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Azienda Ospedaliero Universitaria
Trieste S.C. III Medica
NUOVE CLASSI di FARMACI nelle
DISLIPIDEMIE SEVERE
Luigi Cattin
INHERITED MONOGENIC HYPERCHOLESTEROLEMIAS
Genetic disorders due to mutations of a single gene
(monogenic / Mendelian disease) Biochemical phenotype: LDL-C >95th percentile Clinical phenotype: - Tendon and cutaneous xanthomatosis - Premature coronary artery disease
Dominant transmission Heterozygote LDL-C ↑ ↑
(One mutant allele)
Homozygote LDL-C ↑ ↑ ↑ ↑
(Two mutant alleles)
Gene dosage effect
INHERITED MONOGENIC HYPERCHOLESTEROLEMIAS
Recessive transmission
• Heterozygote LDL-C ↔
(One mutant allele)
• Homozygote LDL-C ↑ ↑ ↑
(Two mutant alleles)
The Number of Familial Dyslipidaemias in Italy
Familial hypercholesterolemias 121.000 Familial combined hyperlipidemia > 600.000 Type III hyperlipidemia 10.000 ? Severe hypertriglyceridemias 200 ? Familial hypertriglyceridemias ? Familial hypobetalipoproteinemias 20.000 Combined hypolipidemia ? Abeta & Chylomicron Retention Disease 50-100 Familial hypoalphalipoproteinemias ? Familial hyperalphalipoproteinemias ?
Percentuale di individui con diagnosi di FH in diversi Paesi espressi come frazione dei soggetti previsti *
*Soggetti teoricamente previsti essere affetti da FH sulla base di una frequenza di 1/500 nella popolazione generale
Ipercolesterolemie Familiari AGENDA
Come riconoscerle ? inquadramento genetico-molecolare diagnosi clinica Come curarle ? statine nuovi farmaci - Inibitori di PCSK9 (Evolocumab; Alirocumab) - Lomitapide - Mipomersen
Ipercolesterolemie Familiari AGENDA
Come riconoscerle ? inquadramento genetico-molecolare diagnosi clinica Come curarle ? statine nuovi farmaci - Inibitori di PCSK9 (Evolocumab; Alirocumab) - Lomitapide - Mipomersen
Disease Gene Prevalence
ADH-1 (Classic FH)
Heterozygous
Homozygous
LDL-R
1 per 500
1 per million
ADH-2 (FDB)
Heterozygous
Homozygous
Apo B-100
1 per 1000
>1 per million
ADH-3
Heterozygous
Homozygous
PCSK9
?
?
DOMINANT HYPERCHOLESTEROLEMIAS - ADH (Familial hypercholesterolemia phenotype)
Disease Gene Prevalence
ADH-1 (Classic FH)
Heterozygous
Homozygous
LDL-R
1 per 500
1 per million
ADH-2 (FDB)
Heterozygous
Homozygous
Apo B-100
1 per 1000
>1 per million
ADH-3 (ADH)
Heterozygous
Homozygous
PCSK9
?
?
DOMINANT HYPERCHOLESTEROLEMIAS - ADH (Familial hypercholesterolemia phenotype)
“DOMAINS”
“Ligand binding” 292 aa
“ EGF precursor homology”
400 aa
“O-linked sugars” 58 aa
“Membrane spanning” 22 aa
“Cytoplasmic” 50 aa
321
567
4
NH2
A B
C
COOH
cysteine
FH in Italy
Heterozygotes n. 121.000
LDL chol. 240-450 mg/dl
Homozygotes and Compound Heterozygotes n. 50
LDL chol. 420-950 mg/dl
Disease Gene Prevalence
FH-1 (Classic FH)
Heterozygous
Homozygous
LDL-R
1 per 500
1 per million
FH-2 (FDB)
Heterozygous
Homozygous
Apo B-100
1 per 1000
<1 per million
FH-3 (ADH)
Heterozygous
Homozygous
PCSK9
?
?
DOMINANT HYPERCHOLESTEROLEMIAS - ADH (Familial hypercholesterolemia phenotype)
LDL
SYNTHESIS OF CHOLESTEROL
HMG CoA Reductase
ACAT
CHOLESTEROL ESTERS
MEMBRANES STEROIDS
BILE ACIDS
SYNTHESIS OF LDL RECEPTORS
INHIBITS
ACTIVATES
EXCESS CHOLESTEROL
RNA
DNA
LDL receptors
LDL
B-100
Disease Gene Prevalence
FH-1 (Classic FH)
Heterozygous
Homozygous
LDL-R
1 per 500
1 per million
FH-2 (FDB)
Heterozygous
Homozygous
Apo B-100
1 per 1000
<1 per million
FH-3 (ADH)
Heterozygous
Homozygous
PCSK9
?
?
DOMINANT HYPERCHOLESTEROLEMIAS (Familial hypercholesterolemia phenotype)
PCSK9 gene (1p32) Exon 1 2 3 4 5 6 7 8 9 10 11 12
5’ 3’
mRNA (3636 nt)
PCSK9 protein (692 aa)
N - 1-30 31-152 153-425 426-692
- C SP PRO Catalytic domain CRR
Synthesized by the liver and secreted into the circulation
Proprotein Convertase Subtilisin/hexin type 9 Serine Protease
ER
Golgi
Endosome Coated Pit
3
2 1
SECRETION OF PCSK9
SYNTHESIS OF PCSK9 RNA DNA
Regulation of LDL-R number by PCSK9 activity
LDL-R degradation
LDL
ER
Golgi
Endosome Coated Pit
3
2 1
SECRETION OF PCSK9
SYNTHESIS OF PCSK9 RNA DNA
M
LDL-R degradation
Reduction of LDL-R number induced by increased PCSK9 activity
M
M
M M M M
Ipercolesterolemie Familiari AGENDA
Come riconoscerle ? inquadramento genetico-molecolare diagnosi clinica Come curarle ? statine nuovi farmaci - Inibitori di PCSK9 (Evolocumab; Alirocumab) - Lomitapide - Mipomersen
CLINICAL DIAGNOSIS OF FAMILIAL HYPERCHOLESTEROLEMIA
Plasma LDL-C level
Clinical history
Family history
Clinical diagnosis
30
25
20
15
10
5
0 <80 101-120 141-160 181-200 221-240 261-280 301-320 341-360 381-400
81-100 121-140 161-180 201-220 241-260 281-300 321-340 361-380 >400
non FH FH LDL cholesterol (mg/dl)
Frequency (%) LDL cholesterol distribution in FH families
Approccio clinico al paziente FH 1
Soffio periombelicale
Soffi Carotidei Soffio Aortico
Arco Corneale
Xantomi Tendinei
0,0
10,0
20,0
30,0
40,0
50,0
60,0
30-34 35-39 40-44 45-49 50-54 55-59 >60
Males (n.216) Females (n.354)
CHD in Italian FH heterozygotes (%)
(Years)
Ipercolesterolemie Familiari AGENDA
Come riconoscerle ? inquadramento genetico-molecolare diagnosi clinica Come curarle ? statine nuovi farmaci - Inibitori di PCSK9 (Evolocumab; Alirocumab) - Lomitapide - Mipomersen
Ipercolesterolemie Familiari AGENDA
Come riconoscerle ? inquadramento genetico-molecolare diagnosi clinica Come curarle ? statine nuovi farmaci - Inibitori di PCSK9 (Evolocumab; Alirocumab) - Lomitapide - Mipomersen
PCSK9 gene (1p32) Exon 1 2 3 4 5 6 7 8 9 10 11 12
5’ 3’
mRNA (3636 nt)
PCSK9 protein (692 aa)
N - 1-30 31-152 153-425 426-692
- C SP PRO Catalytic domain CRR
Synthesized by the liver and secreted into the circulation
Proprotein Convertase Subtilisin/hexin type 9 Serine Protease
ER
Golgi
Endosome Coated Pit
3
2 1
SECRETION OF PCSK9
SYNTHESIS OF PCSK9 RNA DNA
M
LDL-R degradation
Reduction of LDL-R number induced by increased PCSK9 activity
M
M
M M M M
Ipercolesterolemie Familiari AGENDA
Come riconoscerle ? inquadramento genetico-molecolare diagnosi clinica Come curarle ? statine nuovi farmaci - Inibitori di PCSK9 (Evolocumab; Alirocumab) - Lomitapide - Mipomersen
Treatment of Drug-Resistant Hypercholesterolemia
In December of 2012, the United States Food and Drug Administration (FDA) the use of lomitapide for patients with homozygous FH
PHASE 3 STUDY RESULTS: changes in LDL-C through week 78 (pazients n. 23)
Ipercolesterolemie Familiari AGENDA
Come riconoscerle ? inquadramento genetico-molecolare diagnosi clinica Come curarle ? statine nuovi farmaci - Inibitori di PCSK9 (Evolocumab; Alirocumab) - Lomitapide - Mipomersen
Antisense Technology
Treatment of Drug-Resistant Hypercholesterolemia
Mipomersen (ISIS 301012) is an antisense oligonucleotide complementary to the coding region for human apolipoprotein B (apo B) mRNA. Through direct binding to apo B mRNA, mipomersen inhibits apo B production.
In January of 2013, the United States Food and Drug Association (FDA) approved the drug for use in patients with homozygous FH.
In clinical trials, many patients stopped taking the drug due to side effects such as flu-like symptoms, injection site reactions, and liver toxicity.
The Role of Apo B in VLDL Synthesis
Dose Dependent Effect of Mipomersen on
Apo B (A) and LDL-C (B) Levels
Dislipidemie Severe AGENDA
Nuovi farmaci?: - Gene Therapy (Glybera)
Glybera®: Mechanism of action
44
The LPL • Lipoprotein lipase
• Expression: heart, muscle, adipose tissue • Functions: triglyceride hydrolase and ligand/bridging
factor for receptor-mediated lipoprotein uptake (VLDL & chylomicrons)
• Stimulated by: Apo-CII, insulin, heparin
Source: John R Burnett & Amanda J Hooper, Alipogene tiparvovec, an adeno-associated virus encoding the Ser447X variant of the human lipoprotein lipase gene for the treatment of patients with lipoprotein lipase deficiency, 2009 11(6):681-691 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102144/figure/F3/>
predicted tertiary structure for human LPL
LipoProtein Lipase Deficiency Epidemiology
EU prevalence : 2/106 US prevalence : 1/106 Worldwide prevalence : 1-2/106
Founder effect : Eastern Quebec : 1/10,000
Sources : http://www.ncbi.nlm.nih.gov/books/NBK1308/ http://www.ncbi.nlm.nih.gov/pubmed/20427244 La déficience en lipoprotéine lipase chez les canadiens français-Carole Dionne 1991
46
Plasma TG > 20g/L [1]
–Episodes of abdominal pain –Recurrent acute pancreatitis –Eruptive cutaneous xanthomata [2]
–Hepatosplenomegaly
Plasma TG > 40g/L ‒Lipemia retinalis [3]
‒Complications
Plasma TG< 10g/L –Clinical goal
LPLD natural history
Early in childhood
47
Symptoms
Repeated episodes of abdominal pain
Eruptive cutaneous xanthomatosis (fat accumulation in the skin)
<http://www.healthcentral.com>
How patient receives Glybera®
Source : Glybera® EPAR
LPL gene
rAAV vector
Max total dose : 1x 1012 gc/kg Single treatment only One-time series of IM injections in the legs 1.5 x 1012 gc or 0.5 ml of solution for injection/site
Conclusion of the clinical developement
Good tolerance / No dose limiting toxicity TG levels decrease for 3 months post dosing CM decrease & improve of CM metabolism LPLS447X expression in muscle, 6 months after
administration (1)
Follow up: prevention and reduction of pancreatitis
attacks Source : Sier‐Ferreira et al 2012 in prep 50
Indicazioni dei Nuovi Farmaci
Omozigoti o con eterozigosi doppia (in combinazione con LDL aferesi).
Limitatamente a PCSK9-I: - eterozigoti con ischemia d’organo o
equivalente ischemico, che non tollerano o non rispondono alle statine;
- soggetti a rischio cardiovascolare molto elevato, che non tollerano o non rispondono alle statine.