This program is supported by an educational grant from April 30 - May 4, 2011 Philadelphia, Pennsylvania Highlights From the American Transplant Congress 2011 CCO Independent Conference Coverage of the American Transplant Congress 2011* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC

clinicaloptions.com/transplantation Highlights From ATC 2011 Faculty Seth J. Karp, MD Assistant Professor Department of Surgery Harvard Medical School Director, Pancreas Transplantation, Transplant Surgeon Beth Israel Deaconess Medical Center Boston, Massachusetts Flavio Vincenti, MD Professor of Clinical Medicine Kidney Transplant University of California, San Francisco San Francisco, California Please view the PowerPoint notes to review the faculty commentary on each slide

clinicaloptions.com/transplantation Highlights From ATC 2011 Disclosures Seth J. Karp, MD, has no significant financial relationships to disclose. Flavio Vincenti, MD, has disclosed that he has received grants for research support from Astellas, Bristol-Myers Squibb, Genzyme, Novartis, and Pfizer.

Biomarkers

clinicaloptions.com/transplantation Highlights From ATC 2011 mRNA in Urinary Cells Correlate With ACR in Renal Allograft Recipients  Stepwise logistic regression analysis identified several mRNA models that predicted for ACR at biopsy –4-parameter model selected for further analysis because most parsimonious  Expression of 4-parameter diagnostic signature evaluated in urine samples collected longitudinally over 1 yr (included perforin, IP10, TGF-ß1, Foxp3) –Signature expression levels stabilized at ~ Day 30 and beyond in 2224 urine samples from 276 renal allograft recipients with stable allografts who did not undergo biopsy –No significant difference in trajectory of signature expression levels between samples from pts with stable allografts who did not undergo biopsy and 1330 samples from 138 patients who underwent biopsy had normal allografts (P =.11) –Trajectory of signature expression levels increased progressively during follow-up in 534 samples from 49 patients with biopsy-confirmed ACR –Significant difference in trajectory between samples from patients with biopsy-confirmed ACR and samples from patients with stable allografts who did not undergo biopsy (P <.0001) or from patients who underwent biopsy but found to have normal allografts (P <.0001) Suthanthiran M, et al. ATC Abstract 1.

clinicaloptions.com/transplantation Highlights From ATC 2011 Several mRNAs Predictive of Future ACR Prior to Identification of ACR by Biopsy Suthanthiran M, et al. ATC Abstract 1. Time Prior to Biopsy Diagnosis of ACR Predictive mRNAsAUCP Value days Perforin PI-9 IP10 CXCR3 CD3 Foxp3 Granzyme B 0.93< days Perforin IP10 CXCR3 Foxp3 0.88< days Perforin PI <.0001  Stepwise logistic regression analysis

clinicaloptions.com/transplantation Highlights From ATC 2011 Vascular Endothelial Cell Biomarkers Diagnose Cardiac Allograft Vasculopathy  33 adults with heart transplants ≥ 2 yrs earlier included in study  CART analysis identified 5 prediction rules using optimal cut-off levels of VEGF-C, VEGF-A, angiopoietin-1, and angiostatin that diagnose cardiac allograft vasculopathy with 100% sensitivity and 100% specificity Daly K, et al. ATC Abstract 126. Prediction Rules  Measure VEGF-C –If > 267, CAV –If < 267, measure VEGF-A –If < 2243, measure angiopoietin-1 –If < 470, CAV –If > 470, no CAV –If > 2243, measure angiostatin –If < 22,630, CAV –If > 22,630, no CAV

clinicaloptions.com/transplantation Highlights From ATC 2011 Virtual Cross-Matching Used to Allocate Allografts in Sensitized Recipients  Virtual cross-matching may facilitate successful intestinal transplant in sensitized recipients by optimizing organ allocation and minimizing immunologic risk –Procedure involves prospectively comparing recipient HLA- specific antibodies to donor HLA type –Provides prediction of cross-match prior to actual cross- match –DSA strength and specificity determined by mean fluorescence intensity and antibody titer using solid-phase single-antigen assay –Potential donors prospectively screened against recipient DSA Hawksworth JS, et al. ATC Abstract 343.

clinicaloptions.com/transplantation Highlights From ATC 2011 Transplant Outcomes Comparable Between Sensitized and Nonsensitized Pts Hawksworth JS, et al. ATC Abstract 343.  65 isolated intestinal transplants performed in 63 pts with following IS protocol –Induction IS: anti-IL2 induction in nonsensitized pts; thymoglobulin and IVIG in sensitized pts –Maintenance IS: tacrolimus, sirolimus, and prednisone in all pts Outcome, % Sensitized Pts* (n = 21) Nonsensitized Pts (n = 44) P Value Rejection  Acute rejection  Chronic rejection  Explant yr freedom from rejection yr overall survival *All sensitized pts had VXM with DSA titers ≤ 1:1.  No differences in complications observed between study arms

Immunosuppressive Drugs

clinicaloptions.com/transplantation Highlights From ATC 2011 Tofacitinib vs Cyclosporine for de novo Kidney Transplantation Vincenti F, et al. ATC Abstract 4. Patients undergoing immunologically low-/moderate-risk de novo kidney transplantation from deceased donor or HLA-mismatched living donor (N = 322) Tofacitinib 15 mg BID (n = 106) Tofacitinib 15 mg BID (n = 107) Cyclosporine* (n = 109) Month 12Month 6Month 3 Tofacitinib 10 mg BID Transplantation *Targeted to 12-hr whole blood trough levels of ng/mL during Months 1-3 and ng/mL during Months 4-12.

clinicaloptions.com/transplantation Highlights From ATC 2011 Tofacitinib Arms Noninferior vs Cyclosporine Arm for Month 6 BPAR Rate Vincenti F, et al. ATC Abstract 4. Outcome, %Tofacitinib 15 mg Months 1-3 (n = 107) Tofacitinib 15 mg Months 1-6 (n = 106) Cyclosporine (n = 109) BPAR at Month Clinical BPAR at Month Kaplan-Meier estimates of outcomes at Month 12  First BPAR with grade IIB/ III acute/active cellular rejection  First BPAR with grade II/III antibody-mediated rejection  Repeat rejection

clinicaloptions.com/transplantation Highlights From ATC 2011 Significantly Higher GFR at Months 6 and 12 With Tofacitinib vs Cyclosporine 1. Vincenti F, et al. ATC Abstract Tedesco Silva H, et al. ATC Abstract 225. GFR Outcome, mL/minTofacitinib 15 mg Months 1-3 (n = 107) Tofacitinib 15 mg Months 1-6 (n = 106) Cyclosporine A (n = 109) Least square mean of measured GFR [1]  Month 673.6*67.4 † 57.2  Month † 64.6 † 53.9 MDRD eGFR at Month 12 (LOCF) [2] 64.6 ‡ 64.3 ‡ 53.9 Nankivell eGFR at Month 12 (LOCF) [2] 75.4 ‡ 75.6 ‡ 66.9 Nankivell eGFR at Month 12 (imputed LOCF) [2] 71.5 ‡ 72.6 ‡ 64.8 *P <.0001 vs cyclosporine. † P <.01 vs cyclosporine. ‡ P <.05 vs cyclosporine.

clinicaloptions.com/transplantation Highlights From ATC 2011 Significantly Lower Incidence of CAN in Tofacitinib Arms vs Cyclosporine Arm Tedesco Silva H, et al. ATC Abstract 225. Outcome, %Tofacitinib 15 mg Months 1-3 (n = 107) Tofacitinib 15 mg Months 1-6 (n = 106) Cyclosporine A (n = 109) CAN at Month *25.0* 48.3 Increase in CAN score > 0 from implantation to Month * Increase in Banff chronicity score from baseline to Month *60.4 *P <.05 vs cyclosporine.

clinicaloptions.com/transplantation Highlights From ATC 2011 Higher Incidence of Adverse Events With Tofacitinib vs Cyclosporine Safety OutcomeTofacitinib 15 mg Months 1-3 (n = 107) Tofacitinib 15 mg Months 1-6 (n = 106) Cyclosporine (n = 109) Events by Month 12, %  Serious infection  CMV disease (including CMV syndrome)  BKV nephropathy PTLD, n  Months  > Month Vincenti F, et al. ATC Abstract 4.

clinicaloptions.com/transplantation Highlights From ATC 2011 BENEFIT: Phase III Study of Belatacept vs Cyclosporine in Kidney Transplant Pts Patients receiving kidney transplant from living or deceased donor (N = 666) Belatacept MI Regimen Belatacept 10 mg/kg on Days 1, 5, 14, 28, 42, 56, 70, 84, 112, 140, 168; then 5 mg/kg every 4 wks (n = 219) Belatacept LI Regimen Belatacept 10 mg/kg on Days 1, 5, 14, 28, 56, 84, 112; then 5 mg/kg every 4 wks (n = 226) Cyclosporine ng/mL on Days 1-28, then ng/mL thereafter (n = 221) Year 3 current analysis [3] Year 1 primary endpoints [1] Transplantation 1. Vincenti F, et al. Am J Transplant. 2010;10: Larsen CP, et al. Transplantation. 2010;90: Vincenti F, et al. ATC Abstract 227. Year 2 [2]  All patients received basiliximab induction, mycophenolate mofetil, and corticosteroids  Cyclosporine-treated patients also received T-cell–depleting agents if delayed graft function anticipated

clinicaloptions.com/transplantation Highlights From ATC 2011 BENEFIT: Graft Function Similar With Belatacept and Cyclosporine at Year 3 Vincenti F, et al. ATC Abstract 227.  Increased rate of acute rejection observed early with belatacept Outcome at Year 3, %Belatacept MI (n = 219) Belatacept LI (n = 226) Cyclosporine (n = 221) Patients surviving with functioning graft Acute rejection through Year  Months  Months BPAR through Year Efficacy failure* through Year *BPAR, graft loss, death, or lost to follow-up.

clinicaloptions.com/transplantation Highlights From ATC 2011 Month BENEFIT: 3-Yr Sustained Improved Renal Function With Belatacept vs Cyclosporine Vincenti F, et al. ATC Abstract 227. Graphic reproduced with permission Mean Calculated GFR (95% CI)  from CsA  from CsA  from CsA Slope, mL/min/1.73 m 2 /yr (95% CI) Bela MI Bela LI CsA (0.106 to 1.980) (0.309 to 2.149) ( to ) Pts at Risk, n Belatacept MI Belatacept LI Cyclosporine

clinicaloptions.com/transplantation Highlights From ATC 2011 Pooled Data From Phase II/III Belatacept Trials: Adverse Events Larsen C, et al. ATC Abstract 228.  Major safety outcomes generally comparable across belatacept and cyclosporine arms –Infections and CV events most common causes of death (occurring in 1% to 4% of pts)  Incidence of TB slightly higher with belatacept vs cyclosporine therapy –Limited to areas with high endemicity  PTLD the primary safety concern PTLD Outcome, nBelatacept MI (n = 477) Belatacept LI (n = 472) Cyclosporine (n = 476) Total PTLD cases87 3  CNS63 0  Renal allograft24 0  Disseminated00 3 Total deaths due to PTLD44 3  CNS33 0  Renal allograft11 0  Disseminated00 3

clinicaloptions.com/transplantation Highlights From ATC 2011 BENEFIT and BENEFIT-EXT: Development of PTLD According to EBV Status Larsen C, et al. ATC Abstract 228. Patients, %BelataceptCyclosporine All PTLD  EBV negative  EBV positive CNS PTLD  EBV negative5.490  EBV positive0.490 Non-CNS PTLD  EBV negative  EBV positive0.25  Further characterization of belatacept-associated PTLD identified 10-fold higher risk of development in EBV-negative vs EBV-positive recipients –Similar frequency of PTLD in EBV-positive belatacept recipients and cyclosporine recipients

clinicaloptions.com/transplantation Highlights From ATC 2011 Switch From Cyclosporine or Tacrolimus to Belatacept Improves Renal Function  Extension phase of phase II trial among patients receiving cyclosporine (43%) or tacrolimus (57%) with stable graft function 6-36 mos after renal transplant, randomized to continue CNI-based regimen (n = 81) or switch to belatacept (n = 81)  98% in both groups survived with functioning graft at Year 2  Mean cGFR improved at Year 2 with switch to belatacept (+8.8 mL/ min vs +0.3 with continued CNI) –cGFR benefit seen after switch from CsA (+7.8 mL/min) or from TAC (+8.9 mL/min) and unrelated to baseline renal function  Acute rejection at Year 2 –7% with belatacept (all in Year 1) –4% with CNI (all in Year 2) Grinyo J, et al. ATC Abstract 226.

clinicaloptions.com/transplantation Highlights From ATC 2011 Alemtuzumab, Belatacept, and Sirolimus After Renal Allograft: Study Design  19 patients receiving MHC disparate kidneys from live donors included in study of CNI-sparing and steroid-sparing immunosuppression –Induction therapy –Alemtuzumab 30 mg administered intraoperatively –Maintenance therapy –Belatacept 10 mg/kg IV on Days 1, 3, 7, 14, every 2 wks thereafter for 2 mos, every mos thereafter for 3 mos, then dosed at 5 mg/kg monthly thereafter –Sirolimus dosed such that trough levels 8-12 ng/mL during Months 0-6 and then 5-8 ng/mL –Donor bone marrow –Patients randomized 1:1 to receive or not receive 1 dose of unfractionated donor bone marrow consisting of 10 8 nucleated cells/kg on Day 7 –This intervention had no apparent effect on efficacy outcomes; results for all patients pooled Kirk AD, et al. ATC Abstract 56.

clinicaloptions.com/transplantation Highlights From ATC 2011 Alemtuzumab, Belatacept, and Sirolimus Prevents Renal Allograft Rejection  Patients (n = 19) who received alemtuzumab, belatacept, and sirolimus demonstrated favorable outcomes –All patients demonstrated immediate graft function after transplant –No graft loss or patient deaths observed –Serum creatinine rapidly normalized after transplant –Median: 1.1 mg/dL at Month 12  No EBV-associated disease or posttransplant lymphoproliferative disorder observed  Weaning patients to belatacept alone ongoing Kirk AD, et al. ATC Abstract 56.

clinicaloptions.com/transplantation Highlights From ATC 2011 Safe and Successful Tolerance After HLA-Matched Kidney Transplant Busque S, et al. ATC Abstract 163. Graphic reproduced with permission. 15 patients enrolled Chimerism > 6 mosChimerism < 6 mos 12 patients 8 patients Off IS drugs for 1 to 3 yrs 1 patient Reversible acute rejection on maintenance IS 3 patients Weaning phase 3 patients 1 patient No engraftment 2 patients Reversible acute rejection on maintenance IS  After kidney transplant from HLA-matched, living, related donors, patients received conditioning with 5 doses of recombinant antithymocyte globulin 1.5 mg/kg and total lymphoid irradiation  On Day 11, donor CD34+ hematopoietic progenitor cells and CD3+ T cells administered

clinicaloptions.com/transplantation Highlights From ATC 2011 Tolerance Induction Protocol Generally Safe  No GVHD, no graft loss due to rejection, no capillary leak syndrome, and no serious infection  Ratio of Treg:naive CD4+ T cells increased > 3-fold in all patients during the first 24 days after transplant –Returned to near-baseline levels by 94 days after transplant Busque S, et al. ATC Abstract 163.

clinicaloptions.com/transplantation Highlights From ATC 2011 Early Corticosteroid Withdrawal Reduces CV Risk in Renal Transplant Recipients  Prospective study evaluated effect of ECSWD on risk for CV events in renal transplant recipients –714 patients received ECSWD –290 received chronic corticosteroid regimen  Multivariate analysis confirmed known factors associated with CV event risk and showed ECSWD significantly associated with a reduction in CV event risk Schmidt N, et al. ATC Abstract 293. Data reported from abstract. Factor Odds Ratio ECSWD Pretransplant DM Smoking CAD pretransplant P Value <

clinicaloptions.com/transplantation Highlights From ATC 2011 Phase II Study of Alefacept in de novo Kidney Transplant Recipients Bromberg J, et al. ATC Abstract 533. Month 12 *All alefacept arms received alefacept loading dose of 7.5 mg IV on Days 0 and 3 as well as alefacept 15 mg SC at Months 4, 5, and 6. † Low-dose tacrolimus = 3-7 ng/mL on all days; full-dose tacrolimus = ng/mL on Days 0-28, 7-16 ng/mL on Days 29-90, and 5-15 ng/mL on Day 90 and beyond. Adult patients undergoing kidney transplantation (N = 309) Alefacept/Low Tacrolimus/MMF* Alefacept 15 mg SC on Day 7, then weekly for 12 wks + Low-dose Tacrolimus † + MMF + Steroids (n = 77) Alefacept/Full Tacrolimus/No MMF* Alefacept 15 mg SC on Day 7, then weekly for 12 wks + Full-dose Tacrolimus † + Steroids (n = 75) Q2W Alefacept/Low Tacrolimus/MMF* Alefacept 30 mg SC on Day 7, then Q2W for 12 wks + Low-dose Tacrolimus † + MMF + Steroids (n = 78) Month 6 primary endpoint Control Basiliximab + Full-dose Tacrolimus † + MMF + Steroids (n = 79) Transplantation

clinicaloptions.com/transplantation Highlights From ATC 2011 Alefacept Significantly Reduces T-Cell Memory Subsets in Kidney Transplant Bromberg J, et al. ATC Abstract 533. Outcome at Month 6Alefacept/Low Tacrolimus/MMF (n = 77) Alefacept/Full Tacrolimus/No MMF (n = 75) Q2W Alefacept/Low Tacrolimus/MMF (n = 78) Control (n = 79) Kaplan-Meier rate of BPAR, %  P value for noninferiority to control Efficacy failure, %* Renal function  GFR, mL/min/1.73 m Kaplan-Meier estimate of graft survival, % Kaplan-Meier estimate of patient survival, % *BPAR, graft loss, death, or lost to follow-up.  Alefacept significantly reduced T-cell memory subsets; nadirs observed after 8-12 wks –In all arms, CD4+ T cells increased through Week 2 and then began slow, steady decline –CD8+ T cells in alefacept arms increased through Week 2 and then began slow, steady decline  No alefacept arm met noninferiority criteria for acute T-cell–mediated rejection at Month 6

Preventing Rejection

clinicaloptions.com/transplantation Highlights From ATC 2011 Inhibition of Adhesion and Costimulation Pathways Extends Allograft Survival Beus JM, et al. ATC Abstract 2.  Heterologous immunity may play a role in costimulation blockade-resistant rejection –May be overcome with adhesion blockade-based therapies  Current study used mouse model of herpesvirus-mediated heterologous immunity in skin allotransplantation Outcome Antibody Given With Costimulation Blockade None (n = 34) Anti–VLA-4 (n = 11) Anti–LFA-1 (n = 12) Anti–VLA-4 + Anti–LFA-1 (n = 11) Median graft survival, days > 100* Median serum MHV68 at 130 days after weekly treatment, copies/µL † ,198 ‡ *P <.0001 † P <.05 ‡ P <.01

clinicaloptions.com/transplantation Highlights From ATC 2011 Proteasome Inhibitor Bortezomib: Mechanism of Action  Bortezomib effective for prevention of antibody-mediated rejection and cell-mediated acute rejection Reprinted by permission from Macmillan Publishers Ltd: Paramore A, Frantz S. Nat Rev Drug Disc. 2003;2:

clinicaloptions.com/transplantation Highlights From ATC 2011 Bortezomib Provides Effective Reversal of AMR in Kidney Transplantation  Efficacy of bortezomib-based therapy for treatment of early and late AMR evaluated in patients (n = 82) who received kidney transplant at multiple centers –Other solid organ transplant recipients also studied, but data not presented  Bortezomib reduced iDSA levels substantially and to similar degree in both early and late AMR  High rates of histologic improvement, graft survival, and patient survival with bortezomib therapy  Renal function as evidenced by serum creatinine level improved in both early and late AMR with bortezomib therapy –Smaller improvement observed in late AMR vs early AMR  No differences in overall results between originating center and collaborating centers Woodle ES, et al. ATC Abstract 429.

HIV

clinicaloptions.com/transplantation Highlights From ATC 2011 HIV-Related Factors Not Associated With Survival After Kidney or Liver Transplant  Factors associated with mortality differed between kidney and liver recipients –Strongest factors in kidney recipients: HCV coinfection and age –Strongest factors in liver recipients: dual organ transplantation, pretransplantation BMI, and donor age  Transplantation not associated with improved survival in kidney transplant recipients vs those who remained on the waiting list  Transplantation associated with improved survival in liver transplant recipients with MELD score ≥ 15 Roland M, et al. ATC Abstract 377. Patient Survival, % (95% CI) Kidney Transplant Recipients (n = 150) Liver Transplant Recipients (n = 125) Year 195 (90-98)80 (72-86) Year 391 (84-95)67 (56-75)  Patient survival rates higher for kidney transplant vs liver transplant recipients

clinicaloptions.com/transplantation Highlights From ATC 2011 No Difference in Outcomes in HIV+ Kidney Transplantation by NIH vs Other Protocol  Recent multicenter, prospective, nonrandomized trial reported excellent safety and efficacy outcomes of renal transplantation in HIV+ patients with ESRD [1] –Favorable results achieved with careful patient selection, strict adherence to NIH clinical management protocol, coordinated care among multidisciplinary teams  Current study evaluated outcomes among 280 patients at other centers managed according to different protocols [2]  No statistically significant differences in risk of graft loss or death between recipients transplanted according to NIH protocol vs other protocols [2] –Comparison of outcomes based on transplant center experience also identified no statistically differences in risk of graft loss or death between groups Outcome at 1 Yr, % Patients Transplanted at Centers Following NIH Protocol (n = 170) Patients Transplanted at Centers Following Other Protocols (n = 110) HR (95% CI)P Value Graft survival ( ).60 Patient survival ( ) Stock PG, et al. N Engl J Med. 2010;363: Locke JE, et al. ATC Abstract 378.

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