raised TC >7.5 mmol/L in a first- or second-degree relative
Diagnosis
A definite FH diagnosis requires either criteria a and b or criterion c
A probable FH diagnosis requires criteria a and d or criteria a and e

C
Make Early Diagnosis to Prevent Early Death score
Age (years)	First-degree relative with FH (total cholesterol cutpoints) (mmol/L)	Second-degree relative with FH (total cholesterol cutpoints) (mmol/L)	Third-degree relative with FH (total cholesterol cutpoints) (mmol/L)	General population (total cholesterol cutpoints) (mmol/L)
<20	5.7	5.9	6.2	7.0
20–29	6.2	6.5	6.7	7.5
30–39	7.0	7.2	7.5	8.8
>40	7.5	7.8	8.0	9.3

Note: Diagnosis: FH is diagnosed if total cholesterol levels exceed the cut point.

Abbreviations: FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.

Table 2 Effects of PCSK9 inhibitors evolocumab and alirocumab in HeFH

Clinical trial	Subjects (background LLT)	Intervention (dose, frequency)	LDL-C (% change from baseline)
EVOLOCUMAB
RUTHERFORD^Citation45   12 weeks	HeFH, LDL-C ≥100 mg/dL (statin ± ezetimibe)	420 mg Q4W	−56.4%
RUTHERFORD-2^Citation46   12 weeks	HeFH, LDL-C ≥100 mg/dL (statin ± ezetimibe)	140 mg Q2W 420 mg Q4W	−59.2% −61.3%
ALIROCUMAB
ODYSSEY FH I and FH II^Citation39   78 weeks	HeFH, LDL-C ≥100 mg/dL (for primary prevention) or LDL-C ≥70 mg/dL (for secondary prevention) (max tolerated statin ± other LLT)	75 mg Q2W (increased at 150 mg Q2W if LDL-C ≥70 mg/dL at week 8)	FH I: −57.9% FH II: −51.4%
ODYSSEY HIGH FH^Citation41   78 weeks	HeFH, LDL-C ≥160 (stable LLT)	150 mg Q2W	−39%
ODYSSEY ESCAPE^Citation42   18 weeks	HeFH undergoing lipoprotein apheresis (lipoprotein apheresis + stable LLT + diet + exercise)	150 mg Q2W	−42.5%
ODYSSEY LONG TERM^Citation43   78 weeks	HeFH or established CHD or CHD equivalent, LDL-C≥70 mg/dL (max tolerated statin ± other LLT)	150 mg Q2w	−61.9%
ODYSSEY OLE   176 weeks	HeFH who have completed one of the 4 parent studies (max tolerated statin ± other LLT)	ONGOING

Abbreviations: CHD, coronary heart disease; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; PCSK9, proprotein convertase subtilisin kexin 9; Q4W, every 4 weeks; Q2W, every 2 weeks.

Table 3 TEAE frequency in PCSK9 mAbs clinical trials in HeFH patients

TEAEs	PCSK9 mAbs	Placebo
TEAEs (any)	51%–81.7%	28%–82.5%
Serious adverse events	1.8%–18.7%	0%–19.5%
Leading to death	0%–1.9%	0%–1.3%
Leading to treatment discontinuation	0%–7.2%	0%–6.1%
Common adverse events
Injection site reaction	2.4%–12.4%	0%–11%
Nasopharyngitis	7%–13.9%	4%–22.2%
Influenza	4.5%–14.4%	2.9%–10.7%
Headache	4%–9.6%	0%–8.9%
Diarrhea	1.8%–9.8%	0%–8.6%
Nausea	1.8%–4.9%	0%–14.3%
Myalgia	1.9%–9.8%	0%–8.6%

Abbreviations: HeFH, heterozygous familial hypercholesterolemia; mAb, monoclonal antibody; PCSK9, proprotein convertase subtilisin kexin 9; TEAEs, treatment-emergent adverse events.

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