PCSK9 Inhibition in Familial Hypercholesterolemia: a Revolution in Treatment

PCSK9 inhibition in familial hypercholesterolemia: A revolution in treatment

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

Head, Division of Endocrinology & Metabolism Director, Carbohydrate and Lipid Metabolism Research Unit Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa A case of severe hypercholesterolemia

Mrs. TDK

50 year old female. Well. Non smoker and no other risk factors for cardiovascular disease. Serum cholesterol measured because of positive family history of coronary artery disease, her father having undergone coronary bypass surgery at age 52. On examination she had arcus cornealis as well as marked thickening of her tendo-Achilles.

Mrs TDK, a case of severe hypercholesterolemia

Fasting lipid profile

Total cholesterol: 15.6 mmol/L Triglycerides: 1.34 mmol/L HDL-cholesterol: 1.8 mmol/L LDL-cholesterol 13.2 mmol/L Heterozygous vs Homozygous FH

Heterozygous FH Homozygous FH

Prevalence 1:200- 500 Prevalence 1:300 000 -1000 000

LDL-cholesterol LDL-cholesterol 5.0-12 mmol/L 12-20 mmol/L (190-500mg/dL) (500–1000 mg/dL)

CHD onset usually age 30-60 yrs CHD onset in early childhood

Most patients respond to drug therapy, but individual response Poorly responsive to quite variable lipid-lowering drug therapy

Nordestgaard B.G. et al. Eur Heart J 2013;34:3478-3490 Diagnostic definition of homozygous familial hypercholesterolemia

. Genetic confirmation of 2 mutant alleles at the LDL receptor, APOB, PCSK9, or ARH adaptor protein gene locus OR . An untreated LDL cholesterol of 13 mmol/L (>500 mg/dL) or treated LDL cholesterol 7.8 mmol/L (≥300 mg/dL) or treated non-HDL cholesterol 8.5 mmol/L (≥330 mg/dL) together with either:

- Cutaneous or tendonous xanthoma before age 10 years OR - Elevated LDL cholesterol levels before lipid-lowering therapy consistent with heterozygous FH in both parents*

* Except in the case of ARH

Raal FJ, Santos RD. Atherosclerosis 2012;223:262-268 Gidding, Raal et al, The agenda for FH; Circulation 2015;132:2167-2192 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 LDLRAP1/ARH 15 580 13 500 Homozygous APOB defect/PCSK9 gain of 10 390 function Heterozygous FH

5 190 Common or polygenic hypercholesterolemia

0 0

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

Heterozygous FH

Normal Homozygous Compound heterozygous FH

0 5 10 15 20 25 Cholesterol (mmol/L)

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 Cholesterol Synthesis

Acetyl CoA

HMG CoA

STATINS HMG CoA reductase Mevalonic Acid

Dolichols Farnesyl pyrophosphate Ubiquinones Heme

Squalene

Cholesterol

Endo A, et al FEBS letters 1976;72:323-326 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 hypercholesterolemia patients after LLT

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

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 Reduction in of hepatic apo-B LDL lipoprotein receptors 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 Genotype Confirmed HoFH (n=48) (n=35))

Ezetimibe + Ezetimibe + Statin-80 Statin 80 Statin-80 Statin 80 0% 0%

-5% -5%

-5.6% -7.0%

-10% -10%

-15% -15%

CholesterolReduction

- -

-20% -20%

% % LDL % % LDL

-25% -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 hypercholesterolemia

Treated with Rosuvastatin 40mg daily x 3 months

Lipid profile

Total cholesterol: 9.4 mmol/L Triglycerides: 1.20 mmol/L HDL-cholesterol: 1.9 mmol/L LDL-cholesterol 7.0 mmol/L Mrs TDK, a case of severe hypercholesterolemia

Ezetimibe 10mg daily added

Lipid profile

Total cholesterol: 7.6 mmol/L Triglycerides: 1.30 mmol/L HDL-cholesterol: 1.8 mmol/L LDL-cholesterol 5.2 mmol/L Proportion of FH patients on LDL-C targets for different treatment goals

100

80 N=1249 60

20 Attainment Attainment target of (%)

0 1 2 3 4 5 6 7 8 9 10 LDL-C target (mmol/L) Cross-sectional study was conducted in outpatient lipid clinics of 3 Academic Centers and 2 regional hospitals. Patient records of known HeFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, Pijlman AH, Atherosclerosis 2010;209:189-94 safety laboratory results and reasons for not achieving treatment goals SAFEHEART study: Proportion of FH patients at LDL-C target

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

80 70 60 50 40 30

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

80 70 60 50 40 30

20 Attainment of target (%) of target Attainment 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 . Lomitapide (MTP inhibitor) inhibitor (Gemcabene) . PCSK9 inhibitors . ACL/AMP kinase modulator (ETC-1002 or Bempedoic acid) . ANGPTL3 inhibitors . Others e.g. CETP–inhibitors, probucol . AAV-8 LDLR gene replacement therapy

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

(Proprotein convertase subtilisin/kexin type 9)

• PCSK9 is a serine protease that is an extracellular regulator of LDL receptors

• PCSK9 binds to the EGF-A extracellular domain of the LDLR. After binding and internalisation, PCSK9 directs the LDLR to lysosomal degradation rather than for recycling

EGF = epidermal growth factor Seidah. Circ Res 2014:114:1022-36 Catabolism of LDL, the role of PCSK9 and antibody to PCSK9

LDL LDL receptor

Endocytosis

Endosome LDL-R synthesis

Clathrin-coated vesicle

Endoplasmic PCSK9 reticulum processing/ export Golgi Nucleus apparatus SREBP Hepatocyte Lysosome

modified from Hovingh G K, et al. Eur Heart J 2013;34:962-71 PCSK9-inhibitors Rapid progress from discovery to clinic

In 2003 Marianne Abifadel from First MAD phase 1b Phase 3 trials Lebanon described trials with PCSK9 mAb complete for 2 mAbs, two gain-of-function started including FH, BLA* filed and CVD mutations in the non-FH, statin Rx Phase 2 trials in-progress outcome trials started PCSK9 gene which published for REGN727 resulted in a FH including FH, Q2W/Q4W phenotype. dosing

Phase 2 trials Early data on First subjects treated published for CVD benefit with PCSK9 mAb in AMG145 including SAD studies 1st publications MAD HoFH, Statin intol, Q2W/Q4W in FH, nonFH on Marketing statin or diet approval USA/Europe

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2 019 2020

*BLA – Biologics licensing application; SAD – single ascending dose, MAD – multiple ascending dose Seidah. Circ Res 2014:114:1022-36

Pharmaceutical approaches targeting PCSK9

Approach Advantages Disadvantages Compound Development stage Company

mAbs Highly selective IV or Alirocumab/ REGN7272/ FDA approved July Sanofi/Regeneron Less dosing subcutaneous SAR236553 24, 2015 admin. frequencies Evolocumab/ AMG145 FDA approved Aug Amgen No serious adverse High cost 27, 2015 reactions Short shelf life Bococizumab/ RN-316/ Development Pfizer/Genentech PFO4950615 stopped in Nov 2016

RG7652(MPSK3169A) Phase II Genentech/Roche

Mimetic Highly selective Injection SX-PCK9 Preclinical Serometrix peptides Easier production than administration EGF-A peptide Preclinical Merck & Co mAbs

Adnectin Selective Short half-life BMS-962476 Phase I completed BMS-Adnexus Easier & less costly production than mAbs

siRNA Highly selective IV or Inclisiran/ ALN-PCS (IV) Phase I completed Medicines Company subcutaneous ALN-PCSsc (sub) Phase II, III recruiting Alnylam administration Pharmaceuticals;

Small Oral administration Less selective SBC-1 & SBC-1 Preclinical completed Shifa Biomedical molecules Low cost Greater likelihood Corp of side effects

Modified from Bergeron et al. Circulation. 2015;132:1648-66

LDL LDL receptor mAb

Endocytosis Recycling of LDL-R

LDL-R synthesis

Clathrin-coated Endosome vesicle Golgi apparatus

PCSK9 Endoplasmic processing/ reticulum export siRNA or ASO Nucleus SREBP Hepatocyte Lysosome

modified from Hovingh G K, et al. Eur Heart J 2013;34:962-71 Mean percent change from baseline in LDL-C values among healthy volunteers in single-dose studies Subcutaneous administration of Alirocumab

20 Placebo 50 mg 100 mg 150 mg 250 mg

C C (%) - 0

-10

-20

-30

-40

-50

-60 Mean change from baseline from changeLDL in Mean

-70 1 2 4 8 11 15 22 29 43 84 85 106 Study Day

Stein E. N Engl J Med 2012;366:1108-18 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

)

(

Rule of 6 !

-25

C g

-50

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 hypercholesterolemia 600 PCSK9

500

Controls HeFH HoFH

400

300

PCSK9 (ng/mL) PCSK9 200

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/TAUSSIG Homozygous FH -31 ODYSSEY MONO Comparison with ezetimibe in pts with -32 hypercholesterolemia at mod CV risk ODYSSEY COMBO II Comparison with ezetimibe -30 ODYSSEY FH I and II Heterozygous FH -51 to -58 ODYSSEY long-term Combination with statins -62 ODYSSEY ALTERNATIVE Statin intolerance -30 ODYSSEY High FH Severe heterozygous FH -39 ODYSSEY COMBO I On top of maximally tolerated statins ± other -24 to -49 lipid-lowering drugs in high risk patients ODYSSEY OPTIONS I and II Comparison of different strategies to further -20 to -37 reduce LDL-C in high-risk pts. not a goal

De Backer et al. Eur Heart J 2015;36:214-218 ODYSSEY FH I and FH II Studies

Double-Blind Treatment Period (78 Weeks)

HeFH patients on maximally Alirocumab 75 mg Q2W SC with potential  to 150 mg Q2W SC tolerated statin (single 1-mL injection using prefilled pen for self-administration) with or without other LLT N=323 (FH I); N=167 (FH II) R Per-protocol dose  possible based on prespecified LDL-C level LDL-C ≥ 1.8 mmol/L N=153 (FH I); n=72 (FH II)

(≥70 mg/dL) OLE/8 FU OLE/8 week (history of CVD) Placebo Q2W SC or ≥ 2.6 mmol/L (≥ 100 mg/dL) (no history of CVD) W0 W8 W16 W36 W64 Assessments W4 W12 W24 W52 W78

Dose  if LDL-C Primary Pre-specified analysis > 1.8 mmol/L efficacy Efficacy: All patients to W52 (>70mg/dL) at W8 endpoint Safety: Baseline-W78 (at least W52)

OLE=Open Label Extension FU=Follow-up Kastelein JJ et al. Cardiovasc Drugs Ther 2014; 28:281–289 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 3.7 mmol/L Placebo FH II 3.5 mmol/L m

3.0 116 g/dL

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

2.0 77

C, LS C, mean (SE), mmol/L - 1.5 58 LDL 1.8 mmol/L Alirocumab FH II 1.7 mmol/L 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 The Rutherford-2 Study

Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Design: A 12-week, randomized, double-blind, placebo-controlled, multicenter phase 3 study Objective: To evaluate the efficacy and safety of evolocumab (AMG 145) 140 mg Q2W and 420 mg QM administered subcutaneously in a large cohort of HeFH patients unable to achieve an LDL-C < 2.6 mmol/L despite statin therapy with or without ezetimibe

Raal et al. Lancet 2015;385:331-40 Rutherford-2 Study design

Evolocumab 140 mg SC Q2W

N = 111a

Screening Evolocumab 420 mg SC QM Period N = 110 with 2:2:1:1 Placebo

Injection Placebo SC Q2W End End of Study

N = 55a Randomization

Placebo SC QM N = 55

Max. 6 weeks Day 1 Week 2 Week 4b Week 6b Week 8 Week 10 Week 12 Week 14c

Evolocumab or placebo SC Q2W Evolocumab or placebo SC QM

a N’s are number of patients randomized. One patient in each of the placebo Q2W and evolocumab Q2W groups did not receive any doses of the study drug and were not included in the analyses b Injections at weeks 4 and 6 were done at home c Week 14 was a follow-up call for Q2W patients to capture adverse events and concomitant medications Raal et al. Lancet 2015;385:331-40 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)

Change from baseline in LDL cholesterol (%) baseline in Change LDL from cholesterol -80 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 B

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

-30

-40

-50

-60

Percent changes from baseline LDL in baseline from changes Percent -70

-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

* Evolocumab 420 mg SC QM

period (N = 33)

Fasting LDL-C 2:1 5–10 days

Placebo SC QM Study of End before Randomization (N = 17) randomization

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

Placebo (N = 16) -10 Absolute difference

= 2.5 mmol/l (100mg/dL) C, (%) Mean C,

- -20 LDL -30

-40 Evolocumab 420 mg QM (N = 33 ) Percent change from baseline UC in from change Percent

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 Treatment 420 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 TESLA TESLA: Safety and Tolerability

Placebo QM Evolocumab 420 mg QM Adverse events (AE), n (%) N = 16 N = 33 Treatment emergent AEs 10 (63) 12 (36) Serious or leading to discontinuation 0 0 Deaths 0 0 Common treatment emergent AEs* Upper respiratory tract infection 1 (6) 3 (9) Influenza 0 3 (9) Gastroenteritis 0 2 (6) Nasopharyngitis 0 2 (6) Nausea 2 (13) 0 Muscle-related SMQ 1 (6) 1 (3) Musculoskeletal pain 0 1 (3) Potential injection site reactions† 1 (6) 0 Abnormal laboratory tests CK >5 x ULN 1 (6) 1 (3) ALT or AST >3 x ULN 1 (6) 2 (6) Anti-evolocumab antibodies‡ 0 0

*Reported in >1patient in one or both arms. †Searched using high-level term grouping, which includes injection site (IS) rash, IS inflammation, IS pruritus, IS reaction, and IS urticaria. ‡Excludes 1 patient with positive binding antibody test at BL. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; QM, monthly; SMQ, Standard MedDRA Queries; ULN, upper limit of normal Raal et al. Lancet 2015;385:341-50 TAUSSIG Study: LDL-C change between baseline and 48 weeks

30 All patients (n=106) No apheresis (n=72)

20 Apheresis (n=34)

-10

-20

-30

-40

Mean change in LDL cholesterol (%) cholesterol LDL in change Mean -50

-60

-70 Baseline 4 8 12 16 20 24 36 48 Study week

Raal FJ et al. Lancet Diabetes Endocrinol 2017;5:280-290 TAUSSIG Study: LDL-C change between baseline to week 12, by underlying genetic abnormality

60 LDLR neg/neg (5%)

PCSK9 GoF/LDR C (%) C 20 - Negative LDLR unclassified (-25%) LDLR defective (-20%) (-65%) 0

-20

-40 ARH (-15%) -60

Change from baseline in LDL in baseline from Change Apolipoprotein B -80 (-47%)

-100

Raal FJ et al. Lancet Diabetes Endocrinol 2017;5:280-290

TAUSSIG Study: Effect of evolocumab uptitration on LDL cholesterol (n=47)

After ≥12 weeks After 12 weeks of 420 mg of 420 mg evolocumab evolocumab every month every 2 weeks Value at 9.35 (3.35) 9.35 (3.35) baseline, mmol/L

Change from baseline, -1.77 (2.05) -2.57 (2.14) mmol/L

Percentage change -20.1% (21.7) -27.3% (21.1) from baseline

Raal FJ et al. Lancet Diabetes Endocrinol 2017;5:280-290

TAUSSIG: Safety and Tolerability

All patients Adverse events (AE), n (%) N = 106 Treatment emergent AEs 82 (77%) Serious or leading to discontinuation 18 (17%) Deaths 0 Common treatment emergent AEs* Nasopharyngitis 14 (13%) Influenza 13 (12%) Headache 11 (10%) Upper respiratory tract infection 11 (10%)

Muscle-related AEs 0 (0) Musculoskeletal pain 0 (0) Potential injection site reactions† 13 (12%) Abnormal laboratory tests CK >5 x ULN 4 (4%) ALT or AST >3 x ULN 6 (6%) Anti-evolocumab neutralising antibodies 0

Raal FJ et al. Lancet Diabetes Endocrinol 2017;5:280-290 Mrs TDK - A case of severe hypercholesterolaemia

Addition of Evolocumab 140 mg Q2W subcutaneously

Lipid profile

Total cholesterol: 4.2 mmol/L Triglycerides: 1.21 mmol/L HDL-cholesterol: 1.9 mmol/L LDL-cholesterol 1.8 mmol/L Cumulative LDL-Cholesterol lowering effects of statin, ezetimibe and a PCSK9-inhibitor

14 13.2 12

10 47%

8 7.0

C C (mmol/L) 26%

- 6

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

Index case: 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 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.917C>T (S306L) LDL 4.6 mmol/L LDL 4.0 mmol/L LDL 4.6mmol/L FH Amsterdam 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

6.5 ASAP ENHANCE

5.2

C C (mmol/L)levels -

3.9 LDL 2.6 1.3

0 No Simva Atorva Simva Simva Statin + + therapy 40 mg 80 mg 40 mg 80 mg Eze 10 mg PCSK9-inhibitor

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

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

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

Adapted 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 FH exposes people to very high cholesterol from birth, thus reaching a threshold for CHD earlier in life Cumulative exposure (cholesterol yrs) by age: FH vs unaffected (healthy) individuals

Homozygous FH Heterozygous Healthy individuals

10 FH

)

years - Threshold for

g/dL CHD: reached by age 40 for those with HeFH and 5 age 20 for HoFH, > 70 yrs in healthy individuals

Cholesterol year Cholesterolyear score ( 0 1 20 40 60 80 Age (years)

CHD = Coronary heart disease Adapted from Horton et al. J Lipid Res. 2009;50:S172-S177 LDL cholesterol burden

Homozygous FH Heterozygous FH 200

Threshold 48 years Female sex

53 years 12.5 years for CHD 35 years 150 55 years Smoking Start high Hypertension

C C (mmol) dose statin - Diabetes  100 Triglycerides Start low  HDL-C dose statin  Lipoprotein(a)

50 Cumulative LDL Cumulative

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 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