A New Pulse in the Cardiovascular Market · Ended short due to interim analysis not likely to meet end point . No difference in primary endpoint but issues with MI definitions . Difference

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A New Pulse in the Cardiovascular Market

Bradley D. Bruce, PharmD Corporate Pharmacy Resident

November 4, 2015

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Learning Objectives

• Describe newly available cardiovascular pharmaceutical treatment options and how they compare to traditional therapy choices

• Evaluate the clinical trials and published literature of cardiovascular drugs approved by the FDA in 2015

• Assess the financial impact of new medications in the acute care cardiovascular market

• Describe how these new medications will affect current drug therapy

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Heart Disease

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Heart Disease in the United States

• Approximately 600,000 patients die annually • Leading cause of death in the United States for both men and

women • Coronary heart disease makes up about 370,000 deaths annually

CDC, NCHS. Underlying Cause of Death 1999-2013 on CDC WONDER Online Database, released 2015. Data are from the Multiple Cause of Death Files, 1999-2013, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Accessed Feb. 3, 2015.

Ethnic Group Percentage of Deaths

American Indians or Alaska Natives 18.4

Asians or Pacific Islanders 22.2

Non-Hispanic Black 23.8

Non Hispanic Whites 23.8

All Americans 23.5 CDC. Deaths, percent of total deaths, and death rates for the 15 leading causes of death in 10-year age groups, by race and sex: United States, 2013

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Types of Heart Disease

• Coronary heart disease — Myocardial infarction

• About 15% of people who have a heart attack will die from it

— Heart Failure ($32 billion annually) • 5.1 million people in the United States have heart failure

• Stroke (fifth leading cause of death) — $34 billion annually

• Peripheral artery disease — About 8 million Americans

Mozzafarian D, Benjamin EJ, Go AS, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics – 2015 Update: a report from the American Heart Association. Circulation. 2015;131:e29-e322.

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Heart Disease in the United States (2011-2013)

Map information generated from the CDC

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Heart Disease in Tennessee vs. Unemployment Rate

Map information generated from the CDC

Unemployment Rate

Heart Disease

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What Can We Do About This?

Diet & Physical Activity

Weight Management

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Coronary Events

Wannamethee, SG, Shaper, AG, Alberti, KG, Arch Intern Med 2000; 160:2108.

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FDA Drug Approvals (2015)

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Cardiology/Vascular Disease Drug (2005-2015)

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2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Drugs Approved

Data collected from the FDA

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.ReportsMenu

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FDA Approved Drugs for Cardiology/Vascular Diseases (2015)

Jan June Feb March April May July Aug

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Savavsa (edoxaban)

Prestalia (perindopril /amlodipine)

Corlanor (ivabradine)

Kengreal (cangrelor)

Entresto (sacubitril / valsartan)

Praluent (alirocumab)

Repatha (evolocumab)

Sept Oct Nov

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Brilinta (ticagrelor) New Dosage Form

Praxbind (Idarucizumab)

Durlaza (aspirin) New Dosage Form http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.ReportsMenu

Data collected from the FDA

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Savaysa (Edoxaban)

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Savaysa (Edoxaban)

Daiichi Sankyo (January 2015) • Indication: Treatment of deep vein thrombosis, pulmonary

embolism and risk of stroke and embolism due to atrial fibrillation

• Dosing: — 60 mg once daily — 30 mg once daily (poor renal function)

• Adverse effects: Bleeding and Anemia • Drug interactions: Avoid other Anticoagulants and Rifampin

Edoxaban(R) [package insert]. Daiichi Sankyo , Inc., Parsippany, NJ; 2015.

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Savaysa (Edoxaban)

Drug Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Treatment dose Varies 150 mg twice daily 20 mg once daily 10 mg twice daily 60 mg once daily

Renal adjustment

No Yes Yes Yes Yes

MOA Vitamin K inhibitor Thrombin Inhibitor Xa Inhibitor Xa Inhibitor

Xa Inhibitor

Peak Effect 5 - 7 days 1 - 2 hours 2 - 4 hours 3-4 hours 1-2 hours

Half-life 20-60 hours 12-17 hours 5-13 hours 12 hours 10-14 hours

Treatment Cost Varies $330 $330 $500 $277

Reversal Agents Yes Yes No No No

Treatment Cost = WAC per patient month

Edoxaban(R) [package insert]. Daiichi Sankyo , Inc., Parsippany, NJ; 2015. Coumandin(R) [package insert]. Bristol-Meyers Squibb Company, Princeton, NJ; 2015. Pradaxa(R) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; 2015. Xarelto(R) [package insert]. Janssen Pharmaceuticals, Inc., Tiusville, NJ; 2015. Elquis(R) [package insert]. Bristol-Meyers Squibb Company, Princeton, NJ; 2012.

MOA = mechanism of action

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Savaysa (Edoxaban)

The Hokusai-VTE • Non-inferiority/superiority

study • Primary outcome: recurrent

symptomatic VTE • Secondary outcome: Major

or clinically relevant nonmajor bleeding

• 4921 patients (1:1 ratio) — ≥18 years — Dx: DVT or PE

The Engage AF-TIMI 48 • Non-inferiority/superiority

study • Primary Outcome: stroke or

systemic embolism • Secondary outcome: Major

Bleeding • 21,105 patients (1:1:1 ratio)

— ≥21 years — Dx: Afib or CHADS ≥2

Giugliano, R. P., et al. (2013). "Edoxaban versus warfarin in patients with atrial fibrillation." N Engl J Med 369(22): 2093-2104.

(2013). "Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism." New England Journal of Medicine 369(15): 1406-1415.

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(2013). "Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism." New England Journal of Medicine 369(15): 1406-1415.

Savaysa (Edoxaban)

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Savaysa (Edoxaban)


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Savaysa (Edoxaban)


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Savaysa (Edoxaban)

Conclusion The Hokusai-VTE • Edoxaban was non-inferior to warfarin • Edoxaban was associated with less non-major bleeds • Bleeding was no different for major bleeds The Engage AF-TIMI 48 • Both Edoxaban groups were non-inferior to Warfarin • Edoxaban low dose was associated with significantly lower

rates of bleeding

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Corlanor (Ivabradine)

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Amgen (April 2015) • Indication: Reduce the risk of hospitalization for worsening

heart failure • Dosing

— Initial dose: 2.5mg – 5mg po twice daily with meals — Max dose: of 7.5 mg po twice daily with meals

• MOA: A hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker

• Adverse effects: Atrial fibrillation, bradycardia, hypertension, hypotension and syncope

Corlanor(R) [package insert]. Amegen, Inc., Thusand Oaks, CA; 2015.

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• Drug Interactions — CYP3A4 inhibitors — CYP3A4 inducers — Negative chronotropes

• Current Therapy — ACEIs and ARBs — Beta Blockers — Aldosterone — Hydralazine and Isordil — Diuretic therapy — Digoxin — Antiarrhythmics

Corlanor(R) [package insert]. Amegen, Inc., Thusand Oaks, CA; 2015.

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SHIFT Study • Double blind clinical trial with 6,505 patients • 37 countries (677 medical centers) • Primary endpoint: composite of cardiovascular death or

hospitalization for worsening HF • Secondary endpoint: individual components (HF, death,

all-cause hospitalization)

Borer, J. S., et al. (2014). "Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study)." Am J Cardiol 113(3): 497-503.

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Conclusions • SHIFT: Ivabradine with background-based heart failure

therapy was associated with a reduction in the likelihood of recurrent hospitalizations for worsening heart failure

• BEAUTIFUL and SIGNIFY: No benefit in stable coronary artery disease with or without stable heart

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Kengreal (Cangrelor)

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The Medicines Company (June 2015) • Indication: Adjunct to percutaneous coronary intervention

(PCI) to reduce the risk of periprocedural complications • Not to be given in patients:

• Treated with a P2Y12 platelet Inhibitor • Treated with glycoprotein IIb/IIIa Inhibitor

• Adverse Reaction: Bleeding • Drug Interaction: P2Y12 platelet Inhibitors

http://www.theindependentbd.com/assets/news_images/Kengreal.gif

Kengreal(R) [package insert]. The Medicines Company, Parsippany, NJ; 2015.

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Kengreal (Cangrelor) Drug Aspirin Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) Cangrelor (Kengreal®) Form PO PO PO PO IV Dose and Duration

Load: 162-325 mg Maintenance: 81 mg daily Duration: Indefinite

Load: 300-600 mg Maintenance: 75 mg daily Duration: ACS: up to 1 year BMS: minimum 30 days DES: minimum 1 year

Load: 60 mg Maintenance: 10 mg daily Duration: up to 1 year

Load: 180 mg Maintenance: 90 mg BID Duration: up to 1 year

Bolus: 30 mcg/kg IV bolus Maintenance: 4 mcg/kg/min IV infusion Duration: 2 hours or for the duration of PCI, whichever longer

Mechanism of Platelet Inhibition

Irreversible inhibitor of COX-1 causing decrease in thromboxane A2

Irreversible inhibitor of P2Y12 component of ADP receptor (preventing ADP binding and activation of platelets)

Irreversible inhibitor of P2Y12 component of ADP receptor (preventing ADP binding and activation of platelets)

Reversibly modifies P2Y12 component of ADP receptor (preventing ADP binding and activation of platelets)

Reversibly modifies P2Y12 component of ADP receptor (preventing ADP binding and activation of platelets)

Peak Effect 1-3 hours 6 hours (after load) 4 hours (after load) 2 hours (after load) 30 minutes 2 minutes after bolus

Half-life 3 hrs (salicylate) 30 minutes 7 hrs (range 2-15 hrs) 9 hrs (range 6.7-9.1 hrs )

3 to 6 minutes

When to Hold 7 days (optional) 5-7 days 7 days 5 days 60 to 90 minutes

ACS = Acute Coronary Syndrome; PCI = Percutaneous Coronary Intervention; PVD = Peripheral Vascular Disease; BMS = Bare Metal stent; DES = Drug-Eluting Stent; ADP = Adenosine Diphosphate

Kengreal(R) [package insert]. The Medicines Company, Parsippany, NJ; 2015. Plavix(R) [package insert]. Bristol-Meyers Squibb/Sanofi Pharmaceuticals, Bridgewater, NJ; 2015. Effient(R) [package insert]. Eli Lilly and Company, Indianapolis, IN; 2015. Brilinta(R) [package insert]. AstraZeneca, Wilmington, DE; 2015.

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Ended short due to interim analysis not likely to meet end point

No difference in primary endpoint but issues with MI definitions Difference in stent thrombosis and death at 48 hours in secondary

Bhatt, D. L., et al. (2013). "Effect of platelet inhibition with cangrelor during PCI on ischemic events." N Engl J Med 368(14): 1303-1313.

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Bhatt, D. L., et al. (2013). "Effect of platelet inhibition with cangrelor during PCI on ischemic events." N Engl J Med 368(14): 1303-1313.

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• Conclusions — Potential for off-label use — Higher rate of bleed — Very costly — Physician service group

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Entresto (Sacubitril/Valsartan)

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Novartis (July 2015) • Indication: Chronic heart failure (NYHA Class II-IV) • Entresto is usually administered with:

— Other heart failure therapies — But not in combination with ACE inhibitor or ARB

• Dose: 24/26 mg; 49/51 mg; 97/103 mg (twice daily) • Adverse Reactions:

— Angioedema, Hypotension — Impaired renal function, Hyperkalemia

• Drug Interaction: ACE, ARB, Potassium-sparing diuretics, NASIDs, Lithium

Entersto(R) [package insert]. Novartis Pharmaceuticals, East Hanover, NJ; 2015.

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McMurray, J. J., et al. (2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure." N Engl J Med 371(11): 993-1004.

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LCZ696 (n=4187)

Enalapril (n=4212)

Hazard Ratio (95% CI)

P Value

Primary endpoint 21.8% 26.5% 0.80

(0.73-0.87) <0.001

Cardiovascular death 13.3% 16.5% 0.80

(0.71-0.89) <0.001

Hospitalization for heart failure

12.8% 15.6% 0.79

(0.71- 0.89) <0.001

Angioedema 19 10 - -

McMurray, J. J., et al. (2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure." N Engl J Med 371(11): 993-1004.

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Total current spend: $6,668,840 Entresto spend: $10,400,000 Percent change: 125% Total projected spend: $15,068,187

ACE $1,386,896

ARB $5,281,944

Drug Spend: 07/30/14 - 07/29/15

$0

$2,000,000

$4,000,000

$6,000,000

$8,000,000

$10,000,000

$12,000,000

$14,000,000

$16,000,000

Current Spend Projected Spend

ARBACEEntresto

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Entresto (Sacubitril/Valsartan) • Conclusion

— LCZ696 was more effective in reducing the risk of death from cardiovascular causes and any cause

— Hospitalization for heart failure — Adverse Event: Angioedema

• Strengths: — Randomization — Blinding

• Limitations: — Run in period — Baseline characteristics

http://images.alfresco.advanstar.com/alfresco_images/HealthCare/2015/08/04/e568eec2-2f26-4701-a408-37cefe06995f/NP_Entresto_Novartis_web.jpg

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PCSK9 Inhibitors

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Praluent (Alirocumab)

Regeneron Pharmaceuticals/Sanofi Aventis (July 2015) • Indication: Heterozygous familial hypercholesterolemia or

atherosclerotic cardiovascular disease • Dosing:

— 75 mg injection every other week — 150mg injection every other week

• Adverse Reactions: Site reaction, myalgia, muscle spasm, diarrhea

• Drug interaction: None reported

Praluent(R) [package insert]. Regeneron Pharmaceuticals, Inc/Sanofi-aventis U.S. LLC, Bridgewater, NJ; 2015.

http://monroenews.media.clients.ellingtoncms.com/img/photos/2015/07/25/New_Cholesterol_Drug_Have_t1200.jpg?57a0c2296240c280e9492005c3cad63e7cbe80f4

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Repatha (Evolocumab)

Amgen Pharmaceuticals (August 2015) • Indication: Heterozygous familial hypercholesterolemia or

atherosclerotic cardiovascular disease • Dosing:

— 140 mg injection every other week — 420 mg injection monthly

• Adverse Reactions: Nasopharyngitis, nausea, site reaction, myalgia

• Drug interaction: None reported

Repatha(R) [package insert]. Amgen, Inc, Thousand Oaks, CA; 2015.

http://images.techtimes.com/data/images/full/128493/injectable-repatha.png?w=600

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PCSK9 Inhibitors

• Pharmacology Treatment — Bile acid sequestrants (10-30%) — Colesevelam (15-18%) — Nicotinic acid (5-25%) — Niaspan (15-18%) — Fibric acid derivatives (5-20%) — HMG Co-A reductase inhibitors (Statins) (18-63%) — Ezetimide (18%) — PCSK9 inhibitors (50-60%)

Krukemyer JJ, Talbert RL. Lovastatin: a new cholesterol-lowering agent. Pharmacotherapy. 1987;7:198–210. Repatha(R) [package insert]. Amgen, Inc, Thousand Oaks, CA; 2015. Praluent(R) [package insert]. Regeneron Pharmaceuticals, Inc/Sanofi-aventis U.S. LLC, Bridgewater, NJ; 2015. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA. 1997;278:313–321.

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Ford Fiesta or Alirocumab?

• 3.5 - 15 million Americans • WAC: $14,000 per Year • U.S. cost: $49 billion – $210 billion

$0

$5,000

$10,000

$15,000

$20,000

$25,000Health Care Education PCSK9 Wedding

Per Person

$9,255 $10,667

$14,000

$22,274

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ODYSSEY LONG TERM: • Randomized, double-blind, double-dummy, placebo-

controlled, parallel-group, 78-week study — Alirocumab 150 mg Q2W (n = 1553) — Placebo (n = 788) — All patients were receiving concomitant high-dose or maximally

tolerated statin therapy with or without other lipid-lowering agents

Robinson, J. G., et al. (2015). "Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events." New England Journal of Medicine 372(16): 1489-1499.

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Primary Endpoint: • Percentage change in LDL-C from baseline to week 24 Outcome: • Alirocumab provided a mean LDL-C decrease of 61.8 mg/dL in

comparison to placebo (p < 0.001) • At week 24, all secondary lipid variables were significantly

improved in the alirocumab group Adverse events • No difference was found between frequencies of adverse

events between alirocumab and placebo patients

Robinson, J. G., et al. (2015). "Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events." New England Journal of Medicine 372(16): 1489-1499.

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DESCARTES Evolocumab 420 mg every month (n = 599) • Placebo (n = 302) Patients were on one of the following: • Diet alone • Diet with atorvastatin 10 mg daily • Diet with atorvastatin 80 mg daily • Diet with atorvastatin 80 mg daily plus ezetimibe 10 mg daily

Blom, D. J., et al. (2014). "A 52-week placebo-controlled trial of evolocumab in hyperlipidemia." N Engl J Med 370(19): 1809-1819.


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Primary Efficacy Endpoint: — % change in LDL-C from baseline to week 52

Outcome: Mean reduction (p < 0.001 for all comparisons) — 55.7 ± 4.2% among patients who underwent background therapy

with diet alone — 61.6 ± 2.6% among those who received 10 mg of atorvastatin — 56.8 ± 5.3% among those who received 80 mg of atorvastatin — 48.5 ± 5.2% among those who received a combination of 80 mg of

atorvastatin and 10 mg of ezetimibe

Adverse events — AE occurred in 74.2% of placebo-treated patients and 74.8% of

evolocumab-treated patients


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PCSK9 Inhibitors

Conclusion • Alirocumab and evolocumab do adequately lower LDL-C levels

— But their effect on cardiovascular morbidity and mortality have yet to be determined

• PCSK9 are going to try and expand the indication to include CV Risk Reduction (2017)

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Boehringer Ingelheim (October 2015) • Indication: Reversal of the anticoagulant effects of dabigatran

in emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding

Dosing: 5 grams IV (Two 2.5 gram doses ≤ 15 min apart) MOA: Humanized monoclonal antibody fragment that binds to dabigatran Adverse effects: • Antibody formation, thrombosis, headache, hypokalemia,

delirium, constipation, fever

Praxbind(R) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT; 2015.

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Praxbind (Idarucizumab) RE-VERSE-AD Study • Group A: Uncontrollable or life-threatening bleeding (n=51) • Group B: Urgent surgery or intervention (n=39) Intervention • Patient received 5 g IV of Idarucizumab

— Two 2.5 g bolus infusions ≤ 15 min apart

Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520. Praxbind(R) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT; 2015.

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Praxbind (Idarucizumab) Primary end point:

• Maximal reversal of dabigatran based on laboratory assessment within four hours after idarucizumab administration

• Dilute thrombin time or ecarin clotting time Results: Median maximum reversal = 100%

• 68/90 patients (75%) had an elevated dilute thrombin time at baseline

• 81/90 patients (90%) had an elevated ecarin clotting time at baseline

Pollack Jr CV, Reilly PA, Eikelboom J, Glund S et al., Idarucizumab for Dabigatran Reversal, N Engl J Med, 2015;373:511-520.

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What’s in the Pipeline

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Future Direction Lipid lower Agents • Bococizumab

— First published phase II data — Side effect profile

• Anti-PCSK9 vaccine — Given annually

• Adnectin (BMS-962476) — First oral medication

http://assets.bwbx.io/images/ieL2W7uLc4Po/v2/750x-1.jpg http://www.medpagetoday.com/Cardiology/Atherosclerosis/52703

http://assets.bwbx.io/images/ieL2W7uLc4Po/v2/750x-1.jpg




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Future Directions

Reversal agents • Andexanet alfa (Portola Pharmaceuticals) Phase II

— Rivaroxaban, Apixaban, Edoxaban, LMWH and Fondaparinux

• Aripazine (Perosphere) Phase II — Dabigatran, Rivaroxaban, Apixaban, Edoxaban, LMWH, UFH and

Fondaparinux

Heart failure agent • Serlaxin (Norvastis)

• Synthetic form of the hormone relaxin designed to ease blood vessels and treat acute heart failure

Schiele F, van Ryn J, Litzenburger T, Ritter M et al., Structure-guided Residence Time Optimization of a Dabigatran Reversal Agent, MAbs, 2015;7:871-880

LMWH = low molecular weight heparin UFH = unfractionated heparin

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Future Directions

Drug patent expiration: 2015 • Integrilin Drug patent expiration: 2016 • Crestor - July • Azor - October • Benicar/ Benicar HCT - October • Tribenzor - October • Aggrastat - October

http://2.bp.blogspot.com/-4TYO49DNMdM/T_xjzuNuoFI/AAAAAAAAABw/peLY0zCThcw/s1600/b.jpg

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Questions

Documents

A New Pulse in the Cardiovascular Market · Ended short due to interim analysis not likely to meet end point . No difference in primary endpoint but issues with MI definitions . Difference