PCSK9 INHIBITORS, ARNIS, FUNNY CHANNEL INHIBITORS:ARE YOU SURE THESE ARE

REALLY CARDIAC DRUGS?ALLORIE SMITH, PHARM.D.

CARDIOVASCULAR UPDATE CONFERENCE

FEBRUARY 9, 2012

OBJECTIVES

• Explain the pharmacology of Repatha™, Praluent®,

Entresto™, and Corlanor®.

• Learn the indications and doses for each of the

medications listed above.

• Discuss the literature behind the approval of the drugs

above

EVOLOCUMAB (REPATHA™)ALIROCUMAB (PRALUENT®)

PCSK9 INHIBITORS

PCSK9 INHIBITORS: CLASSIFICATION AND MOA

• Class: Proprotien convertase subtilisin kexin type 9

inhibitor (PCSK-9) antibody

• MOA: Binds to the PCSK-9 and prevents it from binding

and degradation the the LDL receptors. This allows for

the LDL receptors to return to the liver cell surface and

clear LDL from the blood, lowering LDL-C levels

Normal Activity

With Repatha

PCSK9 INHIBITORS: INDICATIONS AND DOSING

REPATHA™

• Adjunct to diet and maximum statin

dose in primary hyperlipidemia

• 140 mg subQ every 2 weeks

• 420 mg subQ monthly

• Adjunct to diet and other LDL

lowering therapies for homozygous

familial hypercholesterolemia

• 420 mg subQ monthly

PRALUENT®

• Adjunct to diet and

maximum statin dose in

primary hyperlipidemia

• 75 mg subQ every 2 weeks

• May increase to 150 mg

subQ every 2 weeks if

needed to achieve LDL

lowering goals

PCSK9 INHIBITORS : SIDE EFFECTS

REPATHA™• Nasopharyngitis (11%)

• URI (9%)

• Flu (9%)

• Gastreoenteritis (6%)

• Injection side reaction (6%)

• UTI (5%)

• Less than 5%

• Dizziness (4%), Myalgia (4%), Hypertension (3%),

Fatigue (2%), Nausea (2%), Bruise (1%)

PRALUENT®

• Injection site reactions (7%)

• Influenza (6%)’

• Diarrhea (5%)

• Less than 5%

• Increased liver enzymes (3%), Myalgia

(4%), Spasms (3%), cough(3%)

• Post marketing data/case reports:

confusion, memory impairment

PCSK9 INHIBITORS : DRUG INTERACTIONS/ CONTRAINDICATIONS

REPATHA™

• Interactions

• Belimumab

• Contraindications

• Hypersensitivity

PRALUENT®

• Interactions

• Belimumab

• Contraindications

• Hypersensitivity

PCSK9 INHIBITORS : PRICING

REPATHA™

• ~$650 per 140 mg

injection

• $5 copay coupon for

commercial insurance

PRALUENT®

• ~$670 per 75mg or 150mg

injection

• $0 copay for 6 months then

$10 thereafter coupon for

commercial insurance

REPATHA™: PHASE III STUDY RESULTS

• MENDEL 2: J Am Coll Cardiol. 2014 Jun 17;63(23):2531-40

• LAPLACE-2: JAMA. 2014 May 14;311(18):1870-82.

• DESCARTES : N Engl J Med. 2014 May 8;370(19):1809-19.

• GAUSS-2 : J Am Coll Cardiol. 2014 Jun 17;63(23):2541-8.

• RUTEHRFORD-2: Lancet. 2015 Jan 24;385(9965):331-40.

• TESLA PART B: Lancet. 2015 Jan 24;385(9965):341-50.

• OSLER 1: Circulation. 2014 Jan 14;129(2):234-43.

PRALUENT™: PHASE III STUDY RESULTS

• ODYSSEY MONO : Future Cardiol. 2015;11(1):27-37.

• ODYSSEY COMBO 1: Am Heart J. 2015 Jun;169(6):906-915

• ODYSSEY COMBO 2 : Eur Heart J. 2015 May 14;36(19):1186-94.

• ODYSSEY ALTERNATIVE : J Clin Lipidol. 2014 Nov-Dec;8(6):554-61.

• ODYSSEY FH 1 AND 2 : Eur Heart J. 2015 Nov 14;36(43):2996-

3003

• ODYSEEY LONG TERM : N Engl J Med. 2015 Apr 16;372(16):1489-

99.

SACUBITRIL / VALSARTAN (ENTRESTO™)

ENTRESTO™: INDICATION AND DOSAGE

• Heart failure

• Patients previously taking the

equivalent of >10 mg/day of

enalapril or >160 mg of

Valsartan

• Start 49mg/51 mg BID, double

the dose every 2-4 weeks to the

target dose of 97 mg/ 103 mg

BID

• Patients previously taking the

equivalent of <10 mg/day of

enalapril or <160 mg of

Valsartan

• Start 24mg/26 mg BID, double

the dose every 2-4 weeks to the

target dose of 97 mg/ 103 mg

BID

ENTRESTO™ CLASSIFICATION AND MOA

• Class: Angiotensin Receptor

Blocker (ARB) and Neprilysin

Inhibitor

• MOA:

• ARB: Blocks angiotensin

receptors

• Neprilysin inhibitor:

prodrug that inhibits

neprilysin and increase

levels of naturetic peptides

ENTRESTO™ : SIDE EFFECTS

• Hypotension (~18%)

• Hyperkalemia (up to 16%)

• Increase in SCR (up to 16%)

• Cough (9%)

• Less than 5%:

• Hypotension, Dizziness, Decreased H/H, Angioedema, Renal

failure

ENTRESTO™ : DRUG INTERACTIONS / CONTRAINDICATION

DRUG INTERACTIONS

• ACEI

• Aliskiren

• Lithium

• Trimethoprim

• Simeprevir

CONTRAINDICATIONS

• History of angioedema

Plavix [package insert]

Lexi-comp

Micromedex

ENTRESTO™ : PHASE III STUDY

• PARADIGM-HF

• N Engl J Med. 2014 Sep 11; 371(11): 993-1004

Pharmacotherapy. 2012;32(12):e348-e386

ENTRESTO™ : PRICING

• All strengths: ~$450 for 60 tablets

• 30 days free coupon valid for all insurances (commercial and

government)

• $10 copay card for commercial insurance

IVABRADINE (CORLANOR®)

CORLANOR®: INDICATIONS AND DOSAGE

• Heart failure

• Initial dose: 5 mg BID

• Adjustments after two weeks

• Resting HR > 60 – increase to 7.5 mg BID (max dose)

• Resting HR between 50-60 – maintain dose

• Resting heart rate <60 or Symptoms of bradycardia – reduce to

2.5 mg BID

CORLANOR®: CLASSIFICATION AND MOA

• Class: MISC Cardiovascular agent

• NO FUN!!! I think we should call them funny channel inhibitors

• MOA:

• Selective and specific inhibition of the hyperpolarization-

activated cyclin nucleotide-gated channels (If channels or funny

channels) within the SA node of the cardiac tissue

• Slows diastolic depolarization and firing of the SA node which

reduces heart rate

Corlanor Website https://www.corlanorhcp.com/~/media/amgen/full/www-corlanorhcp-com/diagram-

moa3.ashx?la=en&hash=89DD72F9A1AC0E2F6A32D9AB4E30F6A77073AB05

CORLANOR®: SIDE EFFECTS

• Bradycardia (10%)

• Hypertension (8.9%)

• A Fib (8.3%)

• Phosphene (2.8%)

CORLANOR®: DRUG INTERACTIONS / CONTRAINDICATION

DRUG INTERACTIONS

• QT prolongating agents

• CYP 3A4 drugs

CONTRAINDICATIONS

• Decompensated CHF

• Pacemaker dependent

• Baseline bradycardia

• Hepatic impairment

• Hypotension

• Heart block

CORLANOR®: STUDY

• BEAUTIFUL: Lancet. 2008 Sep 6;372(9641):807-16.

• SHIFT: Lancet. 2010 Sep 11;376(9744):875-85.

• SIGNIFY: N Engl J Med. 2014 Sep 18; 371:1091-1099

Pharmacotherapy. 2012;32(12):e348-e386

CORLANOR®: PRICING

• $375 for 60 tablets

• $20 copay coupon for commercial insurance

REFERENCE

• Corlanor [package insert]. Thousand Oaks, CA: Amgen; 2015.

• Entresto [package insert]. East Hanover, NJ: Novartis; 2015.

• Lexi-Comp Online. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc.;

2016. http://online.lexi.com. Accessed January 25, 2016.

• Micromedex Healthcare Series. DRUGDEX System. Greenwood

Village, CO: Thomson Healthcare; 2016.

http://www.thomsonhc.com/. Accessed January 25, 2016.

• Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2015.

• Repatha [package insert]. Thousand Oaks, CA: Amgen; 2015.

PCSK9 INHIBITORS, ARNIS, FUNNY CHANNEL INHIBITORS:

ARE YOU SURE THESE ARE REALLY

CARDIAC DRUGS?ALLORIE SMITH, PHARMD

CARDIOVASCULAR UPDATE CONFERENCE

FEBRUARY 9, 2012