ORION Program Is Comprehensive Series of Clinical Trials to Profile Inclisiran’S Efficacy and Safety

23rd ANNUAL CONGRESS Lebanese Society of Endocrinology, Diabetes, and Lipids

Cardio-metabolic, Thyroid and Pituitary Diseases

10-11 July 2020 Hilton Habtoor- Beirut - Lebanon Hypercholesterolaemia: a step towards achieving optimal treatment targets and cardiovascular prevention

Professor Frederick Raal FCP(SA),FRCP, Cert Endo, MMED, PHD

Head, Division of Endocrinology & Metabolism Director Carbohydrate and Lipid Metabolism Research Unit University of the Witwatersrand

Presenter Disclosure Information

Frederick J. Raal FCP(SA), FRCP, Cert Endo, MMed(Wits), PhD

Professor Raal has received research grants, honoraria, or consulting fees for professional input and/or delivered lectures from Sanofi, Regeneron, Amgen, Novartis and The Medicines Company. A case of severe hypercholesterolaemia

Mrs. TDK

50 year old female. Well. Non smoker and no other risk factors for ASCVD. Serum cholesterol measured because of positive family history of coronary artery disease, her father having undergone coronary bypass surgery at age 52.

Fasting lipid profile

Total cholesterol: 15.6 mmol/L (604 mg/dL) Triglycerides: 1.34 mmol/L HDL-cholesterol: 1.8 mmol/L LDL-cholesterol 13.2 mmol/L (510 mg/dL)

Familial Hypercholesterolaemia (FH)

One of the most common and serious single gene disorders, affecting approximately 1 in every 311 persons or over 30 million people worldwide

Beheshti SO, et al. J Am Coll Cardiol 2020:75:2553-2566 Hu P, et al. Circulation 2020:141:1742-1759 Familial hypercholesterolaemia (FH) Is not a rare genetic disorder: Prevalence is at least 5x other inherited conditions

5.0 4.5 4.0 3.5 3.2

3.0

2.5 births Frequency per 1,000 births of 2.0 common genetic disorders

Frequency 1,000 per Frequency 1.5 1.0 1.0 0.8 0.5 0.5 0.5 0.5 0.5 0.4 0.4 0.3 0.0 FH Dominant Adult Sickle cell Multiple Huntington’s Fragile X Neuro- Cystic Duchenne otosclerosis PCKD disease exostoses disease syndrome fibromatosis fibrosis muscular dystrophy

Wiegman R, et al. European Heart Journal. 2015;36:2423-2437 Familial hypercholesterolaemia

Mother Father Offspring

X X

X X LDL receptor X locus on chromosome 19

FH Heterozygote FH Homozygote . 1 in 200- 500 in population . 1 in 300000 to 1 million in population . Half normal number of LDL receptors . Few or no LDL receptors . 2-fold increase in plasma LDL-C . 4 to 6-fold increase in plasma LDL-C . ASCVD manifests at age 35 . ASCVD manifests in childhood

Cuchel M et al. Eur Heart J 2014;35:2146-57 Genetics and genetic heterogeneity of FH

A B

x LDLRAP1

PCSK9 APOB

x x x x

LDLR

Normal subject Normal allele

x Chr 1 Chr 2 Chr 19 FH heterozygote FH mutation- FH homozygote bearing allele

LDLRAP1=Low-density lipoprotein receptor adapter protein 1 PCSK9=Proprotein convertase subtilisin/kexin type 9 APOB=Apolipoprotein B LDLR=Low-density lipoprotein receptor Cuchel M et al. Eur Heart J 2014;35:2146-57 Phenotypic variability in FH

LDL cholesterol Clinical Mutation diagnosis diagnosis mmol/L mg/dL Homozygous LDL-receptor negative

20 770 Homozygous FH Homozygous LDL-receptor Compound heterozygous defective or homozygous LDL-receptor APOB/PCSK9 15 580 LDLRAP1/ARH 13 500 Homozygous APOB defect/PCSK9 gain of 10 390 Heterozygous FH function

5 190 Common or polygenic hypercholesterolemia

0 0

Adapted from Cuchel M, Eur Heart J 2014;35:2146-57 Therapy for severe FH

. Pharmacotherapy - lipid modifying drugs . Extracorporeal removal of LDL - LDL apheresis . Surgical therapy - portacaval shunt - partial ileal bypass . Methods to restore LDL receptor activity - liver transplantation - gene therapy

Gidding S. The agenda for FH; Circulation 2015;132:2167-2192 STATIN THERAPY FOR FH

Despite the absence of randomised clinical trial in subjects with FH, since their introduction in the late 1980’s statins have become the mainstay of therapy.

Gidding, S. The agenda for FH; Circulation 2015;132:2167-2192 Compensatory increase in Synthesis of Hepatic LDL Receptors

LDL in plasma

LDL Synthesis uptake HMG-CoA

HMG-CoA Blocked By statins Cholesterol Cholesterol

Brown and Goldstein.Science.1986;232:34. High Dose Simvastatin and Atorvastatin in Homozygous FH % LDL-C Reduction Simvastatin 80 mg/d - 25%

Simvastatin 160 mg/d - 31%

Atorvastatin 40 mg/d - 20%

Atorvastatin 80 mg/d - 33%

Raal et al. Atherosclerosis 1997;135:249-56. Raal et al. Atherosclerosis 2000;150:421-8. Low-density lipoprotein-cholesterol levels in homozygous autosomal dominant hypercholesterolaemia patients after LLT

25 Two null alleles One null and one defective allele Two defective alleles 20

C levels (mmol/L) levels C -

LDL 5

0 Prior to LLT After LLT

Sjouke B. Eur Heart J. 2015;36:560-565 Mechanisms of action of high dose statins in HoFH Receptor Receptor defective negative HoFH HoFH

Upregulation of Reduction in LDL hepatic apo-B receptors lipoprotein synthesis

Raal et al. Atherosclerosis 2000;150:421-8. Mean percentage reduction in LDL-C for patients with HoFH receiving ezetimibe plus statin

Entire Study Cohort (n=48) Genotype Confirmed HoFH (n=35))

Ezetimibe + Ezetimibe + Statin-80 Statin 80 Statin-80 Statin 80

0% 0%

-5% -5% -5.6% -7.0%

-10% -10%

-15% -15%

Cholesterol Reduction Cholesterol

Cholesterol Reduction Cholesterol -

- -20% -20% % LDL % -25% LDL % -25% -26.6% -27.5% -30% -30%

Gagne C. Circulation 2002;105:2469-2475 Reduction in LDL-C in FH with combination lipid-lowering therapy

LDL-C 10 -50% mmol/L 55 - 70 % reduction 10-20% In LDL-C 5 5-10%

Adapted from Nordestgaard B.G. et al. Eur Heart J 2013;34:3478-3490 and Hovingh G.K et al. Eur Heart J 2013;34, 962–971 Mrs TDK, a case of severe hypercholesterolaemia

Treated with Rosuvastatin 40mg daily x 3 months

Lipid profile

Total cholesterol: 9.4 mmol/L (364 mg/dL) Triglycerides: 1.20 mmol/L HDL-cholesterol: 1.9 mmol/L LDL-cholesterol 7.0 mmol/L (270 mg/dL) Mrs TDK, a case of severe hypercholesterolaemia

Ezetimibe 10mg daily added

Lipid profile

Total cholesterol: 7.6 mmol/L (294 mg/dL) Triglycerides: 1.30 mmol/L HDL-cholesterol: 1.8 mmol/L LDL-cholesterol 5.2 mmol/L (201 mg/dL) SAFEHEART study: Proportion of FH patients at LDL-C target

100 CVD (+) / LDL-C Target <1.8 mmol/L (70mg/dL) 90 80

70 60 50

40 target (%) target

Attainment of Attainment 30 20 10 0 1.8 2.6 100 CVD (-) / LDL-C Target <2.6 mmol/L (100mg/dL) 90 80

70 60 50

40 target(%)

Attainmentof 30 20 10 0 0 1.3 2.6 3.9 5.2 6.5 7.8 LDL-C Target (mmol/L)

Perez de Isla et al. J Am Coll Cardiol. 2016;67((11):1275-85 Current/Emerging therapies for severe FH . While statins and ezetimibe constitute first-line therapy, they provide less than optimal LDL-C reduction in severe FH . in particular HoFH requires combination therapy: high-dose statin, ezetimibe, with or without apheresis Therapies for severe FH:

Emerging therapies New therapies . PPAR delta agonists . Mipomersen (apoB inhibitor) . Acetyl CoA carboxylase inhibitor (Gemcabene) . Lomitapide (MTP inhibitor) . ACL/AMP kinase modulator (ETC-1002 or . PCSK9 inhibitors Bempedoic acid) . ANGPTL3 inhibitors - mAbs, Inclisiran . Others e.g. CETP–inhibitors, probucol . AAV-8 LDLR gene replacement therapy

Stein EA, Raal FJ. Curr Cardiol Reports 2015;17:1-11 INHIBITION OF PCSK9 in FH

1. How effective is PCSK9-inhibitor therapy in FH?

1. In patients with HoFH with either no (<2%) or little (2-25%) LDL-receptor activity will PCSK9 inhibition be effective? With each doubling of statin dose only results in a further 6% reduction in cholesterol

)

e 0

(

C Rule of 6 !

-25

i n

-50

h LDL cholesterol with statin C -75 0 20 40 60 80 Statin (mg/day)

Davidson M, J Am Coll Cardiol. 2003;42:398-399 Statin therapy and upregulation of PCSK9 Statins

SREBP-2

PCSK9 LDLR

LDLC SREBP2 = Sterol regulatory element-binding protein -2 Zhang L. Int J Biol Sci 2012;8:310-327 Serum PCSK9 levels in subjects with heterozygous and homozygous familial hypercholesterolaemia 600 PCSK9 500 Controls HeFH HoFH 400

300

200 PCSK9 (ng/mL)PCSK9

100

R=0.68 p>0.001 0 0 5 10 15 20 LDL-Cholesterol (mmol/L)

Raal FJ. J Am Heart Assoc 2013;2:e000028 RCTs (Phase III trials) with PCSK9 inhibitors published or presented

RCT Study Design Net LDL-C reduction (%) DESCARTES Long-term efficacy & safety -49 to -62 LAPLACE-2 Combination therapy with statins -63 to -75 GAUSS-2 Statin intolerance -37 to -39 MENDEL-2 Monotherapy -39 to -40 RUTHERFORD 2 Heterozygous FH -60 to -66 TESLA Homozygous FH -31 ODYSSEY MONO Monotherapy -32 ODYSSEY COMBO II Comparison with ezetimibe -51 to -58 ODYSSEY FH I and II Heterozygous FH -62 ODYSSEY Long-term Combination with statins including HeFH -30 ODYSSEY ALTERNATIVE Statin intolerance -39 ODYSSEY HIGH FH Severe heterozygous FH -24 to -49 ODYSSSEY OPTIONS Different strategies in high risk subjects -20 to -37

De Backer et al. Eur Heart J 2015;36:214-218 ODYSSEY FH I and FH II - Results over 52 Weeks Achieved LDL-C over time on background of maximally tolerated statin with or without other LLT

4.5 174 4.0 mmol/L 4.0 mmol/L Placebo FH I 4.0 155 3.3 135 3.5 mmol/L 3.7 mmol/L mg/dL 3.0 Placebo FH II 116

2.5 Alirocumab FH I 97 1.8 mmol/L 1.9 mmol/L

2.0 77

C, C, mean LS mmol/L (SE), - 1.5 1.8 mmol/L Alirocumab FH II 1.7 mmol/L 58 LDL 1.0 39 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Dose  if LDL-C > 1.8 mmol/L at W8 Time (weeks)

Kastelein JP et al. Eur Heart J 2015;36:2996-3003 Rutherford-2 Mean percentage change from baseline in LDL cholesterol

in the four groups. Mean LDL-C baseline = 4 mmol/L

Placebo monthly (n=55) 0 Placebo every 2 weeks (n=54) -20

-40 140 mg evolocumab every 2 weeks (n=110)

-60

420 mg evolocumab monthly (n=110) -80

(%) baseline LDL in cholesterol from Change Baseline Week 2 Week 8 Week 10 Week 12 Evolocumab every 2 wks ..       Evolocumab monthly ..  ..  ..  .. Study Week Raal et al. Lancet 2015;385:331-40 Rutherford-2 Mean percentage change from baseline in LDL cholesterol

according to FH genotype

C - 0 Negative Defective -10 Unclassified No mutation identified -20

-30

-40

-50

-60

-70

Percent changes from baseline in LDL in baseline from changes Percent -80 Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12

     

Raal et al. Lancet 2015;385:331-40 The TESLA Part B Study

. Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities Part B . Design A 12-week randomized, double-blind, placebo-controlled multicenter phase 3 study . Objective To evaluate the efficacy and safety of evolocumab in patients with HoFH

Raal et al. Lancet 2015;385:341-50

TESLA Study design

Screening period Evolocumab 420 mg SC QM (N = 33)

Fasting LDL-C 2:1

5–10 days before Placebo SC QM End of Study of End

randomization Randomization (N = 17)

Visits: Day 1 Week 2† Week 4 Week 6 Week 8 Week 10† Week 12

Dosing QM: Study drug administration

*Randomization stratified by screening LDL-C (<10.9 mmol/L or ≥10.9 mmol/L). †Week 2 and week 10 study visits were optional. Primary endpoint: Percent change from baseline in Ultracentrifugation LDL-C at week 12 Raal et al. Lancet 2015;385:341-50 TESLA Percent change in UC LDL-C from baseline to week 12

10 C, C, Mean

- 0

Placebo (N = 16) -10 Absolute difference (%) = 2.5 mmol/L (100mg/dL) -20

-30 Percent change from change from Percent

baseline UC in LDL -40 Evolocumab 420 mg QM (N = 33 )

Baseline Week 4 Week 6 Week 8 Week 12 Study drug    administration Study Week

Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values.

Raal et al. Lancet 2015;385:341-50 TESLA LDL-C lowering by type of mutation Percent Change from Baseline in UC LDL-C at Week 12, Mean (SE)

Mutation status N Placebo Evolocumab 420 Treatment mg QM difference All 49 7.9 (5.3) -23.1 -30.9 (6.4)* LDLR Defective/any† 28 11.2 (5.1) -29.6 (3.4) -40.8 (6.1)‡ Defective/defective 13 15.1 (7.3) -31.8 (5.8) -46.9 (9.4)‡ Negative/Defective 9 3.5 (5.8) -21.0 (4.0) -24.5 (7.0)# Unclassified 22 3.8 (11.7) -17.9 (8.8) 21.7 (13.9) Median (Q1, Q3) 7.2 (0.0, 9.9) -39.2 (48.8, 14.6) - Negative/negative 1 - 10.3 - LDLR heterozygous 1 - -55.7 - Apolipoprotein B 2 10.8, 13.1 0 - ARH 1 - 3.5 -

Data are least squares (LS) mean for groups with sufficient data; otherwise actual value at week 12. LS mean is from the repeated measures model, which includes treatment group, screening LDL, scheduled visit and the interaction of treatment with scheduled visit as covariates. *Adjusted P-value < 0.001; †Receptor defective in at least one of two affected alleles. ‡ Nominal P-value < 0.001;#Nominal P-value = 0.013; ǁFunction of one or both LDLR mutations is unknown (includes 6 patients from the defective/any group). Raal et al. Lancet 2015;385:341-50 Santos RD, et al. J Am Coll Cardiol 2020;75:565-74 The Role of PCSK9 Inhibitors

. Inhibition of PCSK9 with fully human mAbs is a very promising, and very effective, approach to reducing LDL cholesterol further in:

• Severe heterozygous FH or non-FH patients who have not responded adequately to statin +/- ezetimibe therapy alone

• The 70-95% of HoFH patients with defective LDLR activity

• Patients with progressive coronary artery disease despite high dose statin +/- ezetimibe therapy

• Patients unable to tolerate statins or effective doses of statins - “statin intolerance”

Adapted from Stein EA, Raal FJ. Endocrinol Metab Clin N Am 2014;43:1007-33

Pharmacokinetics and pharmacodynamics of evolocumab: changes in PCSK9 and LDL-C levels in response to evolocumab

500 Total AMG 145 (evolocumab) 160

Free PCSK9 450 140 LDL LDL-C

400 - 120 Mean C Change (%) 350 300 100 250 80

200 60 150 40

100

50 20

0 0

Free evolocumab concentration (ng/mL evolocumab Free concentration x 0.01) Free PCSK9 concentration (ng/mL)PCSK9 concentration Free 0 14 28 42 56 70 84 Study Day

Stein EA & Raal FJ Annu. Rev. Med. 2014. 65:417–31. Model predicted time course of LDL-C after multiple evolocumab doses

-20

-40 280 mg QM

420 mg QM C (% change change baseline)(% from C

- -60

140 mg Q2W LDL

-80 0 2 4 6 8 10 12 Time (weeks)

Gibbs et al. J Clin Pharm. 2017;57:616 INCLISIRAN: Background and rationale Harnessing the natural process of RNAi

Small interfering double-stranded RNA1 . Harnesses the natural process of RNAi . Nucleotides modified for durability and low immunogenicity . Distributed to liver due to GalNAc conjugation . Inhibits production of PCSK9 in hepatocytes

Fitzgerald et al. N Engl J Med 2016;376:41-51 Small interfering RNA (siRNA) targeted to PCSK9: Mechanism of action

siRNA Long DNA

Cytoplasm GalNAc 5’ 3’ GalNAc GalNAc Deer

AGO2

Hepatic ASP INCLISIRAN RISC receptor

RISC assembly

Cleaved sense strand Target mRNA recognition

Sense strand Antisense strand Recycled RISC-siRNA Target mRNA cleavage activated complex Target mRNA RISC = RNA-induced silencing complex

Whitehead et al. Nat Rev Drug Discov 2009;8:129-38 The ORION program is comprehensive series of clinical trials to profile inclisiran’s efficacy and safety

Study Countries Population Control Group Total Subjects Treatment Period Status Pivotal Phase 3 Studies (LDL-C)

ORION-111 E.U., SA ASCVD & Risk Equivalents Placebo 1,617 18 months Complete

ORlON-102 U.S. ASCVD Placebo 1,561 18 months Complete ORlON-93 U.S., E.U., SA, Ca HeFH Placebo 482 18 months Complete

ORlON-54 HoFH Placebo 56 6+18 months Recruitment completed

Phase 3b Studies (CVOT and LDL-C Extension) ORlON-45 U.S., U.K. ASCVD Placebo ~15,000 ~60 months On going Extension for ORION- ORlON-86 None ~3,400 ~48 months On going 9/10/11 Phase 2 Studies ORION-16 U.S., E.U., Ca ASCVD Placebo 501 12 months Complete

ORlON-37 U.S., E.U., Ca Extension for ORION-1 None 490 36 months On going

ORlON-26 U.S., E.U., SA HoFH pilot None 4 6 months Complete Phase I Studies ORlON-67 U.S. Hepatic None 28 6 months Complete ORlON-78 NZ Renal None 31 6 months Complete ORlON-126 U.S. T-QT Moxifloxacin, placebo 48 6 months Complete ALN-PCSSC-0016 E.U. SAD/MD Placebo 69 6 months Complete

1. NCT03400800; 2. NCT03399370; 3. NCT03397121 4. NCT03851705; 5. NCT03705234; 6. Novartis data on file; 7. NCT03060577; 8. NCT03159416. ORION-1: Efficacy: Two-dose starting regimen: Robust, Sustained LDL-C reductions – Optimal start regimen

300 mg x2 9 months time adjusted

55.5% 52.6% mean 50% reduction

± 10 Placebo 0 100 mg -10 P-value for all comparisons to placebo <0.0001 200 mg -30 300 mg

95% CI) 95% -30 -40

-50 Mean percent percent Mean change ( -60 0 30 60 90 120 150 180 210 240 270 Days from first injection

Ray KK, et al. N Engl J Med. 2017;376:1430-1440; Ray KK, et al. FP 2977.ESC201915:261-272 ORION-9 Study endpoints Inclusion criteria: age ≥18 years; HeFH diagnosed by genetic testing and/or Simon Broome criteria; LDL-C ≥2.6 mmol/L on maximally tolerated statin with or without ezetimibe

Effectiveness • Co-primary: Percent LDL-C change vs placebo (at day 510; average over days 90 to 540) • Secondary: LDL-C absolute change over time; changes in PCSK9 and other lipids Safety and Tolerability • Treatment emergent adverse events • Laboratory parameters Exploratory • Treatment response by FH genotype

Raal FJ, et al. N Engl J Med 2020;382:1520-30

ORION-9 Study Design 18 months treatment and observation 482 patients with HeFH randomised 1:1 inclisiran 300 mg vs placebo – with maximally tolerated statins

Raal FJ, et al. N Engl J Med 2020;382:1520-30

ORION-9 LDL-C percent change

Injections 20 8.2%

Placebo Time averaged difference -44.3% -20 -47.9%

Inclisiran 95% CI) 95% ± -40 -39.7%

-60 baseline(

Meanfrompercentage -80 P value <0.001 for all point comparisons

-100 0 3 6 9 12 15 18 Months

Raal FJ, et al. N Engl J Med 2020;382:1520-30 ORION-9 Placebo-adjusted mean percent change in LDL-C from baseline by genetic testing

+20

-20

-40 C C baselinefrom

- -60 LDL

-80 Placeboadjusted % change in -100 0 3 6 9 12 15 18 Months LDLR variants Two variants ApoB PCSK9 GOF Non identified

Raal FJ, et al. N Engl J Med 2020;382:1520-30, Supplementary Appendix ORION-2: PILOT STUDY OF INCLISIRAN IN HoFH

60 60

Patient A Patient B

40 40 20 20 0 0 -20 -20 -40 -40

-60 -60

from baseline from

from baseline from Percent change Percent -80 change Percent -80 -100 -100 BL 14 30 60 90 120 150 180 BL 14 30 60 90 120 160 180 210 240 270 180 Visit day Visit day

60 Patient C 60 Patient D

40 40 20 20 0 0 -20 -20 -40 -40

-60 -60

from baseline from

from baseline from Percent change Percent Percent change Percent -80 -80 -100 -100 BL 14 30 60 90 120 150 180 210 240 270 180 BL 14 30 60 90 120 150 180 210 240 Visit day Visit day LDL-C PCSK9

Patient A Patient B Patient C Patient D Variant Homozygous LDLR Compound heterozygous Homozygous LDLR Compound heterozygous LDLR c.681C.G (defective) LDLR c.681C.G (defective) c.1784G>A; detection exons 12-18 c.681C.G; c.1285C>A (defective/not determined) (defective/null) Baseline LDL-C 13.7 mmol/L 14.1 mmol/L 15.9 mmol/L 4.9 mmol/L

Hovingh GK et al. Circulation 2020;141:1829-1831 ORION- 4 Design

Patients with stable atherosclerosis N~15,000 (prior MI, stroke or PAD); on optimised lipid-lowering therapy

R 1 : 1 INCLISIRAN Double Blind 300 mg SC PLACEBO (Randomisation, M3, then q6M)

Median duration of follow-up 4-5 years

Primary endpoint: CHD death, MI, stroke, or urgent coronary revascularisation

Clinical Trials.gov: NCT03705234 Clinical implications of the siRNA PSCK9 inhibitor Inclisiran

Administration Safety . Renally excreted (48 h), no dose . Compared to placebo more Injection adjustments site reactions but the majority are mild and all transient . Addresses missed doses .Consistent LDLC lowering and safety including mild, moderate, and severe renal impairment A paradigm shift in treating lipids

. Inclisiran is a twice-a-year SC injection that can be administered in health practitioner office, and potentially outside(e.g. pharmacy) . Durable efficacy allows opportunity to continue addressing CV risk factors, treating other comorbidities, and bringing LDL-C down further with LLT

Prevent Treat Mrs TDK - A case of severe hypercholesterolaemia

Addition of a PCSK9 inhibitor

Lipid profile

Total cholesterol: 4.2 mmol/L (162 mg/dL) Triglycerides: 1.21 mmol/L HDL-cholesterol: 1.9 mmol/L LDL-cholesterol 1.8 mmol/L (70 mg/dL) Cumulative LDL-Cholesterol lowering effects of statin, ezetimibe and a PCSK9-inhibitor 14 13.2 12

10 47%

8 7.0

C (mmol/L) C 6 26% - 5.2

LDL 4 65% 2 1.8

0 Baseline Statin Plus Plus PCSK9- Ezetimibe inhibitor Dutch Dutch

CABG age 52 Died age 74 Died age 90 Alzheimer’s disease

TC 16.0 mmol/L TC 8.0 mmol/L FH Age 50 FH FH TC 15.6 mmol/L Died aged 62 Age 45 LDL 13.2 mmol/L MI

14 17 11 TC 6.4 mmol/L TC 5.6 mmol/L TC 6.4 mmol/L = C.1690A>C (N564H) LDL 4.6 mmol/L LDL 4.0 mmol/L LDL 4.6 mmol/L 2458 - 2466 del = C.917C>T (S306L) FH Amsterdam LDL levels in FH From a lethal disorder to a manageable dyslipidaemia 1986 2016

11.7 First synvinolin study 10.4 RUTHERFORD ODYSSEY I & II

9.1 TESLA, TAUSSIG

7.8 ORION-9, ORION-5

6.5 ASAP ENHANCE

C C levels -

(mmol/L) 5.2 LDL 3.9 2.6 1.3 0 No therapy Simva 40 Atorva 80 Simva 40 Simva 80 Statin + + mg mg mg mg Eze 10 mg PCSK9-inhibitor

Adapted from Kastelein JJP. Nat Rev Cardiol. 2014;11:629-631 Severe FH Treatment algorithm for severe FH patients

Initiation of high-intensity Statin statin monotherapy is standard of care

Ezetimibe is added when patient Cholesterol is not at LDL-C threshold absorption inhibitor Bile acid sequestrants, ? fibrates and niacin are added alone or in combination for those Bile acid ? Niacin not at LDL threshold ? Fibrate sequestrant Add a PCSK9 inhibitor PCSK9 Apheresis for patients on maximally inhibitor tolerated therapy and LDL-C > 7.8 mmol/L (300mg/dL) or CAD and LDL- C > 5.2 mmol/L (200mg/dL). Apheresis ANGPTL3 Lomitapide inhibitors Mipomersen

Updated from Sniderman A, et al JACC 2014;63:1935-47 A CURE FOR FH?

WITH THE ARRIVAL OF NOVEL DRUGS; GENE THERAPY ETC, WE HOPE SO LDL cholesterol burden

Homozygous FH Heterozygous FH 200 Threshold for 48 years Female sex

12.5 years CHD 35 years 53 years C C

- 150 55 years Smoking Start high dose statin Hypertension Diabetes 100 Start low  Triglycerides (mmol) dose statin  HDL-C  Lipoprotein(a) Cumulative LDL Cumulative 50

Without FH 0 0 3 6 9 12 15 28 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Age (years)

Nordestgaard B.G. et al. Eur Heart J 2013;34:3478-3490 SUMMARY

• The phenotypic expression of “severe FH “, both HeFH and HoFH is highly variable.

• Although the genotype has a major effect on LDL-cholesterol levels, cardiovascular outcome and response to lipid lowering therapy varies.

• One treats the phenotype (LDL-cholesterol level) not the genotype

• With the new lipid-lowering drugs now available and under development the future for severe FH looks bright

Thank you for your attention