Dr. Mohammed Al Dubayee Consultant Pediatric Endocrinology King - - PowerPoint PPT Presentation

PCSK9 Inhibitors In Pediatric homozygous FH Saudi Arabia Experience

• Dr. Mohammed Al Dubayee

Consultant Pediatric Endocrinology King Abdullah Specialized Children Hospital-Riyadh, Saudi Arabia

• Cholesterol filled foam cell 20-week-old fetus

at autopsy

.(Am J Pathol97:327-358,1979)

• Fatty streak formation occurs in human

fetal aortas and is enhanced by maternal hypercholesterolemia

• Lipid deposits in most plaque cells

included numerous non-membrane- bound deposits of variable electron density

Pathophysiology

Molecular Defects in the Low-Density Lipoprotein Receptor Pathway

• Deletion, missense, nonsense, and insertion

mutations in (LDLR) affecting receptor function (>1,600 mutations reported to date);

• Mutations in apolipoprotein B (APOB) that

affect the ability of the ligand to recognize LDLR

• Gain-of-function mutations in PCSK9 causing a

reduction in LDLR on the cell surface;

• Mutations in LDLR accessory protein 1

(LDLRAP1) causing improper placement of LDLR on the hepatocyte membrane

• Homozygous or compound heterozygous mutations in the LDLR

gene (low-density lipoprotein receptor) encoding null or negative alleles that are associated with <2% of LDLR activity.

• Homozygotes or compound heterozygotes for LDLR-defective

alleles encoding LDLRs with 2% to 25% activity

Early intervention improves outcome

• Kaplan–Meier curves of event-free

survival in a cohort of 214 familial hypercholesterolaemia subjects treated from childhood compared with their parents

• Kaplan-Meier estimates of cumulative

coronary heart disease-free survival among patients with familial hypercholesterolemia according to statin treatment.

Cox proportional hazards model with time-varying benefit from statin therapy comparing treated with untreated person-years for survival (A) and first major adverse cardiovascular event (MACE) (B) in patients with homozygous familial hypercholesterolemia, with year of birth fixed as the mean year of birth.

king Abdullah Specialist Children's Hospital KASCH

• 14 pediatric HoFH, and more than 40 HeFH
• Open specialized pediatric lipid clinic and adult

lipid clinic

• We offer LDL apheresis program
• Cascade screening program, in house genetic

testing done in KAIMRC

• Multidisciplinary team approach

Middle East Advisory ry Panel FH

Current Vascular Pharmacology, 2015, 13, 759-770

J Atheroscler Thromb, 2018; 25: 751-770.

• Patients with clinical ASCVD and substantially elevated LDL-C levels.

Patients should be on maximally tolerated statin therapy (ideally with concomitant ezetimibe), or unable to tolerate three or more statins.

• Familial hypercholesterolaemia (FH) patients without clinical ASCVD but

with substantially elevated LDL-C levels

• Patients should be on maximally tolerated statin therapy plus ezetimibe

• The TESLA (Trial Evaluating PCSK9 antibody in Subjects With LDL Receptor

Abnormalities), proof-of-concept, part A study, performed in HoFH patients, showed reductions of 16.5% and 13.9% with evolocumab 420 mg Q4W and Q2W, respectively

Patients carrying the same mutations in homozygosity exhibited a heterogeneous response to the therapy ( 7.1% up to 56%), which, again, shows that the response to the medication is not consistant.

• The TAUSSIG study is an open-label study evaluating the long- term (5 years)

efficacy and safety of evolocumab in HoFH patients with LDL-C levels not controlled by current lipid-lowering therapy (statin alone or in combination with ezetimibe).

• An interim analysis showed that evolocumab produced a stable long-term

reduction of LDL-C levels

European Heart Journal (2018) 39, 1169–1171

PCSK9 inhibitors is very effective and very tolerable option to reduce LDL cholesterol Based on current guidelines:

• Patients with FH or ASCVD and statin resistance (on max dose) for additional

LDL lowering effect.

• In FH patients to avoid apheresis
• 2nd line to addition of ezetimibe for statin intolerant patients

Thank you