Managing Hyperlipidemia: A New

Charge for Specialty Pharmacy

with the Advent of PCSK9

Inhibitors

Erin Hohman, PharmD, BCPSDirector of Clinical Pharmacy Services

Amber Pharmacy

Omaha, Nebraska

Pharmacy Accreditation

Pharmacy Times Continuing Education is

accredited by the Accreditation Council for

Pharmacy Education (ACPE) as a provider of

continuing pharmacy education. This activity

is approved for 1.0 contact hours (0.10

CEU) under the ACPE universal activity

number 0290-0000-16-031-L01-P. The

activity is available for CE credit through

May 5, 2016.

Faculty Disclosure

Erin Hohman, Pharm D, BCPS,

has no relevant financial

relationships with commercial

interest to disclose.

This activity is sponsored by

Pharmacy Times Continuing

Education and supported by

educational funding provided by

Amgen and an educational grant

from sanofi-aventis U.S. and

Regeneron Pharmaceuticals.

Learning Objectives

• Compare lipid-lowering therapy based on clinical practice guideline recommendations and large-scale clinical trial results

• Distinguish PCSK9 inhibitors and their clinical benefits in individualized patient management

• Examine cost and utilization management of PCSK9 inhibitors

Hyperlipidemia

71 millionElevated LDL-C level

34 millionon lipid-lowering therapy

11 milliontreated and uncontrolled

2015 Heart Disease and Stroke

Statistics

• CVD accounted for ≈1 of every 3

deaths in 2011

– High cholesterol is a major risk factor for

CVD and stroke

• LDL is the major atherogenic

lipoprotein

– 22% relative risk reduction of major

ASCVD events by lowering LDL-C ≈39

mg/dL

ASCVD: atherosclerotic cardiovascular disease; CVD:

cardiovascular disease; LDL: low-density lipoprotein; LDL-C:

low-density lipoprotein cholesterol.

Mozaffarian D, et al. Circulation. 2015;131(4): e29-322; CDC. MMWR. 2011;60(4):109-114.

Familial

Hypercholesterolemia (FH)

• Inherited genetic disorder

– Autosomal dominant

– Early onset coronary heart

disease

– 20 times higher risk of heart

disease

– Cholesterol may deposit in the

skin, tendons & eyelids

– ~20% diagnosed

Hopkins P, et al. J Clin Lipidology. 2011;5:S9-17; Mozaffarian D, et al. Circulation.

2015;131(4): e29-322; Nordestgaard BG, et al. Eur Heart J. 2013;34(45): 3478-3490.

• Total cholesterol >240 mg/dL

31 million

• HeFH

• 1/300-1/500

• TC 350-550 mg/dL

644,000

• HoFH

• 1 in 1 million

• TC 650-1000 mg/dL

322

Genetics of FH

• LDLR (loss-of-function)

– > 90% of FH cases

– >1200 to 1600 known mutations

• Apolipoprotein B (APOB) mutation

– Arg3500Gln is most common

– ≈ 5% of FH cases

• PCSK9 (gain-of-function)

– > 20 mutations identified

– ≈ 1%

• Homozygous mutation

– Same gene from both parents

• Compound heterozygous

mutation

– Different mutation from

each parent

• LDLR & LDLRAP (aka

autosomal recessive

hypercholesterolemia [ARH])

LDLR: low-density lipoprotein receptor; LDLRAP: low-density lipoprotein receptor & adaptor

protein; PCSK9: proprotein convertase subtilisin/Kexin type 9

Nordestgaard BG, et al. Eur Heart J. 2013;34(45): 3478-3490; Hopkins P, et al. J Clin Lipidology. 2011;5:S9-17

HeFH HoFH

Statin & Non-statin Utilization• Statins are underutilized; even in CVD

• Prime Therapeutics claims data study

– 54,000 members with established CVD

– 1 in 5 utilizing high-dose statin

– 27% had no statin claim

– 45% had no statin claim or were non-adherent

• 1 in 4 tried a second statin in the past 4 years

• Gorcyca et al. MarketScan Research Database

– 185,293 identified with ASCVD or diabetes

– 55% being treated with LLT

• 12% on high-intensity statin

• 36% on low- to moderate-intensity statin

• 6% on non-statin

• 35% achieved LDL-C ≤ 70 mg/dL; 79% ≤ 100 mg/dL

Gorcyca K, et al. J Clin Lipid. 2015;9(3):424.; Prime Therapeutics website. https://www.primetherapeutics.com/Files/PCSK9_statin-

use_release_final.pdf. Published July 21, 2015

AMI: acute myocardial infarction; CVD: cardiovascular disease; LLT: lipid-lowering therapy

Statin Intolerance• Many discontinue statin therapy due to intolerance

• Limits effective treatment for patients at risk of CV events

• Adverse reactions occur in ≈5-15%

– Most common are muscle-related events

• Myalgia reported in ≈1-5% in RCTs

• Observational studies report myalgia as high as 11-29%

• Rechallenge

– Retrospective cohort study: 107,835 patients

• 17.4% experienced statin-related adverse effect

– 59.2% discontinued statin therapy at least temporarily

– 59.1% of the discontinued patients were rechallenged with 92.2% success

Banach M, et al. Arch Med Sci. 2015; 11(1): 1-23; Newman C, et al. JAMA. 2015;313(10):1011-1012; Rosenson R, et al. J Clin Lipid.

2014;8:S58-71; Zhang H, et al. Ann Intern Med. 2013;158(7):526-534.

RCTs: randomized controlled trials

American College of Cardiology/

American Heart Association

(ACC/AHA) • 2013 Guideline: Treatment of Blood Cholesterol to

Reduce ASCVD Risk in Adults

– RCTs & Meta-analyses of RCTs

– ASCVD risk reduction

– Risk Calculator – Pooled Cohort Equations

– Diet & lifestyle modifications

– Regular lipid follow-up to assess adherence (no longer a

treatment target)

– Patient-provider communication important

Stone N, et al. Circulation. 2014; 129:S1-45

ACC/AHA Statin Benefit Groups

Stone N, et al. Circulation. 2014;129:S1-45; Jacobson T, et al. J Clin Lipidol. 2015;9(2):129-69.

ACC/AHA Treatment Goals

• Diet & Lifestyle – Heart healthy diet

– Regular exercise

– Avoiding tobacco products

– Maintain a healthy weight

High-intensity daily dosage (lowers LDL-C ≥ 50%)

Atorvastatin, 40-80 mg

Rosuvastatin, 20-40 mg

Moderate-intensity daily dosage (lowers LDL-C 30% to <50%)

Atorvastatin, 10-20 mg

Fluvastatin, 40 mg bidFluvastatin XL, 80 mg

Lovastatin, 40 mg

Pitavastatin, 2-4 mg

Pravastatin, 40-80 mg

Rosuvastatin, 5-10 mgSimvastatin, 20-40 mg

Stone N, et al. Circulation. 2014; 129:S1-45.; Jacobson T, et al. J Clin Lipidol. 2015;9(2):129-69.

Non-statin Therapies• Routine use not recommended to

further reduce ASCVD events

• ASCVD, LDL-C ≥ 190 mg/dL, or

diabetes

– Below anticipated response

– Unable to tolerate recommended

statin intensity

– Statin intolerant

Stone N, et al. Circulation. 2014; 129:S1-45; Jacobson T, et al. J Clin Lipidol. 2015;9(2):129-69

Drug Class

LDL-C ↓15-30%

Non-HDL-C ↓4-16%

HDL-C ↑3-5

TG ↑0-10%

LDL-C ↓5-25%

Non-HDL-C ↓8-23%

HDL-C ↑15-35%

TG ↓20-50%

LDL-C ↓5-↑20%

Non-HDL-C ↓5-19%

HDL-C ↑10-20%

TG ↓20-50%

LDL-C ↓13-20%

Non-HDL-C ↓14-19%

HDL-C ↑3-5%

TG ↓5-11%

LDL-C ↓6-↑25%

Non-HDL-C ↓5-14%

HDL-C ↓5-↑7%

TG ↓19-44%

Bile acid sequestrant

Nicotinic acid

Fibric acid

Cholesterol absorption inhibitor

Long-chain omega-3 fatty acid

Lipid/lipoprotein Effect

HDL-C; high-density lipoprotein cholesterol; TG:

triglycerides

Diagnosis of FH• Simon Broome Registry

• Dutch Lipid Clinic Network

• Make Early Diagnosis to Prevent Early

Deaths (MEDPED)

• AHA Agenda for FH– Supporting development of ICD-10 codes for HeFH,

HoFH & family history of FH

Austin M, et al. Am J Epidemiol. 2004;160(5):407-20; Gidding S, et al. Circulation. 2015;132:00-00; Nordestgaard, et al. Eur. Heart J. 2013;34:3478-

90; Williams RR, et al. Am J Cardiol. 1993;72(2):171-176

AHA FH Recommendations

• Clinical criteria alone

– LDL-C

– Family history

– Aortic valve disease

– Xanthomata < 20 yo

• Clinical criteria plus

genetic testing

• 50% reduction in LDL-C

• Initial: high-intensity statin

• 2-drug: ezetimibe

• 3-drug: BAS, Niacin, & PCSK9 inhibitors

• Complex: 4-drug & apheresis

Gidding S, et al. Circulation. 2015;132:00-00.

Diagnosis Treatment

FH Guidelines

Genest J, et al. Can J Card. 2014;30:1471-1481; Hopkins P, et al. J Clin Lipidology. 2011;5:S9-17 Nordestgaard, et al. Eur. Heart J. 2013;34:3478-90

NLA EAS CCS

Screening

Patient or family member with:

- LDL-C ≥ 190 mg/dL or

non-HDL-C ≥ 220 mg/dL- Premature CHD

● Physical findings:

- Tendon xanthomas - Corneal Arcus (< 45 yo)

- Tuberous xanthomas or

xanthelasmas (<20-25 yo)

● Cascade screening

Patient or family member with:

- Cholesterol ≥ 310 mg/dL

- Premature CHD- Sudden premature cardiac

death in a family member

● Tendon xanthomas

● Cascade screening

LDL-C >193 mg/dL

Early CVD in patient/family

● Physical findings

(xanthomas, xanthelasmas, or corneal arcus)

● Cascade screening

Clinical

Diagnosis

● SBR

● DLCN

● MEDPED

● DLCN ● SBR

● DLCN

CCS: Canadian Cardiovascular Society; CHD: coronary heart disease; CVD: cardiovascular disease; DLCN: Dutch Lipid Clinic

Network; EAS: European Atherosclerosis Society; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol;

MEDPED: Make Early Diagnosis to Prevent Early Deaths; NLA: National Lipid Association; non-HDL-C: non high-density lipoprotein

cholesterol; SBR: Simon Broome Registry

FH Guidelines

Genest J, et al. Can J Card. 2014;30:1471-1481; Hopkins P, et al. J Clin Lipidology. 2011;5:S9-17 Nordestgaard, et al. Eur. Heart J. 2013;34:3478-90.

NLA EAS CCS

Treatment

● Lifestyle Modifications

- Statin- Ezetimibe

- Niacin

- BAS

- Referral to specialist

● Lifestyle Modifications

- Max statin dose- Ezetimibe

- BAS

- Apheresis (FH with CHD)

● Lifestyle Modifications

- Statin- Max statin +/- ezetimibe or

BAS

LDL-C

Target

● >50% LDL-C reduction

● High risk:LDL-C < 100 mg/dL and

non-HDL-C <130 mg/dL

● LDL-C <100 mg/dL

● CHD or DM <70 mg/dL

● Primary prevention

>50% LDL-C reduction

● Secondary prevention

LDL-C < 77 mg/dL

BAS: bile acid sequestrant; CCS: Canadian Cardiovascular Society; CHD: coronary heart disease; DM: diabetes mellitus; EAS:

European Atherosclerosis Society; FH: familial hypercholesterolemia; HoFH: homozygous familial hypercholesterolemia; LDL-C:

low-density lipoprotein cholesterol; NLA: National Lipid Association; non-HDL-C: non high-density lipoprotein cholesterol

Statin Limitations

• 15% abandonment rate

• 50% discontinue within 1 year

• Patient-related non-adherence

– Low health literacy

– Lack of disease knowledge &

effectiveness of therapy

– Psychological issues or cognitive

impairment

– Poor past experience

• RCT evidence lacking:

– Adults <40 years old

– Low 10-year, but high

lifetime ASCVD risk

– Comorbidities

• Human immunodeficiency virus (HIV)

• Rheumatic/Inflammatory disease

• Solid organ transplant

Cheetham TC, et al. J Manag Care Pharm. 2013;19(5):367-73.; Maningat P, et al. Curr Atheroscler Rep. 2013; 15(1): 291.; Stone N, et al. Circulation.

2014; 129:S1-45.

ACC/AHA 2013 Guidelines

Adherence & Persistency

Statin Limitations

• Adverse reactions (≈5-15%)

– Myalgia

– Diabetes

– Memory impairment

– Elevated LFTs

• Yun H et al. statin therapy

upon hospital discharge

– 31.2% AMI as secondary

diagnosis

– 60.5% AMI as primary

diagnosis

Banach M, et al. Arch Med Sci. 2015; 11(1): 1-23; Yun H, et al. J Am Heart Assoc. 2015; 4(2)

e001208 ; Zhang H, et al. Ann Intern Med. 2013;158(7):526-534.

AMI: acute myocardial infarction; LFTs: liver function tests

Inadequate Response

Statin Intolerance Statin Underutilization

What is PCSK9?• Discovery of PCSK9

– 2003 gain-of-function mutations in PCSK9 identified

– 2005 loss-of-function mutations in PCSK9 described

• Y142X & C679X: 28% LDL-C & 88% coronary heart disease

reductions

• R46L: 15% LDL-C & 47% CHD reductions

• Primarily expressed in the liver, kidney, and intestine

• Regulated greatly by intracellular cholesterol concentrations

through activation of SREBP2

• Key role in cholesterol homeostasis

SREBP2: sterol-responsive element-binding protein 2

Cohen J, et al. N Engl J Med. 2006;354:1264-72; Farnier, M. Cardiovascular Disease. 2014; 107:58-66.

PSCK9 and Cholesterol Homeostasis

Cohen JC, Hobbs HH. Genetics. Simple genetics for a complex disease. Science. 2013;340(6133):689-90.

doi: 10.1126/science.1239101.Reprinted with permission from AAAS.

Alirocumab (Praluent)

• First FDA approved

PCSK9 inhibitor

• Human monoclonal

antibody (IgG1 isotype)

In addition to diet & maximally

tolerated statin therapy in adults:

• HeFH

• Clinical ASCVD

Who require additional LDL-C

lowering

Indications

Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis US. October 2015. Picture: www.fda.gov

HeFH: heterozygous familial hypercholesterolemia; Ig: immunoglobulin

Alirocumab Dosing,

Administration & Storage

• Dosage Forms– 75 mg/mL & 150 mg/mL

prefilled PEN

– 75 mg/mL & 150 mg/mL

prefilled SYRINGE

• Storage– Refrigerator at 36˚F to 46˚F

(2˚C to 8˚C)

– Protect from light in original container

– Can be stored up to 77˚F for ≤ 24 hours

• Subcutaneous Dosing– Starting dose

• 75 mg every 2 weeks

– Maximum dose

• 150 mg every 2 weeks

Allow to warm to room temperature for 30 to 40

minutes prior to use

Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis US. October 2015.

Evolocumab (Repatha)

• Second FDA approved

PCSK9 inhibitor

• Human monoclonal

antibody (IgG2 isotype)

Adjunct to diet and:

– Maximally tolerated statin

therapy for adults with

HeFH or clinical ASCVD

– Other LDL-lowering

therapies (e.g. statins,

ezetimibe, LDL apheresis)

in patients with HoFH

Repatha [package insert]. Thousand Oaks, CA: Amgen. August 2015 v1.; www.fda.gov. Accessed April 15, 2016.

Indications

• Dosage Forms– 140 mg/mL Prefilled SureClick

autoinjector

– 140 mg/mL Prefilled SYRINGE

• Storage– Refrigerator at 36˚F to 46˚F

(2˚C to 8˚C)

– Protect from light in original

container

– Can be stored up to 77˚F for 30

days

Evolocumab Dosing,

Administration & Storage

• Subcutaneous Dosing

– HeFH & Clinical ASCVD

• 140 mg every 2 week

OR

• 420 mg once monthly

– HoFH

• 420 mg once monthly

Repatha [package insert]. Thousand Oaks, CA: Amgen. August 2015 v1.

Allow to warm to room temperature for 30

minutes prior to use

Contraindications, Warnings

& Precautions

• Contraindications– History of a serious hypersensitivity

reaction to alirocumab

• Warnings & Precautions– Allergic Reactions: Hypersensitivity

reactions (e.g., pruritus, rash,

urticaria), including some serious

events (e.g., hypersensitivity

vasculitis and hypersensitivity reactions requiring hospitalization),

have been reported

• Contraindications– History of a serious hypersensitivity

reaction to evolocumab

• Warnings & Precautions– Allergic reactions: Rash and urticaria

have occurred

– Discontinue evolocumab if signs or

symptoms of serious allergic

reaction occur and treat according to standard of care

Alirocumab Evolocumab

Repatha [package insert]. Thousand Oaks, CA: Amgen. August 2015.; Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis US.

October 2015.

Adverse ReactionsAlirocumab Evolocumab

Adverse ReactionAlirocumab

(%)

Placebo

(%)

Nasopharyngitis 11.3 11.1

Injection Site Reactions 7.2 5.1

Urinary Tract Infection 5.7 4.6

Diarrhea 4.7 4.4

Bronchitis 4.3 3.8

Myalgia 4.2 3.4

Muscle Spasms 3.1 2.4

Sinusitis 3.0 2.7

Cough 2.5 2.3

Contusion 2.1 1.3

Musculoskeletal Pain 2.1 1.6

Adverse ReactionEvolocumab

(%)

Placebo

(%)

Nasopharyngitis 4 3.9

Back Pain 2.3 2.2

Upper Resp Infection 2.1 2

Arthralgia 1.8 1.6

Nausea 1.8 1.2

Fatigue 1.6 1

Muscle spasms 1.3 1.2

Urinary Tract Infection 1.3 1.2

Cough 1.2 0.7

Influenza 1.2 1.1

Contusion 1 0.5

Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis US. October 2015; Repatha [package insert]. Thousand Oaks, CA: Amgen. August 2015.

Clinical Trials

• Alirocumab Clinical

Trial Program

– 15 global phase 3

trials

– Over 23,500

patients

• Evolocumab Clinical

Trial Program

– 14 phase 3 trials

– Nearly 30,000

patients total

ODYSSEY PROFICIO

ODYSSEY clinical trial backgrounder. Sanofi and Regeneron Pharmaceuticals. Updated October 2013.; Proficio: The Evolocumab

Clinical Trial Program. Amgen, Inc. Updated March 18, 2014.

Familial Hypercholesterolemia

Aliro

cu

mab

Randomized, double-blind, placebo-controlled, maximally tolerated statin therapy, +/- other LMT

Study NDuration

(weeks)Patient Population Alirocumab Dosing Results

ODYSSEY FH I 249

78

HeFH

• CV event & LDL-C >/= 70 mg/dL

mg/dL

• NO history of CV event &

LDL-C >/= 100 mg/dL

Start:

75 mg SQ Q2W

Up-titration at W12:

150 mg SQ Q2W(If LDL-C goal not

reached at W8)

• W24:-48.8% (FHI) &

-48.7% (FHII) LS mean

LDL-C change from baseline*

• 42% titrated to 150mg

Q2W at W12 • Over 70% reached

prespecified LDL-C goal at

W24

ODYSSEY FH II 486

ODYSSEY HIGH FH 107 78 HeFH: LDL-C >/= 160 mg/dL 150 mg SQ Q2W

• 57% alirocumab vs. 11%

placebo reached LDL-C <100

mg/dL*

• 32% alirocumab vs. 3%

reached LDL-C <70 mg/dL*

ODYSSEY LONG

TERM2341 78

HeFH, established CHD or CHD

risk equivalents⁺150 mg SQ Q2W

• W24: -61% LS mean LDL-

C change from baseline with

alirocumab*

* statistically significant (P-value <0.05)

⁺ CHD risk equivalents (ischemic stroke, peripheral artery disease, moderate chronic kidney disease, or diabetes mellitus plus ≥2 risk

factors: hypertension, ankle-brachial index of ≤ 0.90, microalbuminuria, macroalbuminuria, retinopathy, family history CHD)

Ginsberg H Presented at the ESC Congress 2014, Barcelona, Spain; Kastelein J, et al. Euro Heart J. 2015;36:2996-3003; Kastelein J, et al.

Cardiovasc Drugs Ther. 2014;28:281-289; Robinson J, et al. N Engl J Med. 2015;372:1489-99.

Familial Hypercholesterolemia

Evo

locu

mab

Randomized, double-blind & placebo-controlled

StudyDesign

(N)

Duration

(weeks)

Patient

Population

Evolocumab

DosingResults

RUTHERFORD-2

Combination

Therapy:

statin therapy +/-

LLT

(329)

12 HeFH

140 mg SQ Q2W

OR

420 mg SQ

MONTHLY

• Lowered LDL-C 60% and 66% with

Q2W & monthly dosing, respectively*

• Achieved LDL-C <70 mg/dL: 67% &

80% evolocumab Q2W & monthly

dosing, respectively*

TESLA (Part B)

Combination

Therapy:

statin therapy +/-

LLT

(49)

12 HoFH420 mg SQ

MONTHLY

• W12: -23.1% mean change in LDL-C

from baseline*

*statistically significant (P <.05)

Hassan M, Glob Cardiol Sci Pract. 2014; 2014(4): 360–366; Raal F, et al. The Lancet. 2015;385(9965):341-50; Raal F, et al. Presented at

the ISA. Amsterdam, Netherlands. May 26, 2015.

Cardiovascular Disease

Aliro

cu

mab

Randomized, double-blind, placebo-controlled, maximally tolerated statin therapy, +/- other

LMT

Study NDuration

(weeks)Patient Population Alirocumab Dosing Results

ODYSSEY

Combo I316 52

Hypercholesterolemia

• Established CHD or CHD

risk equivalents⁺

Start:

75 mg SQ Q2W

Up-titration at W12:

150 mg SQ Q2W

(If LDL-C goal not reached at W8)

• W24: -48.2% mean

change from LDL-C

baseline with alirocumab*

* statistically significant (P <.05)

⁺ CHD risk equivalents (ischemic stroke, peripheral artery disease, moderate chronic kidney disease, or diabetes mellitus plus

≥2 additional risk factors)

ITT: intent to treat

Randomized, double-blind, double-dummy, ezetimibe-controlled, maximally tolerated statin

ODYSSEY

Combo II720 104

Hypercholesterolemia

• Established CHD or CHD

risk equivalents⁺• vs ezetimibe

Start:

75 mg SQ Q2W + oral

placebo

SQ placebo + ezetimibe 10

mg/dayUp-titration at W12:

150 mg SQ Q2W

(If LDL-C goal not reached

at W8)

• W24: 77% alirocumab

vs. 45.6% ezetimibe

LDL-C <70 mg/dL (ITT)*

Cannon C, et al. Euro Heart J. 2015;36:1186–1194; Colhoun H, et al. BMC Cardiovascular Disorders. 2014;14:121.

Statin Intolerant

Aliro

cu

mab

ODYSSEY ALTERNATIVE

• 314 patients

• Mean baseline LDL-C =

191.3 mg/dL

• Intolerance to ≥ 2 statins

• -34.7% mean LDL-C

difference

• Significantly lower rates of

musculoskeletal adverse

effects (AEs)

Randomized, double-blind, double-dummy, ezetimibe-controlled

Reprinted from J Clin Lipidol, 9(6), Moriarty PM, et alEfficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin

rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial., 758-69, Copyright (2015), with permission from Elsevier.

Statin Intolerant

Evo

locu

mab

Reprinted from J Amer Coll Card, 63(23), Stroes E, et al, AntiPCSK9 Antibody Effectively Lowers Cholesterol in Patients With Statin Intolerance The

GAUSS2 Randomized, Placebo-Controlled Phase 3 Clinical Trial of Evolocumab, 2541-48.Copyright (2014), with permission from Elsevier.

GAUSS-2• 307 patients

• Mean baseline LDL-C =

193 mg/dL

• Intolerance to ≥ 2 statins

• Reduction in LDL-C from

baseline

– Evolocumab 53-56%

– Ezetimibe 15-18%

• Achieved goal <100

mg/dL

– Evolocumab >75%

– Ezetimibe <10%

• Similar discontinuation

for muscle-related ADEs

Randomized, double-blind, placebo- & ezetimibe-controlled

CV Outcomes

• ODYSSEY OUTCOMES

– 18,600 estimated enrollment

– October 2012 - February 2018

– Inclusion

• Age > 40 years

• Recent ACS event

– Primary endpoint

• Time to first CV event

• FOURIER

– 27,564

– January 2013 - February 2018

– Inclusion

• ≥ 40 to ≤ 85 years

• History of CVD at risk of

recurrent event

• Fasting LDL-C ≥ 70 mg/dL or

non-HDL-C ≥ 100 mg/dL

• Fasting TG ≤ 400 mg/dL

– Primary endpoint

• Time to first CV event

Alirocumab Evolocumab

ACS: acute coronary syndrome.

Sanofi. ClinicalTrials.gov [Internet]. NCT01663402.; Amgen. ClinicalTrials.gov [Internet]. NCT01764633.

Investigational PCSK9 Inhibitors

• Bococizumab

– Subcutaneous monoclonal

antibody targeting PCSK9

– SPIRE Phase 3 program

• Lipid-lowering efficacy

• CV outcome studies

• LY3015014

– Subcutaneous monoclonal

antibody targeting PCSK9

Phase 3 Phase 2

• Evolocumab

– sNDA: SINGLE 420 mg

monthly injection

– PDUFA: July 10, 2016

Filed

PDUFA: Prescription Drug User Fee Act; sNDA: supplemental new drug application.

Bococizumab (RN316). BioPharm Insight. Infinata, Web. 21 Aug. 2015.; LY3015014. BioPharm Insight. Infinata,. Web. 21 March 2016.

PCSK9 Inhibitors as

Specialty Medications

• Cost– Financial support

• Copay card

• Grants/Foundation

• Manufacturer Patient Assistance Programs

• Prior authorizations (PAs) & appeals

• Injection training & education

• Adherence & persistency

Challenges for Specialty

Pharmacies (SPs)

• Prescribers– Unaccustomed to working with SPs

• Patients – Unfamiliar with the benefit and role

of an SP

• HUBs– Connecting patients to services

– Streamlining communication

• SPs are central component to

all aspects of the referral

Challenges for SPs

• PAs/Appeals

– Documentation, Documentation, Documentation

– Knowledgeable clinical staff

– Ongoing management

• PA/appeal expiration

• Tracking grant/foundation funding

• Proactively reapply

• No ICD-10 code for HeFH, HoFH or family history of FH

ICD: International Classification of Disease

Cost Comparison

Medication DosingAWP

Pricing ($/unit)

Estimated

Monthly $

Alirocumab

75 mg syringe/pen

75 mg every

2 weeks672.00 1150.00

Alirocumab

150 mg syringe/pen

150 mg every

2 weeks672.00 1150.00

Evolocumab

140 mg syringe/pen

140 mg every

2 weeks650.77 1100.00

420 mg

monthly650.77 1650.00

Rosuvastatin 40 mg tablet 40 mg daily 9.94 250.00

Atorvastatin 80 mg tablet 80 mg daily0.24749+

(ACA-FUL)7.50

• PCSK9 inhibitors have a

higher monthly cost

– Higher copay tier

– Higher coinsurance

• Rosuvastatin [Crestor] LOE

May 2016

– Savings card

• Cost-saving generic lists

+ Source: March 2016 Affordable Care Act –Federal Upper Limit Source: Medi-Span Price Rx 3/21/16

AWP: average wholesale price; LOE: loss of exclusivity; PCSK9: proprotein convertase subtilisin/kexin type 9

Crestor Savings Card. https://www.crestortouchpoints.com/patient-support/money-saving-offers/savings-card.html. February 2016.

Cost Concerns &

Perspectives

• Acquisition & Discounts

• Appropriate Staffing:– Skilled & efficient intake team

– Knowledgeable PA/appeal staffing

– Retention & ongoing support

• Cold Ship• Disease prevalence

• UM criteria & Formulary

status

• Product cost/Rebates

Specialty Pharmacy

Payer

Patient

• Out-of-pocket cost

Estimated Lives Affected in a

Health Plan

3003

Patients25,02538,50070,0001 Million

7% ACS or

stable CHD55% on LLT

65% ≥ LDL-C

>70 mg/dL

12% on high-

intensity statin

Gorcyca K, et al. J Clin Lipid. 2015;9(3):424.

Conclusions• FH is underdiagnosed & undertreated

• Clinical guidance varies slightly on screening, clinical diagnosis, treatment and target recommendations

• PCSK9 play an important role in regulating LDL-C levels

• Alirocumab and evolocumab have proven to significantly reduce LDL-C levels

• Alirocumab and evolocumab’s effect on cardiovascular morbidity and mortality has yet to be determined

• SPs high-touch service models and focus on minimizing out-of-pocket expense for patients may lessen the burden of the higher cost of novel PCSK9 inhibitors compared to standard of care

• Due to the cost associated with PCSK9 inhibitors and its large population within indication, most Payers have established UM Criteria to minimize the impact on drug expenditures

Additional Resources• American Heart Association

– www.heart.org

• European Atherosclerosis Society (EAS)– www.eas-society.org

• FH Canada– www.fhcanada.net

• FH Foundation– www.thefhfoundation.org

• HEART UK– www.heartuk.org.uk

• International FH Foundation– www.fh-foundation.org

• National Lipid Association (NLA)– www.lipid.org

• National Organization for Rare Disorders (NORD)– www.rarediseases.org

• Preventive Cardiovascular Nurses Association– www.pcna.net/patients/familial-hypercholesterolemia