Transplant Overview. Timothy J. Schroeder President and CEO CTI Clinical Trial and Consulting Services November 10, 2005

Transcription

1 Transplant Overview Timothy J. Schroeder President and CEO CTI Clinical Trial and Consulting Services November 10, 2005

2 CTI Clinical Trial and Consulting Services Drug Development Company focused in key therapeutic areas Services are designed to span the entire lifecycle of a product Merging Clinical and Commercial Expertise to Achieve Extraordinary Results

3 CTI Focuses in Specific Disease Areas Hepatitis Immunology Solid Organ Transplant End-Stage Organ Disease Oncology/Bone Marrow Transplant

4 Kidney Transplantation First Successful Kidney Transplant Between Identical Twins Boston Dr. Joseph Murray Nobel Prize

5 Kidney Transplantation in the US Some Facts. ~300,000 Americans with chronic kidney failure requiring dialysis or kidney transplantation ~67,000 deaths per year due to ESRD Current cost of treating ESRD in the U.S. per year = ~$17.9 billion ~80,000 patients are waiting for an organ transplant and only about 25,000 patients will be transplanted each year ~60,000 patients are waiting for a kidney transplant and only about 13,000 kidney transplants are performed annually U.S centers performed 50% of all kidney transplants worldwide Kidney transplants represented 60% of all solid organ transplants performed in the U.S. National Kidney Foundation:

6 U.S. Transplant Activity 2003 Total Transplants = 23,506 Heart (8%) Liver (22%) Kidney (60.4%) Kidney-Pancreas (3%) Lung (4%) Pancreas (2%) Multi-Organ (.8%) Heart-Lung (.1%) Cecka JM and Terasaki PI Clinical Transplants 2003, pgs.532, 546, 557, 578, 579, 594, and 614.

7 Kidney Transplant Waiting List OPTN/SRTR Annual Report, Kidney Waiting List Total Kidney Donors Transplants

8 Rationale for Immunosuppression in Transplantation Unchecked, the allogeneic response will destroy the graft Immunosuppression regimens necessary to prevent rejection but also minimize adverse events Patients generally receive immunosuppression for the life of the transplanted organ Smith SL. Immunosuppressive Therapies in Organ Transplantation. Organ Transplant (

9 Approved Immunosuppressant Agents in the US Maintenance Calcineurin Inhibitors: Prograf (Astellas) Neoral / CsA (Novartis, Multiple Generic Manufacturers) Anti-Proliferative Agents: CellCept MMF (Roche) Rapamune - Sirolimus (Wyeth) Myfortic - MMF (Novartis) Azathioprine (Multiple Generic Manufacturers) Anti-inflammatory: Corticosteroids (Multiple Generic Manufacturers) Norman DJ. Primer on Transplantation. 1998; pg

10 Approved Immunosuppressant Agents in the US Induction or Rejection Therapy Biological Agents: OKT3 (Ortho Biotech) ATGAM (Pfizer) Thymoglobulin (Genzyme) Daclizumab (Roche) Basiliximab (Novartis) Norman DJ. Primer on Transplantation. 1998; pg

11 New Immunosuppressive Regimens 6 5 Number of Agents Year Primary Immunosuppressant Induction Agent Adjunct Agent Rescue Therapy Denton MD, Magee CC, Sayegh MH The Lancet. 353:

12 Immunosuppressive Regimens Which antibody? OKT3, Atgam, Thymo, Zenapax, Basiliximab Which calcineurin inhibitor? Neoral, Prograf, Generic CsA Need a TOR Inhibitor? Rapamune Which Antimetabolite? Imuran, CellCept, Myfortic Need corticosteroids? Yes or No Initial Regimen Thymoglobulin Tacrolimus CellCept Steroids Must tailor for each individual patient!! London Health Science Center:

13 A Typical Day for the Transplant Recipient The average kidney transplant patient: Takes ~10 different medications daily Swallows at least 20 capsules/ tablets a day Encounters various side effects of these medications Is concerned about the cost of medication and medication coverage Concerned about the impact of diet and fluids along with medications General Information for Primary Care Physicians Regarding Renal Transplant Patient Management. London Health Sciences Center. (

14 A Typical Medication Schedule 8AM Noon 8PM Bedtime Tacrolimus Mycophenolate Prednisone X X X X X Valcyte X X X Nystatin X X X X Bactrim X BP medication X Multivitamin X Pepcid / Zantac X X Other supplements X Penn State Milton S. Hershey Medical Center (

15 The competition for patients able to be enrolled in solid organ transplant trials is the most competitive in recent history 9 compounds in phase 2 3 compounds in phase 3 6 compounds in early phase 4 (<5 yrs) 8 compounds in late phase 4 (>5 yrs) 1 compound pending approval

16 Solid Organ Transplant Drugs in Development Companies with Transplant Immunosuppressive Compounds Adprotech Astellas Atherogenics Berlex Bristol Myers Squibb Chiron Enzon Fournier Genzyme IDUN Isotechnika Novartis Pfizer Roche Y s Therapeutics

17 Immunosuppressive Market 2004 in U.S. CNI $894.0 M (48%) Sandimmune/ Neoral 23% 12% 66% CyA Generic Prograf Antibody $138.2 M (7%) Adjunctive $836.7 M (45%) Zenapax Simulect 13% 12% OKT-3 10% 64% Thymoglobulin & Atgam $1,869 M Azathioprine 5% 19% Rapamune 76% CellCept & Myfortic Source: IMS National Sales Perspectives

18 Immunosuppressive Relative Value Rank Drug Lipitor Zocor Prevacid Nexium Procrit Zoloft Epogen Plavix Advair Diskus Zyprexa.. Seroquel TOTAL Immunosuppressive 2004 US Sales - $ Million $ 7,691 $ 4,575 $ 3,802 $ 3,782 $ 3,192 $ 3,094 $ 2,990 $ 2,979 $ 2,914 $ 2,826.. $ 1,979 $1,869

19 Immunosuppression: Common Adverse Events Tacrolimus Diabetes Renal dysfunction Hypertension CsA Diabetes Renal dysfunction Hypertension MMF Bone marrow suppression Nausea, vomiting and diarrhea Sirolimus Hyperlipidemia Wound healing Hypertension Azathioprine Leukopenia Cholestatic hepatic abnormalities Steroids Diabetes Hyperlipidemia Hypertension Lo A and Alloway RR. Strategies to Reduce Toxicities and Improve Outcomes in Renal Transplant Recipients. Pharmacotherapy. March 2002; 22(3), pg

20 The Challenge of Calcineurin Inhibition Nephrotoxicity Metabolic Adverse Events Acute Rejection Chronic Rejection ith SL. Immunosuppressive Therapies in Organ Transplantation. Organ Transplant (

21 The Importance of Calcineurin Down-Regulating Signal 1 Inhibition Prograf Calcineurin Cyclosporine NFAT p NFAT NFAT Promoter IFN - γ IL - 4 IL - 2 TNF - GM - CSF CYTOKINES Halloran PF and Miller LW J. Heart Lung Transplant. 15:

22 CsA Nephrotoxicity Constriction of the afferent arteriole in normal vs. CsA treated rat kidney Kahan,BD. and Ponticelli, C. Priniciples and Practice of Renal Transplantation; 2000, pg. 378

23 Cyclosporine Isolated in 1970 from a strain of fungi imperfect, tolypocladium inflatum gams Immunosuppressive properties identified in 1972 Molecular weight ~1203 Hardinger K. Clinical Pharmacokinetics: Immunosuppressants

24 Timeline for the Development of Cyclosporine Formulations Sandimmune Trials Sandimmune Approved Cyclosporine G Trials Neoral Trials Neoral FDA Hardinger K. Clinical Pharmacokinetics: Immunosuppressants

25 Neoral vs. Sandimmune Pharmacokinetics AUC Curve Concentration Time

26 Timeline for the Development of Cyclosporine Formulations SangCya Trials SangCya Approved Gengraf/Sang 2000 Trials EON Approved Gengraf Approved Hardinger K. Clinical Pharmacokinetics: Immunosuppressants

27 Development of Generic Cyclosporine Formulations Definition of a generic drug: Identical active ingredient Excipient may be different Bioequivalence demonstrated in healthy volunteers in controlled trials - Single dose, overnight fast - Non-smokers, no significant disease states - Randomized cross-over design - N=18-24, healthy males, USPHARMD Pharmacist Student Consumer Information Website (

28 Bioequivalence Calculations Ratio Test/Reference % Drugs Drugs A and B have test-to-reference ratios of 97% and 90%; they are not bioequivalent to the reference (CIs extend beyond 80% boundary) Drugs C and D have mean ratios of 100% and 96%, respectively Their CIs are within the ranges and therefore bioequivalent Series1 Series2 Series3

29 Tacrolimus Features First primary immunosuppressant alternative since 1982 Macrolide metabolite of Streptomyces tsukubaensis Inhibits transcription of cytokine genes through immunophilin binding Suppresses T lymphocyte proliferation Prograf Product Monograph. Fujisawa Healthcare

30 Tacrolimus Mechanism of Action Binds with a unique immunoglobulin, FKBP-12 Inhibits the earliest stages of T-cell activity at low concentrations (in vitro) Approximately 100-fold more potent in vitro than cyclosporine and 10-fold more potent in vivo in inhibiting T-cell activation Prograf Product Monograph. Fujisawa Healthcare

31 Tacrolimus Mechanism Cytosolic transduction of T-cell receptor signal Tacrolimus + FKBP12 Inhibits Calcineurin Prograf Product Monograph. Fujisawa Healthcare

32 Clinical Efficacy Tacrolimus vs Cyclosporine n Regimen (mg/kg/day) Time (mo) Pt Survival Graft Survival AR European TAC Multicenter Study 303 TAC 0.3 AZA + CS % 85% 83% 72% 26% (Mayer 1997 Mayer 1999) 145 CsA 8 AZA + CS % 88% 86% 71% 46% US TAC Kidney Transplant Group 205 TAC 0.2 AZA + CS % 92% 91% 82% 31% (Pirsch 1997 Jensik 1998) 207 ALA CsA 10 AZA + CS % 92% 88% 79% 46% ALA Mayer. Transplantation 1997; 64: Mayer. Transplant Proc 1999; 31(suppl 7A): s27-28 Jensik. Transplant Proc 1998; 30: Pirsch Transplantation 1997; 63:

33 Calcineurin inhibitors are the most prescribed immunosuppressant agents 93% of transplant patients receive a calcineurin inhibitor Prograf dominates the calcineurin inhibitor market with 53% market share In spite of generic competition, Neoral continues to generate $1 billion WW in sales Source: UNOS and IMS 60% 50% 40% 30% 20% 10% 0% 53% 30% 8% 3% Prograf Neoral Gengraf Generic CsA

34 Whether Physicians Minimize Calcineurin Inhibitors and In Which Kidney Patient Populations (n=76) 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% Yes No 0% Renal Dysfunction CI Adverse Events All Patients Rationale for the positive responses CTI Data on File

35 Whether Physicians Withdraw Calcineurin Inhibitors and In Which Kidney Patient Populations (n=77) 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% Yes No 0% Renal Dysfunction CI Adverse Events All Patients CTI Data on File Rationale for the positive responses

36 Concerns Regarding Calcineurin Inhibitor Avoidance (n=72)* 100% 80% 60% 40% 20% 0% Acute Rejection Graft loss Re-transplant *Multiple responses were allowed CTI Data on File

37 Solid Organ Transplant Drugs in Development Phase I Company Compound Isotechnika TAFA93 Serono/Genmab HuMax-TAC Phase II Phase III Company Compound Company Compound Adprotech/Inflazyme Mirococept Astellas MR4 Astellas FK778 Bristol-Myers Squibb LEA29Y Belatacept AtheroGenics AGI-1096 Chiron Pulminiq Berlex Campath DOR BioPharma Inc. orbec Enzon ATLI Genzyme Thymoglobulin Isotechnika ISA247 Novartis Certican Pfizer CP Y s Therapeutics YSCMA

38 Summary The primary adverse events of the current calcineurin inhibitors are: Cardiac Hypertension Hyperlipidemia Post Transplant Diabetes Mellitus Renal Dysfunction Nephrotoxicity

39 Summary Calcineurin Inhibitors currently remain the cornerstone of immunosuppression Tacrolimus is now the market leader Calcineurin inhibitors are minimized or eliminated in a minority of patients They are generally utilized with CellCept (>75% of market) or Rapamune Continues to be a need for a less toxic immunosuppressive agents