Download - Bioabsorbable Drug-Eluting Cardiac Stent Analysis

Abbott’s Bioabsorbable-Everolimus Eluting Stents The Future Of Coronary Stents

Meghana Venkatesh, Sean Wadel, Shirley Cai, Miki Stanikic & Abi Saiyanthan

Cardiovascular Disease

1.2 Million Heart

Attacks

Does the proposed fix:

●Prove the improved safety and efficacy of the bioabsorbable stent over drug-eluting stents in a high risk population?

●Increase market share for the bioabsorbable stent?

Decision Criteria for Implementing Our Proposal

Outline

Coronary Artery Disease

Result of accumulation of atherosclerotic plaque

Arteries supplying the heart muscle are occluded

Oxygen-rich blood does not reach the heart

Symptoms are angina and myocardial infarction

http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html

Coronary Atherosclerosis

AngiogramVisualize blockagesCatheter is inserted into the

leg or armContrast dye for visualizationX-ray is taken of the arteries

Health Care Guideline: Stable Coronary Artery Disease. Institute for Clinical Systems Improvement. !3th ed., 2009

Other TestsEKGStress testEchocardiographBlood work

Treatments for CAD

Health Care Guideline: Stable Coronary Artery Disease. Institute for Clinical Systems Improvement. !3th ed., 2009

Video: Stenting Procedure

http://www.youtube.com/watch?v=gvRtP3wl_AY

http://www.youtube.com/watch?v=gvRtP3wl_AY

Outline

Three Generations of Stents

Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

Restenosis

http://www.evgn.org/home/imagesnew/stentv2web.jpg

Restenosis and Neo-Intimal Hyperplasia

Tissue re-growth into the stent area

Drug Eluting Stents:The Problem

Curfman GD, Morrissey S, Jarcho JA, Drazen JM. Drug-eluting coronary stents—promise and uncertainty. NEJM. 2007;256:1059-1060

Stent Thrombosis

Cola, C. Brugaletta, S., Yuste, V. M., Campos, B., Angiolillo, D. J. & Sabete, M. (2009). Diabetes mellitus: a prothrombotic state implications for outcomes after coronary revascularization. Vascular Health and Risk Management, 5, 101-119.

Thrombosis: Early vs. Late Events

Cola, C. Brugaletta, S., Yuste, V. M., Campos, B., Angiolillo, D. J. & Sabete, M. (2009). Diabetes mellitus: a prothrombotic state implications for outcomes after coronary revascularization. Vascular Health and Risk Management, 5, 101-119.

DES: The Market Leader

Xience outperforms Taxus Express in SPIRIT IV, Dave Fornell, Diagnostic and Invasive Cardiology. Retrieved on Nov 26th, 2009 from http://www.dicardiology.net/node/34463/3 Sipkoff, M. (2009, Jul 1). Drug-eluting stents make a comeback. ModernMedicine. Retrieved online http://www.modernmedicine.com/modernmedicine/Modern+Medicine+Feature+Articles/Drug-eluting-stents-make-a-comeback/ArticleStandard/Article/detail/607928

Stents: Product Label – On or Off?

• FDA approved lesion parameters– Lesion length < 30 mm– Vessel diameter: 2.5 mm to

3.75mm

• Off label examples– Lesion in by pass graft– Bifurcation lesion

Source: FDA Guidance Document on Drug Eluting Stents

Outline

Kirk. N. Garratt. (2009). Update on DES and Biodegradable Stents 2009

BVS Functionality


The BVS Stent: Polymers• PLLA (Poly-L-Lactic Acid)

backbone

• PDLLA (Poly-D,L-lactic acid) coating

• Both degrade to lactic acid

• Entire stent absorbs in 2 years


BVS vs. DES: The Thrombosis Issue

Drug – Eluting Stent Bioabsorbable stent

Polymer not biocompatible Polymers are biocompatible

All the drug is not eluted 100% drug is eluted in 4 months

Incomplete healing of endothelium

Complete healing of endothelium

Problems with late and very late ST

No reports of ST from phase I study

Curfman GD, Morrissey S, Jarcho JA, Drazen JM. Drug-eluting coronary stents—promise and uncertainty. NEJM. 2007;256:1059-1060

Advantages of the BVS Stent

ABSORB: First In-man Study

• 30 patients, single de novo lesions

• Composite endpoint: – Cardiac death, Myocardial Infarction, Target

lesion revascularization (TLR)

• Secondary end points:– In-stent late loss, late ST

• Results: - 0% thrombosis, 0% TLR, MACE (3.3%)


Bare-Metal vs. Drug-Eluting vs. Bioabsorbable Stents

Results taken from the 2006 Spirit IV trial (3, 690 patients), 2002 Sirius trial (1,058 patients) and the Absorb trial (30 patients). All trials were done in patients with similar lesions. The results reported are after 1-year follow-up.

Second Generation BVS Stent

More even support of arterial wall

Lower late stent area loss

Higher radial strength


Regulatory Pathway for BVS Based on Drug-Eluting Stents

Drug Eluting Stent

Stent Platform and Delivery

System

DrugCarrier

“Polymer”

PMA – Class III Device

Source: Food and Drug Administration, U.S.A

Center for Devices and Regulatory

Health

Center for Drug

Evaluation and Research

Key Players in the Bioabsorbable Stent Market

Outline

Diabetes Mellitus (DM) Characteristics:

More progressive, diffuse and multi-vessel coronary disease

Complicated lesions in DM patients

Pro-inflammatory and pro-thrombic states

High platelet reactivity

Win, H. K., Caldera, A. E., Maresh, K., Lopez, J., Rihal, C. S., Parikh, M. A., Granada, J. F., Marulkar, S., Nassif, D., Cohen, D. J. & Kleiman, N. S. (2007). Clinical Outcomes and Stent Thrombosis Following Off-Label Use of Drug-Eluting Stents. The Journal of the American Medical Association, 297(18), 2001-2009.

Cypher: Benchmark Stent in Diabetic Population

Machecourt, J. et al. (2007). Risk Factors for Stent Thrombosis After Implantation of Sirolimus-Eluting Stents in Diabetics and Non-Diabetic Patients: The EVESTENT Matched-Cohort Registry. Journal of the American College of Cardiology, (50)6, 501-508

Value Proposition for Proposed Study in Diabetics

Proposal to Abbott Vascular: ABSORB DIABETES trial

Budget: $7.4 million

ABSORB DIABETES: Endpoints

1. Ormiston et al.(2008). A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions(ABSORB): a prospective open-label trial. The Lancet. 371, 899-907

2. Personal communication with Dr. Robert Cottone, Orbus Neich

Yearly Revenue Projections

ROI = 39.5%

3%

5%

10%

8%

8%

6%

Price of stents:

$2200 DES (Cypher)

$3000 BVS (Abbott)

Break Even Point

Break Even: 5.2 months

Cost = Marginal Cost of 35% + trial

budget

Quantitative Analysis Assumptions

Costs remain the same in:

Cost differential occurs in:

ProcedureInitial

hospitalizationRoutine follow-ups

Acquisition of stentSerious adverse

eventsAnti-platelet

therapy (DAT)

Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514.

Cost Total = Cost Stent + Cost Serious Adverse Events + Cost DAT

Cost-Benefit Analysis of BVS on Thrombosis and TLR Rates

Filion, K. B., Roy, A. M., Baboushkin, T., Rinfret, S. & Eisenberg, M. J. (2009). Cost-Effectiveness of Drug-Eluting Stents Including the Economic Impact of Late Stent Thrombosis. The American Journal of Cardiology, 103(3): 338-44.

Price of stents:

$2200 DES (Cypher)

$3000 BVS (Abbott)

Cost Effectiveness(CE) Analysis

Incremental Cost Effectiveness Ratio (ICER)

The lower the ICER, the better

Compare CE of BVS to DES


Equations for ICER Calculation


ICER – Incremental Cost Effectiveness Ratio BVS – Bioabsorbable Stents SAE – Serious Adverse Events BMS – Bare Metal StentsDAT – Dual Anti-platelet Therapy Freq - Frequency

Historical Precedence

ICER (BMS vs Balloon) $5000/SAD Avoided

ICER (DES vs BMS) $5098/SAD Avoided


ICER of BVS with Three Estimates of Study Outcome

Stent Feature Matrix

Bare-Metal Stents

Drug-eluting Stent

Bioabsorbable drug- eluting Stent

Reduced Dual-Antiplatelet Therapy

No neointimal hyperplasia

Restoration of Vasomotion

Material (Biocompatible)

Lobodzinski, S. S. (2008). Bioabsorbable Coronary Stents. Cardiology Journal, 15(6), 569-571.

Conclusion Large coronary stent market BVS improves on thrombosis

Proposed trial: to demonstrate favourability of BVS over DES in diabetics

BVS has the potential to be economically feasible for device manufacturer and healthcare insurers

Acknowledgements Dr. Jayson Parker, M.Biotech

Dr. Michael Kutryk, St. Michael’s Hospital

Dr. Geoff Puley, Trillium Health Center

Jennie Kim, Abbott Vascular, U.S.A

Dr. Robert Cottone, Orbis Neich

Dr. Janarthan Nikhil, Credit Valley

Dr. Sidney Kremer, Credit Valley

Dr. Kirandeep Nagi, Credit Valley

Joanne Barrette, Abbott Vascular

Margaret Chong, Abbott Vascular

Dr. Jeffrey Pang, Sunnybrook Health Sciences Center

Dr. Linda Mackeigan, Leslie Dan School of Pharmacy

Dr. Peter Seidelin, Toronto General Hospital

http://www.utm.utoronto.ca/mbiotech

Thank you for listening.

Questions?

Supplementary Slides

Trial Budget Breakdown

Trial Requirements Cost Incurred

Follow up, 5 years, 50 patients $7500 x 50 x 5 = $1,875,000

Angiographies, 50 patients, 2 per patient

$720 x 50 x 2 = $72000

Cost of IVUS for 50 patients, 2 per patient

$600 x 50 x 2 = $60,000

MCT for 50 patients, 1 per patient $2000 x 50 x 1 = $100,000

Liability Insurance $2.5 million

Resource costs, 50 patients, 2 years

$7244 x 50 x 2 = $724,000

Medical costs, 50 patients $11345 x 50 x 2 = 1,134,500

CRO associated costs $978,000

Total trial cost $7,443,500 million

The BVS Stent Design

Circumferential PLLA hoopsStruts:150 µm thickHoops directly joined by

straight bridges


The BVS Stent: Polymers

Lactic Acid

AssumptionsPre-supposed approval of BVS stent by FDA$2200 average stent in America Our price of $3000 based on historical

precedence of initial entrance of DES at $3200 20% hurdle rateCombination of MI, death and revascularization

are the only serious adverse events caused by stent thrombosis Cost of MI = $10, 000Cost of Death = $10, 000Cost of revascularization = $11, 620 Cost of stenting = $10, 000Cost of CABG = $19, 000

Profit margin of 65%

ROI CalculationCAGR calculated across a 6 year time period

CAGR = (102 million/7.4 million)1/6 -1 = 39.5%

Total cost of BVS after 3 years assuming a 1/4 reduction thrombosis and a 5% reduction in TLR (conservative)

Cost of procedure 7000cost of stent (BVS) 3000

thrombosis year 1 thrombosis rate 0.024rate of death following thrombosis 0.4cost of death 10000rate of non-fatal MI 0.6cost of non-fatal MI 12428Total cost of thrombosis after 1 year 274.9632

year 2 thrombosis rate 0.00675rate of death following thrombosis 0.4cost of death 20000rate of non-fatal MI 0.6cost of non-fatal MI 12428Total cost of thrombosis after year 2 104.3334

year3 thrombosis rate 0rate of death following thrombosis 0.4cost of death 10000rate of non-fatal MI 0.6cost of non-fatal MI 12428Total cost of thrombosis after year 3 0

TLR year 1-3 revascularization rate 0.055rate of new stent procedure 0.82cost of new stent 10000revascularization rate 0.055rate of CABG 0.18cost of CABG 19000# of years 3Total cost of TLR after 3 years 1917.3cost of 6 months of Plavix 607

Total 12903.6

Total cost of BVS after 3 years assuming a 1/2 reduction in thrombosis and a 5% reduction in TLR (moderate)




year 3 thrombosis rate 0rate of death following thrombosis 0.4cost of death 10000rate of non-fatal MI 0.6cost of non-fatal MI 12428Total cost of thrombosis after year 3 0


Total 12654.58

Total cost of BVS after 3 years assuming a 3/4 reduction in both thrombosis and TLR (optimistic)




year 3 thrombosis rate 0rate of death following thrombosis 0.4cost of death 10000rate of non-fatal MI 0.6cost of non-fatal MI 12428Total cost of thrombosis after year 3 0


Total 12432.57

Evolution of Angioplasty

Pros Cons

Balloon Angioplasty

-Enlarges narrow artery-Relieves chest pain

-Elastic recoil of artery -High early restenosis

Bare Metal Stents

-Permanently prop open vessel less elastic recoil-Lower early restenosis

-Metal scars endothelial tissue-Leads to neointimal growth response-Contributes to late restenosis

Drug Eluting Stent

-Antiproliferative drug mitigates adverse response to metal reduce restenosis

-Incomplete healing induce chronic inflammatory response -Increased risk of thrombosis

Lobodzinski, S. S. (2008). Bioabsorbable Coronary Stents. Cardiology Journal, 15(6), 569-571.

History of Angioplasty First stainless steel Stent inserted in human artery

1986

2006

30 patients enrolled in the first ever human clinical trial testing a fully Bioabsorbable Drug-eluting Stent (ABSORB trial, Abbott)

Drug eluting stents introduced to EU and USA markets

2001-2003

1999

First bioabsorbable PLLA stent in human coronary arteries (Igaki-Tamai)

1977

First Coronary AngioplastyDr. Andreas Gruentzig

The BVS Stent – Everolimus Drug

Immunosuppresant

Aids in preventing restenosis

Inhibits Mammalian Target of Rampamycin (mTOR) prevents degradation of p27kip – cyclin dependant kinase inhibitor

Result: inhibition of smooth muscle cell proliferation

http://prospect.rsc.org/blogs/cw/wp-content/uploads/2009/04/487px-everolimussvg.png

Treatment Algorithm

Sensitivity Analysis – ICER of BVS with Three Estimates of Study Outcome

Comparator: ICERDrug Eluting Stent = $5866/per ADE avoided

Machecourt, J. et al. Risk factors for stent thrombosis after implantation of sirolimus-eluting stents in diabetic and nondiabetic patients: the EVASTENT Matched-Cohort Registry. Journal of American College of Cardiology 2007; 50: 501-8

ABSORB Trial Inclusion Criteria

Inclusion Criteria> 18 yearsSingle de novo lesion in native coronary artery12 mm stent –> length < 8mm18 mm stent length < 14 mmDiameter of lesion = 3.0 mmStenosis diameter >50% and <100%

Cypher vs. Taxus - DiabeticsInclusion CriteriaDiabetes mellitusAngina pectorisA maximum of 2 significant stenoses in

different native coronary vessel

Total cost of CYPHER drug-eluting stent after 3 years

Cost of procedure 7000cost of stent (CYPHER) 2200




TLR year 1-3 revascularization rate 0.058rate of new stent procedure 0.82cost of new stent 10000revascularization rate 0.058rate of CABG 0.18cost of CABG 19000# of years 3Total cost of TVR after 3 years 2021.88cost of 1 year of Plavix 1208

Total 13002.72

Deaths from Cardiovascular Disease

Source: NCIS

Coronary Stent Market

Global Industry Analysts, Inc. Coronary Stents Market to Exceed $7.2 Billion by 2012. http://www.newsguide.us/health-medical/cardiology/Coronary-Stents-Market-to-Exceed-7-2-Billion-by-2012-According-to-New-Report-by-Global-Industry-Analysts-Inc.

World Market = $5 billion