ISIS 301012: The Reduction of Atherogenic Lipids in

Drugs
in (Familial) Hypercholesterolemia
Meeike Kusters
Current treatment options
 Statins
 Ezetimibe
 Bile Acid Sequestrants
 Fibrates
 Niacin
Statins
Approved statins
 Simvastatin: 10 years
 Pravastatin: 8 years
 Rosuvastatin: 6 / 10 years
 Atorvastatin: 6 / 10 years
 Fluvastatin: 10 years
 Lovastatin: 10 years
Statins
 LDL-C lowering 25-60%
 Doubling dose  incremental reduction 6-7%
 Excellent safety profile in children
 In adults, statins have convincingly been shown to be safe and well
tolerated agents that reduce CVD morbidity and mortality in a wide
range of patients
Avis, ATVB 2007
Avis, ATVB 2007
Avis, ATVB 2007
Monitoring Statin Therapy
 Hepatic aminotransferases, creatine kinase and creatine levels
before treatment is started
 Monitor weight, growth, physical and sexual development and
hepatic aminotransferases
 Plasma CK levels should be measured if musculoskeletal symptoms
are reported
 Fasting glucose levels should be measured every 6 months in
children on high doses who are obese or have impaired glucose
intolerance
Ezetimibe
Ezetimibe in children
 Registered from the age of 10 years
 Kusters DM, J Pediatrics, 2015:
 Randomized, double blind placebo-controlled trial children 6-10
years of age
 Mean LDL-C reduction 27%
 Safe, well tolerated
Ezetimibe in sitosterolemia
 Sitosterolemia:
 ↑serum plant sterol levels
 Mutation in ABCG5 / ABCG 8
 Premature atherosclerosis and xanthomas
 Treatment with ezetimibe:
 40-50% reduction of sitosterol and campesterol levels
 Safe and well tolerated
Ezetimibe in children
 Attractive in children:
 Low peripheral blood concentrations
 Limited side effects, palatable tablet
 Significant lipid lowering
 Well tolerated
 Action beyond lipid-lowering?
Primary Endpoint
On-Treatment
HR 0.924 CI (0.868, 0.983)
p=0.012
Simva — KM 32.4%
2079 events
EZ/Simva — KM 29.8%
1932 events
7.6% Treatment effect
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (> 30 days after randomization), or stroke
Bile Acid Sequestrants
 Long been considered the only suitable lipid-lowering drug in
children and are recommended in the 1992 NCEP guidelines
 Mechanism of action:
 binding to bile acids in intestinal lumen  interrupts the
enterohepatic circulation of bile acids  increased
conversion of cholesterol into bile in the liver.
The resulting decreased cholesterol levels in hepatocytes
induce the liver to upregulate LDL-receptor activity,
causing an increased clearance of LDL-C from the
circulation
Bile Acid Sequestrants
 Not systemically absorbed  considered safe
 Side effects:
 Gastro-intestinal complaints
 Interference with vitamin uptake
 Available options:
 Colestyramine
 Colesevelam
Fibrates
 Not well studied in children; no registration
 Mechanism of action is complex and largely unknown
 Decreased production of very low-density lipoprotein
cholesterol (VLDL-C) and an increased clearance of
triglycerides
 Adverse reactions are similar to those of statins
 In children, fibrates are used rather for patients with severe
elevations in triglycerides with an associated risk for
pancreatitis than for the prevention of CVD
Nicotinic Acid (Niacin)
 Niacin favorably affects VLDL, LDL-C and increases HDL-C
 Important adverse effects
 Niacin is not registered and not recommended for pediatric
use
Novel treatment options
 Apo B mRNA antisense drugs
 PCSK9 inhibitors
 MTP inhibitors
 CETP inhibitors
Apo B mRNA antisense drugs
 Mipomersen: a subcutaneously administered antisense
oligonucleotide (ASO)
 Inhibits apoB-100 synthesis in the liver, independent of LDLR
activity
 Side effects: flu-like symptoms, injections site reactions
 Approved in the US only for homozygous patients
Dose Dependent Reduction in
ApoB vs. Time
Odyssey Outcomes IM 10-6-15 - slides contain off label data
PCSK9 inhibitors
22
PCSK9 inhibitors
 Inhibition of proprotein convertase subtilisin/kexin type 9, that
promotes the lysosomal degradation of the LDLR within hepatocytes
 Heterozygous FH:
 LDL-C ↓ 61% relative to placebo
 ApoB ↓ 49% relative to placebo
 Lp(a) ↓ 32% relative to placebo
 Homozygous FH
 LDL-C ↓ 32% relative to placebo
 ApoB ↓ 23% relative to placebo
 Lp(a) ↓ 12% relative to placebo
 Phase III
The Use of a PCSK9 Monoclonal AB
in HeFH Patients: Results
Odyssey Outcomes IM 10-6-15 - slides contain off label data
MTP inhibitors: lomitapide
 Inhibition of microsomal triglyceride transfer protein which transfers
triglycerides into VLDL and chylomicrons in hepatocytes and
enterocytes
 Heterozygous FH:
 LDL-C ↓ up to 50.9% from baseline
 ApoB ↓ up to 55.6% from baseline
 Homozygous FH:
 LDL-C ↓ 50% from baseline
 ApoB ↓ 49% from baseline
 Lp(a) -15-19%; no significant change after 78 weeks of
treatment
 Approved by US and EMA for homozygous FH patients
The Inhibition of Cholesterol Ester Transfer Protein
CETP inhibitors
 Inhibition of cholesteryl ester transfer protein resulting in
reduced exchange of cholesterol from HDL particles to VLDL
and LDL particles
 Heterozygous FH:
 LDL-C ↓ 39.7% relative to placebo
 ApoB ↓ 24.8% relative to placebo
 LP(a) ↓ 27.9% relative to placebo
 HDL-C ↑ 102.1% relative to placebo
 Phase III
Terminated treatment strategies
 ACAT Inhibitors
 Inhibition of acyl-coenzyme A:cholesterol acyltransferase
which catalyzes the intra-cellular esterification of free
cholesterol and fatty acids to cholesteryl esters
 Squalene Synthase Inhibitors
 Inhibition of farnesyldiphosphate farnesyltransferase 1
that plays a critical role in the mevalonate pathway
 Thyroxin Receptor Agonists
 Selective affinity for thyroid hormone receptor b, which is
expressed in the liver
Questions?