PCSK9 Inhibitors: Practical Aspects of their use in Patients with Familial

James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA Preventive CV Medicine, and Hypertension Clinical Assistant Professor of Medicine NYU Medical School & NYU Center for CV Prevention Director, Bellevue Hospital Lipid Clinic Treasurer National Lipid Asssociation Outline

• FH Overview • PCSK9 overveiw – Science – Inhibition • FH Diagnosis • PCSK9 Utilization in FH patients – Data in FH patients with currently available PCSK9i’s – Current Recommendations – Insurance Coverage – (a) & FH • Future Directions Familial Hypercholesterolemia FH: A Clinically Recognizable Genetic Disorder • The most common inheritable, autosomal dominant disorder associated with morbidity and mortality in man – present in 1 in 250 people1,2 • Usually due to mutations in LDL receptor gene3-5 of which over 1600 have been described, and result in decreased clearance of LDL1 – Other mutations include those in the ApoB and PCSK9 • Results in severe hypercholesterolemia and lifelong accumulation of LDL in tissues and arteries • Evidence of CVD early in life

FH = familial hypercholesterolemia; CVD = . 1. Marais AD. Clin Biochem Rev. 2004;25:49-68. 2. Nordestgaard BG, et al. Eur Heart J. 2013;34:3478-90. 3. Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology. 2008. 4. Rader DJ, et al. J Clin Invest. 2003;111:1795-1803. 5. Hopkins PN, et al. J Clin Lipidol. 2011;5(3 Suppl):S9-175. 6. Williams RR, et al. JAMA. 1986;255(2):219-224. 7. Weigman A. Lancet. 2004;363(9406):369-70. Visible Signs of FH Bilateral xanthelasma (<25 yrs of age)

Bilateral Corneal Arcus (<45 yrs of age)

Extensor Tendon Xanthoma of Hand (Any time)

Extensor Tendon Xanthoma of Achilles (Any Time)

Genest et al. 1473 CCS Position Statement on Familial Hypercholesterolemia Canadian Journal of Cardiology 30 (2014) 1471e1481 Familial Hypercholesterolaemia: A Global Call To Arms

A.J. Vallejo-Vaz et al. / Atherosclerosis 243 (2015) 257e259 Goal attainment

UK 2008 CASCADE-FH Netherlands 2010 100% Treated LDL-C<100 mg/dl

50% 30% 25% 21% 0% 100% Reduction in LDL-C≥50% 64% 60% 50% 41%

0% Pijlman Atherosclerosis 2010;209:189. Hadfield Annals Clin Biochem 2008;45:199. Monogenic Causes of FH

• Defective LDLR ( 19) – Homozygous 1/1,000,000 – Heterozygous 1/500

• Defective ApoB 100 (chromosome 2) – Homozygous 1/4,000,000 – Heterozygous 1/1000

• PCSK9 gain-of-function mutation () • and IDOL – 1/2500

• Autosomal recessive FH (chromosome 1) – <1/1,000,000 • STAP1 (chromosome 4) Mechanisms causing familial hypercholesterolemia linked to low- density lipoprotein (LDL) receptor (LDLR) function

Gidding, S. Circulation. 2015;132: In Press Different domains in the low-density lipoprotein (LDL) receptor are encoded by specific regions in the LDL receptor

Gidding, S. Circulation. 2015;132: In Press Classes of LDL Receptor Mutations

Gidding, S. Circulation. 2015;132: In Press Phenotypic Variability in HoFH

Cuchel M, et al. Eur Heart J. 2014;eurheartj.ehu274 FH Prevalence

B.G. Nordestgaard et al. European Heart Journal 2013 doi:10.1093/eurheartj/eht273 PCSK9: Rapid Progress From Discovery to Clinic

• Adenoviral  expression in mice • PCSK9 KO mouse  LDL-C

• PCSK9 LOF mutations found with 28%  LDL-C • First subject treated and 88%  CHD risk with PCSK9 mAb • • PCSK9 (NARC-1) discovered Humans null for PCSK9 have LDL-C • First patients with FH ~15 mg/dL & nonFH treated with • PCSK9 GOF mutations PCSK9 mAb associated with ADH  LDL-C in mice and non- Plasma PCSK9 First binds to LDLr human primates treated with anti-PCSK9 mAb publication POC in patients

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012

Seidah. Proc Natl Acad Sci USA 2003;100:928-33, Abifadel. Nat Genet 2003;34:154-6, Maxwell KN. Proc Natl Acad Sci USA 2004;101:7100-5, Rashid. Proc Natl Acad Sci USA 2005;102:5374-79, Lagace et al. JCI 2006;116:2995-3005 Cohen. N Engl J Med 2006;354:1264-72, Zhao. Am J Hum Genet 2006;79:514- 23, Hooper. Atherosclerosis 2007;193:445-8, Chan. Proc Natl Acad Sci USA 2009;106:9820-5; Stein et al N Engl J Med 2012;366:1108-18 PCSK9 Regulates LDL-R Expression

PCSK9 mediated degradation of LDL-R

PCSK9 = protein convertase subtilisin/kexin type 9; LDL-R = low density lipoprotein receptor. Adopted from Lambert G, et al. J Lipid Res. 2012;53(12):2515-24. Impact of an PCSK9 mAb on LDL Receptor Expression mAB binding of PCSK9

mAb

No LDL-R degradation; LDL-R is recycled

mAb = monoclonal . Adapted from Lambert G, et al. J Lipid Res. 2012;53(12):2515-24. NON – PCSK9 Mediated LDL Receptor Degradation

Circ Res. 2014;115:542-545 Pharmacokinetic Profiles of PCSK9 Inhibitors

Alirocumab Human that Human monoclonal antibody that MOA binds to PCSK9 binds to PCSK9

Half-life 17 – 20 days 11 – 17 days

After 2 – 3 doses or Steady State After 12 weeks 4 – 6 weeks

Max Effect ~ 4 – 8 hours ~ 4 hours

MOA = mechanism of action. http://www.pdr.net/drug-summary/praluent?druglabelid=3765. Accessed September 21, 2015. Currently Available PCSK9 Inhibitors

Alirocumab Evolocumab FDA approval July 2015 August 2015 Adjunct to diet and max tolerated Adjunct to diet and max tolerated for adults with HeFH, or clinical statin for adults with HeFH, or clinical Indication ASCVD, who require additional ASCVD, who require additional lowering of LDL-C, HoFH pts on lowering of LDL-C other LTT 140 mg or 420 mg SC Q2W; 420 mg Dosing 75 – 150 mg SC Q2W SC monthly for HoFH Single-dose pre-filled pens and pre- Single-use pre-filled syringe or How supplied filled glass syringes that deliver – SureClick® autoinjector that deliver – 75 mg/mL or 150 mg/mL solution 1mL of 140 mg/mL solution Nasopharyngitis, injection site Nasopharyngitis, injection site Side effects reactions; hypersensitivity reactions reactions; hypersensitivity reactions The effect of alirocumab/evoloumab on CV mortality and morbidity has not been established. HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous FH. LLT = lipid lowering therapy. Evolocumab - Repatha. Drugs@FDA FDA Approved Drug Products. August 2015. http://www.accessdata.fda.gov/ Alirocumab - Praluent. Drugs@FDA FDA Approved Drug Products. July 2015. http://www.accessdata.fda.gov/ Accessed September 8, 2015. Phase 2 and 3 clinical trials of monoclonal against PCSK9 in FH patients

Curr Atheroscler Rep (2015) 17: 28 ODYSSEY FH I and FH II: Alirocumab in Patients with FH at Week 24 All patients on background max-tolerated statin ± other lipid-lowering therapy

Mean baseline LDL-C: Mean baseline LDL-C: ~145 mg/dL ~135 mg/dL FH I FH II 20 9.1 Alirocumab 10 2.8 75/150 mg Q2W Placebo 0

N = 322 N = 163 N = 166 N = 81 C from from C - -10

-20 43.4% 38.6% had dose had dose LDL-C -30 increase at increase at reductions W12 W12 -40 maintained

-50 over 52 wks

-48.8 -48.7 % in Change % LDL Baseline to Week 24 24 (SE) to Week Baseline -60

-70 -57.9% (2.7); P<0.0001 -51.4% (3.4); P<0.0001 LS Mean Difference (SE) vs Placebo

Kastelein JJ, et al. Eur Heart J. 2015 Sep 1. pii: ehv370. [Epub ahead of print] RUTHERFORD-2: Evolocumab in Patients with FH at Week 12

Mean baseline LDL-C: Mean baseline LDL-C: 20 ~151 mg/dL ~162 mg/dL ~151 mg/dL ~155 mg/dL

10

0

C Change Change C 6 - -10 Placebo Q2W -2 (N=54)

-20 Placebo QM (N=55) -30 Evolocumab 140 mg Q2W -40 (N=110)

SE from Baseline from SE -50 Evolocumab 420 mg QM ± (N=110) -60 -56

-70 -61 Adjusted LDL % Mean Adjusted -61%* -59%*

*P<0.001; SE = standard error. Raal FJ, et al. Lancet. 2015;385(9965):331-40. Trial Evaluating Evolocumab, a PCSK9 Antibody, in Patients with Homozygous FH (TESLA Part B) A Global, Phase 3, Randomized, Double-blind, Placebo-controlled Trial 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. SC = subcutaneous; QM = every 4 weeks; LDL-C = low-density lipoprotein

Primary endpoint: % change from baseline in ultracentrifugation LDL-C at week 12

Raal et al. Lancet 2014; doi.org/10.1016/S0140-6736(14)61399-4 TESLA Part B: Patient Genotype and Receptor Function

Placebo QM Evolocumab 420 mg QM Total N = 16 N = 33 N = 49 Genotype, n (%) LDLR 14 (88) 31 (94) 45 (92) Homozygous 7 (43) 15 (45) 22 (45) Compound heterozygous 7 (43) 16 (49) 23 (47) Heterozygous* 0 1(3) 1 (2) 2 (13) 0 2 (4) ARH 0 1(3) 1 (2)

LDLR functional status, n (%) 14 (88) 31 (94) 45 (92) Defective/any† 8 (50) 20 (61) 28 (57) Defective/defective 5 (31) 8 (24) 13 (27) Negative/defective 3 (25) 6 (18) 9 (20) Unclassified‡ 6 (31) 16 (48) 22 (43) Negative/negative 0 1 (3) 1 (2)

*Patient met clinical diagnostic criteria for HoFH based on history of untreated LDL-C concentration 13 mmol/L plus either xanthoma before 10 yr or evidence of heterozygous FH in both parents. †Receptor defective in at least one allele. ‡Function of one or both LDLR mutations is unknown (includes 6 patients from the defective/any group). ARH, autosomal recessive hypercholesterolemia; LDLR, LDL receptor

Raal et al. Lancet 2014; doi.org/10.1016/S0140-6736(14)61399-4 TESLA Part B: Percent Change in UC LDL-C from Baseline to Week 12 20

10 +6% 0

-10 -31% P<0.001

-20

C, C, Mean (%) - -26% LDL -30

-40 Percent Change from in UC from Change Baseline Percent

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

Placebo (N = 16) Evolocumab 420 mg QM (N = 33 ) 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 2014; doi.org/10.1016/S0140-6736(14)61399-4 TESLA Part B: 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 (3.8) -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)§ Unclassifiedǁ 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 - - 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 2014; doi.org/10.1016/S0140-6736(14)61399-4 Criteria for the clinical diagnosis of FH

European Heart Journal (2013) 34, 962–971

European Heart Journal (2013) 34, 962–971 FH Diagnostic Categories

Gidding, S. Circulation. 2015;132: In Press Role of Genetic Testing

Many patients with phenotype may not have mutations and many with mutations May not have typical phenotypic presentations Availability of genetic testing varies by geographic region, and type of testing available Insurance coverage also varies based on insurance and area of country.

B.G. Nordestgaard et al. European Heart Journal Advance Access published August 15, 2013 Proposed Treatment Protocols

Gidding, S. Circulation. 2015;132: In Press National Lipid Association Recommendations Part 2 PCSK9i in FH

Until cardiovascular outcomes trials are completed with PCSK9 inhibitors, these drugs should be considered heterozygous FH patients without ASCVD who have LDL-C >130 mg/dL (non-HDL-C >160 mg/dL) while on maximally-tolerated statin (+/- ) therapy

Strength: B Quality: Moderate

Journal of Clinical Lipidology (2015) 9, S1–S122 European Heart Journal European Heart Journal Advance Access published February 24, 2016

Change in LDLC on Statin and Event Rates

European Heart Journal Advance Access published February 24, 2016 LDL-C response variability to high-intensity statin therapy & implications for the allocation of PCSK9 inhibitors

European Heart Journal Advance Access published February 24, 2016 National Lipid Association Recommendations Part 2 PCSK9i in FH

Journal of Clinical Lipidology (2015) 9, S1–S122 Insurance Coverage for PCSK9i in FH Patients • Documentation , Documentation ! • Know preferred status by Rx provider not Insurer • Understand Insurer FH criteria, but this can be negotiable • Physical Exam KEY • Family History • Persistence • Utilization of Support Provided by Pharma PCSK9 Inhibitors for Treatment of High Cholesterol: Effectiveness, Value, and Value-Based Price Benchmarks

Institute for Clinical and Economic Review, 2015 https://mail.nyumc.org/owa/redir.aspx?C=XlMkhpTnZUiOQGNCa7lJY5YzBdSOVdMIlXiT6pUj8rvvV8Hy x0tFi8mjDLhPMD8r2gaAgLJ1naw.&URL=http%3a%2f%2fcepac.icer-review.org%2fwp- content%2fuploads%2f2015%2f04%2fFinal-Report-for-Posting-11-24-15.pdf Base Case and Clinical Outcomes among Patients with FH

Institute for Clinical and Economic Review, 2015 https://mail.nyumc.org/owa/redir.aspx?C=XlMkhpTnZUiOQGNCa7lJY5YzBdSOVdMIlXiT6pUj8rvvV8Hy x0tFi8mjDLhPMD8r2gaAgLJ1naw.&URL=http%3a%2f%2fcepac.icer-review.org%2fwp- content%2fuploads%2f2015%2f04%2fFinal-Report-for-Posting-11-24-15.pdf What is the frequency of FH in the US ?

Circulation. 2016;133:1067-1072. Overall Incidence 1:250 in US

Circulation. 2016;133:1067-1072. Now lets do the math …

• ICER $/QALY for FH = $ 290,000 based on 1/500 HeFH • ICER estimate 605,000 in 2015 • SO real # is 1.2 million • FH (FAMILIAL Hypercholesterolemia) impacts families (Average US family size ? ) • The average household size for the U.S. in 2015 is 2.6 people per household. It is calculated by dividing the household population by total households • SO perhaps real QALY should be 290,000/2/2 ?

• $ 100,000.00 QALY at minimum !

http://www.arcgis.com Lipoprotein(a) and FH

• Lp(a) is increased in patients with FH and associated with increased ASCVD risk • Lp(a) is associataed with increased risk of Aortic Stenosis ( Seen in patients with homozygous FH ) • Lp(a) is lowered by PCSK9i (But NOT an approved indication) • Lp(a) may be an additional target when elevated in patients with FH for which PCSK9i can by utilized in the future J. Am. Coll. Cardiol. 63, 1982–1989 Arterioscler. Thromb. Vasc. Biol. 20, 522–528 Thanassoulis , G JLR 2016 Lipoprotein(a) in Calcific Aortic Valve Disease: Article in Press Lipoprotein (a) and the LDL Receptor

Koschinsky ML, JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 290•NUMBER 18•MAY 1, 2015 Reduction in Lipoprotein(a) with PCSK9 Monoclonal Antibody Evolocumab (AMG 145) A Pooled Analysis of More than 1,300 Patients in 4 Phase II Trials

Error bars represent standard error. * P < 0.001 Raal et al JACC 2014;63:1278-88. Alirocumab: Lp(a) Reductions in ODYSSEY Combo II, Long Term, FH I and FH II Studies

Combo Long Term FH I FH II 0

-5 -3.7 -6.1 -10 -7.5 -10 -15

-20

-25 baseline to Week 24 Week to baseline -25.2 -27.8 LS mean (SE) % change from from % (SE) LS meanchange -30 -29.3 -30.3 -35 All comparisons vs. placebo are P<0.0001 Alirocumab + max-tolerated statin ±other LLT Placebo + max-tolerated statin ±other LLT

Adjusted mean (SE) shown for Lp(a). LLT = lipid-lowering therapy. Robinson, Farnier. Presented at the ESC; Barcelona, August 31, 2014. Future Directions of PCSK9i in FH

• Pediatrics • Early Combination Therapy • Role of Genetic Testing • Unknown impacts Pediatric PCSK9i Trials

HAUSER-RCT Trial Assessing Efficacy, Safety and Tolerability of PCSK9 inhibition in Pediatric Subjects with Genetic LDR Receptor Disorders (Evolocumab) Children with Genetic LDL Receptor Disorders (efficacy and safety trial )

Not Enrolling yet Robinson,J Emerging innovative therapeutic approaches targeting PCSK9 to lower lipids Accepted Article, doi: 10.1002/cpt.281 LDL Cholesterol “ Burden”

B.G. Nordestgaard et al. European Heart Journal Advance Access published August 15, 2013 Genetic Testing in FH

• Genetic Testing not yet “Gold Standard” in US • Regional differences in availability and cost. • Overlap exists between phenotype and genotype • Variability in testing technology and genes screened • Rarely required for diagnosis , but if so, and positive still does not guarantee approval • May be an adjunct to risk assessment in future.

Source: ClinicalTrials.gov Targeting PCSK9 for Theraputic gains: Have we addressed all the concerns?

Atherosclerosis 248 (2016) 62e75 Life Cycle of PCSK9 and its important pleiotropic functions

Atherosclerosis 248 (2016) 62e75 Summary • FH is a common disorder with multiple monogenic causes , LDL-R most often seen • PCSK9 plays an important role in regulating the LDL-R • PCSK9 inhibition has been demonstrated to be safe and efficacious in patients with both HoFH and HeFH • The diagnosis and documentation of such is an important part of obtaining PCSK9i approval for use in the US • Several organizations and associations have already published guidance for PCSK9i utilization and these offer the practitioner guidance when dialoging with payors • There may be a role for PCSK9i in patients with FH and elevated Lp(a) levels • The role of genetic testing is evolving in the US. • The use in of PCSK9i in pediatric patients has yet to be determined