The document discusses Abbott's bioabsorbable everolimus-eluting stent and its potential advantages over drug-eluting stents. It proposes a clinical trial to test the bioabsorbable stent in diabetic patients to demonstrate improved safety and efficacy compared to drug-eluting stents in a high risk population. Quantitative analyses estimate the cost-effectiveness and return on investment of the bioabsorbable stent if thrombosis and revascularization rates are reduced compared to drug-eluting stents.

1. Abbott’s Bioabsorbable-Everolimus Eluting Stents The Future Of Coronary Stents Meghana Venkatesh, Sean Wadel, Shirley Cai, Miki Stanikic & Abi Saiyanthan

2. Cardiovascular Disease 1.2 Million Heart Attacks

3. 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?

4. Decision Criteria for Implementing Our Proposal

5. Outline

6. Outline

7. 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

8. Coronary Atherosclerosis

9. Angiogram Visualize blockages Catheter is inserted into the leg or arm Contrast dye for visualization X-ray is taken of the arteries Health Care Guideline: Stable Coronary Artery Disease. Institute for Clinical Systems Improvement . !3th ed., 2009 Other Tests EKG Stress test Echocardiograph Blood work

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

12. Video: Stenting Procedure http://www.youtube.com/watch?v=gvRtP3wl_AY

13. Outline

14. Three Generations of Stents Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

15. Restenosis http://www.evgn.org/home/imagesnew/stentv2web.jpg Restenosis and Neo-Intimal Hyperplasia Tissue re-growth into the stent area

16. 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

17. 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.

18. 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.

19. 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

20. 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

21. Outline

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

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

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

25. BVS vs. DES: The Thrombosis Issue Curfman GD, Morrissey S, Jarcho JA, Drazen JM. Drug-eluting coronary stents—promise and uncertainty. NEJM . 2007;256:1059-1060 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

26. Advantages of the BVS Stent

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

28. 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.

29. Second Generation BVS Stent More even support of arterial wall Lower late stent area loss Higher radial strength Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

30. Regulatory Pathway for BVS Based on Drug-Eluting Stents Drug Eluting Stent Stent Platform and Delivery System Drug Carrier “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

31. Key Players in the Bioabsorbable Stent Market

32. Outline

33. 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.

34. 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

35. Value Proposition for Proposed Study in Diabetics

36. Proposal to Abbott Vascular: ABSORB DIABETES trial Budget: $7.4 million

37. ABSORB DIABETES: Endpoints 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 Personal communication with Dr. Robert Cottone, Orbus Neich

38. Yearly Revenue Projections ROI = 39.5% 3% 5% 10% 8% 8% 6% Price of stents : $2200 DES (Cypher) $3000 BVS (Abbott)

39. Break Even Point Break Even: 5.2 months Cost = Marginal Cost of 35% + trial budget

40. Quantitative Analysis Assumptions Costs remain the same in: Cost differential occurs in: Procedure Initial hospitalization Routine follow-ups Acquisition of stent Serious adverse events Anti-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

41. 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)

42. Cost Effectiveness(CE) Analysis Incremental Cost Effectiveness Ratio (ICER) The lower the ICER, the better Compare CE of BVS to DES Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514.

43. Equations for ICER Calculation Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514. ICER – Incremental Cost Effectiveness Ratio BVS – Bioabsorbable Stents SAE – Serious Adverse Events BMS – Bare Metal Stents DAT – Dual Anti-platelet Therapy Freq - Frequency

44. Historical Precedence ICER (BMS vs Balloon) $5000/SAD Avoided ICER (DES vs BMS) $5098/SAD Avoided Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514.

45. ICER of BVS with Three Estimates of Study Outcome

46. 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.

47. 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

48. 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

49. Thank you for listening. Questions?

50. Supplementary Slides

51. 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

52. The BVS Stent Design Circumferential PLLA hoops Struts:150 µm thick Hoops directly joined by straight bridges Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

53. The BVS Stent: Polymers Lactic Acid

54. Assumptions Pre-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 rate Combination of MI, death and revascularization are the only serious adverse events caused by stent thrombosis Cost of MI = $10, 000 Cost of Death = $10, 000 Cost of revascularization = $11, 620 Cost of stenting = $10, 000 Cost of CABG = $19, 000 Profit margin of 65%

55. ROI Calculation CAGR calculated across a 6 year time period CAGR = (102 million/7.4 million) 1/6 -1 = 39.5%

56. Total cost of BVS after 3 years assuming a 1/4 reduction thrombosis and a 5% reduction in TLR (conservative) Cost of procedure 7000 cost of stent (BVS) 3000 thrombosis year 1 thrombosis rate 0.024 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after 1 year 274.9632 year 2 thrombosis rate 0.00675 rate of death following thrombosis 0.4 cost of death 20000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 2 104.3334 year3 thrombosis rate 0 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 3 0 TLR year 1-3 revascularization rate 0.055 rate of new stent procedure 0.82 cost of new stent 10000 revascularization rate 0.055 rate of CABG 0.18 cost of CABG 19000 # of years 3 Total cost of TLR after 3 years 1917.3 cost of 6 months of Plavix 607 Total 12903.6

57. Total cost of BVS after 3 years assuming a 1/2 reduction in thrombosis and a 5% reduction in TLR (moderate) Cost of procedure 7000 cost of stent (BVS) 3000 thrombosis year 1 thrombosis rate 0.016 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after 1 year 183.3088 year 2 thrombosis rate 0.0045 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 2 51.5556 year 3 thrombosis rate 0 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 3 0 TLR year 1-3 revascularization rate 0.052 rate of new stent procedure 0.82 cost of new stent 10000 revascularization rate 0.052 rate of CABG 0.18 cost of CABG 19000 # of years 3 Total cost of TLR after 3 years 1812.72 cost of 6 months of Plavix 607 Total 12654.58

58. Total cost of BVS after 3 years assuming a 3/4 reduction in both thrombosis and TLR (optimistic) Cost of procedure 7000 cost of stent (BVS) 3000 thrombosis year 1 thrombosis rate 0.008 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after 1 year 91.6544 year 2 thrombosis rate 0.00225 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 2 25.7778 year 3 thrombosis rate 0 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 3 0 TLR year 1-3 revascularization rate 0.049 rate of new stent procedure 0.82 cost of new stent 10000 revascularization rate 0.049 rate of CABG 0.18 cost of CABG 19000 # of years 3 Total cost of TLR after 3 years 1708.14 cost of 6 months of Plavix 607 Total 12432.57

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

60. 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 Angioplasty Dr. Andreas Gruentzig

61. 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

62. Treatment Algorithm

63. Sensitivity Analysis – ICER of BVS with Three Estimates of Study Outcome Comparator: ICER Drug 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

64. ABSORB Trial Inclusion Criteria Inclusion Criteria > 18 years Single de novo lesion in native coronary artery 12 mm stent –> length < 8mm 18 mm stent  length < 14 mm Diameter of lesion = 3.0 mm Stenosis diameter >50% and <100%

65. Cypher vs. Taxus - Diabetics Inclusion Criteria Diabetes mellitus Angina pectoris A maximum of 2 significant stenoses in different native coronary vessel

66. Total cost of CYPHER drug-eluting stent after 3 years Cost of procedure 7000 cost of stent (CYPHER) 2200 thrombosis year 1 thrombosis rate 0.032 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after 1 year 366.6176 year 2 thrombosis rate 0.009 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 2 103.1112 year 3 thrombosis rate 0.009 rate of death following thrombosis 0.4 cost of death 10000 rate of non-fatal MI 0.6 cost of non-fatal MI 12428 Total cost of thrombosis after year 3 103.1112 TLR year 1-3 revascularization rate 0.058 rate of new stent procedure 0.82 cost of new stent 10000 revascularization rate 0.058 rate of CABG 0.18 cost of CABG 19000 # of years 3 Total cost of TVR after 3 years 2021.88 cost of 1 year of Plavix 1208 Total 13002.72

67. Deaths from Cardiovascular Disease Source: NCIS

68. 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