Treatment of a patient homozygous for familial defective apolipoprotein B-100 (FDB) with evolocumabRolf L. Andersen, MD, FACC, FNLA, Tina M. Davis, CRNP, Lars H. Andersen, BA, Heidi L. Testa, BSN, Joseluis Ibarra, MD, FACC

Lancaster General Health/Penn Medicine Research Institute

RLAnders@lghealth.org

Familial defective apolipoprotein B (FDB) is an autosomal co-dominant

disorder of lipid metabolism characterized by elevated LDL-C and

generally considered to be a type of familial hypercholesterolemia

(FH).1-4 In contrast with autosomal dominant hypercholesterolemia

caused by mutations in LDLR, most cases of FDB identified to date

result from a single mutation in APOB known as R3500Q or

p.Arg3527Gln (rs5742904).5,6 R3500Q appears frequently among

genetically confirmed cases of FH in many European nations.7-11 To

date, relatively few patients homozygous for R3500Q have been

detected, and the phenotypic data and therapeutic responses of these

patients occurred before the release of monoclonal antibody inhibitors of

proprotein convertase subtilisin/kexin type 9 (PCSK9).12-17

We retrospectively analyzed the patient’s electronic health record

to determine the patient’s lipid levels before and after the

addition of PCSK9 inhibitor evolocumab to statin/ezetimibe

therapy. We further examined the subject’s cardiovascular

medical history, recorded lipid values, social history, family

history, genetic status, and concomitant medications.

Background

Objective

Methods

Results

The subject is a male aged 40 with a history of premature ST-elevated myocardial

infarction at age 37 followed by three coronary artery bypass grafts, as well as non-ST-

elevated myocardial infarction at age 39. The subject is a current every day smoker

with a family history of premature coronary artery disease. Prior to treatment, the

subject displayed a maximum LDL-C of 318 mg/dL which was reduced to 180 mg/dL

with atorvastatin 80 mg daily and ezetemibe 10 mg daily. Based on these lipid levels,

the subject was phenotypically diagnosed with heterozygous FH. The subject was

placed on 140 mg/mL evolocumab following its approval as indicated for prior ASCVD

requiring additional lipid-lowering therapy as well as heterozygous FH. The subject’s

LDL-C then dropped from 180 mg/dL to 108 mg/dL, a reduction of 40%. After beginning

evolocumab therapy, the subject received genetic testing demonstrating his status as

homozygous for R3500Q.

ConclusionSimilar to FDB homozygotes previously described, the subject presented with lipid

levels lower than those typically displayed by patients homozygous for mutations in

LDLR, leading to his initial identification as a heterozygote. The disparity between

phenotypic and genotypic diagnosis in the case of this subject demonstrates the

increasing relevance of genetic testing to dyslipidemia, as a diagnosis of homozygous

FDB/FH qualifies the subject for an increase in evolocumab monthly dosage as well as

other adjunct therapies such as mipomersen sodium and lomitapide. While the subject

did not reach NLA lipid goals for patients with prior ASCVD, there was an observed 40%

reduction in LDL-C after treatment with evolocumab 140 mg/mL.18 This may be due to

enhanced LDLR-mediated uptake of VLDL and IDL particles as well as larger LDL

particles as previously described in an FDB homozygote.13

Here we report the first known case study of the use of PCSK9

inhibitors in a patient homozygous for R3500Q. We sought to

determine the effect of PCSK9 therapy (140 mg/mL evolocumab) on the subject’s lipid profile related to goal lipid levels for a patient in secondary prevention. We also compare the subject’s baseline levels to other R3500Q homozygotes previously reported.

Lipid values

(mg/dL)

Off treatment 80 mg atorvastatin

10 mg ezetimibe

80 mg atorvastatin

10 mg ezetimibe

140 mg/mL evolocumab

LDL-C 318 180 108

Non-HDL-C 334 197 125

Triglycerides 87 83 85

HDL-C 44 44 39

VLDL-C 16 17 170

50

100

150

200

250

300

350

Off treatment 80 mg atorvastatin, 10 mgezetimibe

80 mg atorvastatin, 10 mgezetimibe, 140 mg/mL

evolocumab

LD

L-C

(m

g/d

L)

Figure 1. R3500Q homozygous subject lipid levels Figure 2. Lipid levels with increasing treatment intensity

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