Belatacept: A Revolution in Solid Organ Transplantation Or Simply a New Toy?

Barrett Crowther, Pharm.D.

PGY2 Solid Organ Transplant Pharmacy Resident Department of Pharmacy, University Health System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio September 10, 2010

Learning Objectives: 1. Describe the current challenges with immunosuppression in renal transplantation 2. Assess the benefits and risks of belatacept use in renal transplantation 3. Devise an evidence-based approach for use of belatacept in renal transplantation

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BACKGROUND
I. Why is Belatacept Important? A. First biologic agent to be tested in fully powered phase III trials as primary maintenance immunosuppressant in solid organ transplantation i. Primarily studied in renal transplantation B. Potentially first new drug in more than 25 years to impact long-term allograft survival

II. Trends in Renal Transplantation A. Renal transplant is treatment of choice for end-stage renal disease1-2 i. Increased patient survival, increased quality of life, and decreased costs vs. dialysis B. Organ demand vs. supply1,3-5 i. Demand for donor organs far exceeds supply a. Currently, almost 86,000 patients are awaiting kidney transplantation in US3 b. In 2008, 16,500 renal transplants occurred in US1 ii. Efforts to increase organ availability1,4 a. Improve organ donation awareness b. Increase living donation c. Establish criteria for increased cadaveric organ utilization [governed by United Network for Organ Sharing (UNOS)] 1. Donation after cardiac death (DCD)4 2. Expanded criteria donors (ECDs)1,5 a) Includes donors who are 60 years old or donors 50-59 with two of the following: history of hypertension, death due to a cerebrovascular accident, or terminal SCr 1.5 mg/dL5 b) May increase risk of delayed graft function, primary graft nonfunction, or shortened graft survival C. One-year rejection treatment rates i. Declined drastically over past decade from approximately 30% to 10%6 D. Trends in allograft and patient survival7 i. Increase in graft survival from late 1980s to mid 2000s ii. From 1997 to 2005, graft survival rates have remained steady

100% Graft Survival Rates 80%

60%
1 year

40% 20% 0%
1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

3 year 5 year 10 year

Year of Transplant
Figure 1: Unadjusted Graft Survival for Deceased-Donor, non-ECD Kidney Transplants7

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III. Current Immunosuppression and Challenges in Transplantation A. Current regimens i. Most common maintenance regimen at time of renal transplant in US is tacrolimus + mycophenolate corticosteroids1 B. Drug toxicity i. Nephrotoxicity with calcineurin inhibitors (CNIs)1,8-11 a. Both tacrolimus and cyclosporine cause significant vasoconstriction of the afferent arteriole, leading to reduced renal blood flow and decreased glomerular filtration rate (GFR) b. Initially, may be reversible after discontinuation or improved with dose reduction of CNI c. Long-term effects may lead to irreversible chronic kidney disease 1. Average decline in GFR is 1-2 mL/min/1.73m2 per year10 2. Chronic renal failure in non-renal transplantation is 16.5%11 ii. Metabolic and cardiovascular complications1,12-13 a. Common with CNIs, mTOR inhibitors, and corticosteroids b. New onset diabetes after transplant (NODAT) rates approximately 30% within first two years of kidney transplantation12 1. Risk factors include obesity, family history of diabetes, African or Hispanic ancestry, hepatitis C, increased recipient age (>40 years), CNI use, and corticosteroid use1 c. Cardiovascular disease is leading cause of death in long-term transplant recipients13 Table 1: Immunosuppressant Adverse Effects Which Impact Morbidity and Mortality14-15 Calcineurin Inhibitors (CNIs) mTOR Inhibitors Corticosteroids (CS) (Cyclosporine and Tacrolimus) (Sirolimus and Everolimus)
Glucose intolerance Hyperlipidemia Hypertension Nephrotoxicity Neurotoxicity Hyperlipidemia Hypertriglyceridemia Impaired wound healing Glucose intolerance Hyperlipidemia Hypertension Peptic ulcers Weight gain

C. Over-immunosuppression i. Infection16-17 a. Net state of immunosuppression encompasses all factors which contribute to risk of infection, including dose, duration, and sequence of immunosuppressants b. Viral infections may have immunomodulatory effects 1. Herpes viruses are most common a) Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus (HSV), and Human Herpes Virus 8 (HHV-8) ii. Malignancy18-20 a. Most common malignancies post-transplant 1. Nonmelanoma skin cancers occur in up to 82% of transplant recipients19 2. Post transplant lymphoproliferative disorder (PTLD) occurs in 1-11% of all transplant recipients; reported in up to 2.3% of renal transplant recipients19-20 a) Often associated with EBV, which infects B-cells i.) In a non-immunosuppressed individual, EBV-specific cytotoxic T-cells typically control EBV infected B-cells and prevent over-proliferation ii.) In a significantly immunosuppressed patient, T-cells can no longer control B-cells, which leads to over-proliferation of B-cells

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b) Mortality 40-60% c) Risk factors i.) EBV mismatch: EBV-negative transplant recipient from EBV-positive donor ii.) Lymphocyte-depleting therapy [e.g. rabbit anti-thymocyte globulin (rATG, Thymoglobulin) and muromonab-CD3(OKT3)] iii.) Male gender iv.) Transplant before the age of 18 v.) CMV disease or CMV mismatch D. Renal graft complications i. Delayed graft function (DGF)1,21 a. Defined as need for dialysis within 7 days from transplant b. Independent risk factor for acute rejection and impaired renal function within 1 year c. May reduce 1-year graft survival rates d. Risk increased with extended cold/warm ischemia times, ECDs, and DCDs ii. Acute rejection (AR)1,22-24 a. Predominantly T-cell mediated, where T-cells infiltrate allograft b. Most cases occur within 3 months from transplant c. Previously thought to be gold-standard to predict graft survival rates d. Impact of AR on graft survival 1. Early (3-6 months) vs. late (>1 year) AR a) Risk for graft failure increases with later AR22 2. More severe AR increases risk of graft failure22 3. Return of renal function to baseline after AR a) Overall 6-year graft survival similar to patients without AR23 4. Number of AR episodes a) Improved survival with one vs. two or more AR episodes22 e. Tacrolimus vs. cyclosporine 1. Reduced rates of AR with tacrolimus vs. cyclosporine, which may not affect patient or graft survival24 iii. Renal function at one year post-transplant a. Correlates with long-term graft survival25 iv. Interstitial fibrosis and tubular atrophy (IFTA)1 a. Often referred to as chronic rejection or chronic allograft nephropathy (CAN) b. Slow and indolent form of fibrosis and graft loss c. Causes 1. CNI nephrotoxicity 2. Viral infections 3. Hypertension 4. Slowly progressing immunologic activity 5. Donor related factors a) Ischemia time b) Undetected kidney disease 6. Recurrence of kidney disease in recipient

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E. Economical impact i. Cost of immunosuppressants Table 2: Annual Costs for Renal Transplant Immunosuppressants (US 2008)1 Brand tacrolimus (Prograf) Brand cyclosporine, microemulsion (Neoral ) Generic cyclosporine, microemulsion Brand mycophenolate mofetil (CellCept ) Sirolimus (Rapamune) Prednisone

$15,000

$13,700 $12,400 $12,100 $10,900 $160

a. Significant cost of maintenance immunosuppressants may impact medication adherence1 ii. Therapeutic drug monitoring (TDM)26 a. TDM is considered standard of care with CNIs and mTOR inhibitors b. Cost of TDM contributes to overall healthcare expense IV. New Drug Development in Transplantation A. New drug approvals by US Food and Drug Administration (FDA) are typically based on trials using noninferiority design27-31 i. Unethical to use placebo as comparator, when effective immunosuppressant combinations exist27 ii. Trials demonstrating superiority treatment regimens would require an unreasonably large number of patients27 iii. Belatacept trials followed this noninferiority approach29-31 B. Noninferiority studies seeking FDA approval must be compared to FDA-approved regimens, which may not reflect common clinical practice32 i. Examples with belatacept trials a. Basiliximab was induction agent utilized, although rATG (Thymoglobulin) is most common induction agent in practice1,29-31 1. rATG is only approved for treatment of acute rejection in renal transplant32 b. Cyclosporine + mycophenolate mofetil + corticosteroids was maintenance immunosuppressant regimen utilized, although tacrolimus + mycophenolate mofetil steroids is most common regimen in US29-31,32 1. Combination of tacrolimus and mycophenolate mofetil did not receive FDA approval in renal transplant until May 19, 2009

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OVERVIEW OF BELATACEPT
V. Belatacept A. Novel biological immunosuppressant fusion protein B. First inhibitor of Signal 2 in T-cell activation for transplantation VI. Review of T-Cell Activation1 A. Signal 1 i. Antigen presenting cell (APC) displays antigen to T-cell via the major histocompatability complex (MHC) ii. Antigen binds to T-cell receptor (TCR) causing an activation of the T-cell iii. Inevitably leads to increased production of interleukin-2 (IL-2) B. Signal 2 i. APC binds to T-cell via CD80 (B7-1) and CD86 (B7-2) interaction with CD28 a. Both CD80 and CD86 can bind with CD28 to regulate T-cell clonal expansion and differentiation b. When CD80 and CD86 bind with cytotoxic T-lymphocyte antigen-4 (CTLA-4), also known as CD152, T-cell activation and proliferation are inhibited, leading to anergy or apoptosis 1. CTLA-4 is only expressed during T-cell activation ii. This process is referred to as costimulation and is required for T-cell proliferation C. Signal 3 i. IL-2 binds to CD25 on T-cell ii. Results in stimulation of cell cycle leading to T-cell proliferation

Figure 2: T-Cell Activation Pathway34

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VII. Belatacept Development and Mechanism of Action1,35-36 A. In vitro models demonstrated T-cell anergy, or antigen-specific unresponsiveness, when signal 2 was blocked (no CD28 engagement)1 B. Abatacept35-36 i. First recombinant immunoglobulin fusion protein, combining extracellular portion of CTLA-4 with constant-region fragment (Fc) of human IgG1 ii. Provides selective costimulation blockade of T-cell activation a. Binds surface costimulatory ligands (CD80 and CD86) of APCs 1. Interferes with interaction of CD80/86 and surface costimulatory receptor CD28 of T-cells (signal 2), which is required for T-cell activation iii. Approved for treatment of rheumatoid arthritis as Orencia iv. In rodent models, significantly prolonged transplanted organ survival time v. In non-human primate models, found to be ineffective at preventing transplanted solid organ transplant rejection C. Belatacept (LEA29Y)35-36 i. Differs from abatacept by two amino acids, allowing for greater binding capacity a. 2 times the binding strength to CD80 and 4 times the binding strength to CD86 compared with abatacept35 b. Same mechanism of action as abatacept

Figure 3: Development of Belatacept36 ii. In non-human primate models found to effectively prolong renal allograft survival a. Mean renal allograft survival time with belatacept monotherapy was 45 days, compared to 8 days with abatacept35 iii. Also found to inhibit the production of anti-donor antibodies, which are believed to contribute to CAN/IFTA35 VIII. Belatacept Pharmacokinetic Profile37-39 A. Steady state volume of distribution: 10.6 L; 0.12 L/kg37-38 B. Terminal half-life: 8-11 days37-38 C. Belatacept clearance increased with baseline body weight, supporting weight-based dosing38 D. Clearance unaffected by38 i. Age, gender, and race ii. Renal and hepatic function iii. Dialysis E. Belatacept does not interact with mycophenolate, unlike cyclosporine which decreases exposure by ~40%1,39

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CLINICAL TRIALS
IX. Belatacept Phase II Trial A. One-year Phase II data29
Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353(8):770-81. To assess efficacy and safety of a belatacept- vs. cyclosporine-based regimen in kidney transplant recipients Purpose Design Enrollment Randomized, partially-blinded, parallel, active-controlled, multicenter (22 centers in US, Canada, and Europe) Phase II study between 2001-2003 Inclusion Adult recipients of renal allograft from non-HLA-identical living or deceased donor No more than 10% of included patients could have an increased risk for AR as determined by study investigators, including a panel of reactive antibodies (PRA) > 20% and previous renal transplant Exclusion Underlying renal disease which could recur, infection which would prevent transplant, history or evidence of cancer, positive crossmatch, history of drug or alcohol abuse or psychotic disorders, previous treatment with basiliximab, use of investigational drug within 30 days of transplant, and high risk kidney donors (donor age > 60 years/< 6 years, DCD, cold-ischemia time > 36 hours) Randomized to one of three treatment arms Belatacept Intensive 0-3 months: 10 mg/kg/dose on day 1, 5, 15, 29, 43, 57, 71, 85 4-6 months: 10 mg/kg/dose on day 113, 141, 169 7-12 months: 5 mg/kg every 4 or 8 weeks Belatacept Less Intensive (LI) 0-1 month: 10 mg/kg/dose on day 1, 15, 29 2-3 months: 10 mg/kg/dose on day 57, 85 4-12 months: 5 mg/kg every 4 or 8 weeks Cyclosporine (CsA), modified Initial dose: 4-10 mg/kg/day 0-1 month: Dose adjusted to trough CsA concentration of 150 400 ng/mL 2-12 months: Dose adjusted to trough CsA concentration of 150 300 ng/mL All patients received basiliximab (20 mg on day 0 and day 4), mycophenolate mofetil (MMF) 2 g/day, and corticosteroid taper Belatacept administered as 30 minute infusion Primary endpoint Clinically-suspected (rise in SCr > 0.5 mg/dL), biopsy-proven acute rejection (BPAR) at 6 months Secondary endpoints Measured GFR (iohexol clearance), hypertension, hyperlipidemia, incidence of BPAR or presumed AR, and overall safety Other analyses NODAT, rate of death and graft loss, calculated GFR, pharmacokinetics, and immunogenicity Post hoc: CAN incidence, treatment of hypertension Intention to treat with all patients who underwent transplantation Primary endpoint was noninferior if upper bound of 95% confidence interval (CI) of difference < 20% Projected 70 patients per treatment arm would provide 85% power assuming a 15% rate of clinicallysuspected, biopsy-proven AR and a 10% dropout rate Enrolled 218 patients (Intensive = 74, LI = 71, CsA = 73) 164 patients completed 12 month phase (Intense = 58, LI = 55, CsA = 51; dropout rates = 22%, 23%, and 30%, respectively) Baseline donor and recipient characteristics similar Belatacept MI 7% -1.5% -11.3, 8.3% Belatacept LI 6% -2.6% -12.3, 6.7% CsA 8% -

Methods

Outcomes

Statistics

Results

AR at 6 months Difference from CsA 95% CI

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CAN at 12 months Difference from CsA 95% CI Mean measured GFR at 12 months (n=96) in mL/min/1.73m2 Mean calculated GFR at 12 months (n=169) in mL/min/1.73m2 Graft loss (#) (all due to technical reasons) Patient death (#) Prevalence of hypertension Hyperlipidemia requiring lipidlowering medication NODAT (%)

Belatacept MI 29% -15.6% -34.6%, 3.4% 66.3 (p=0.01) 72.4 3 1 22% 36% (p=0.03) 12%

Belatacept LI 20% -24.1 % -42.1%, 6.0% 62.1 (p=0.04) 73.2 1 0 24% 32% (p=0.03) 6%

CsA 44% 53.5 68.0 2 4 (2 d/t CV reasons) 31% 53% 12%

Conclusions

Strengths

Limitations

AR endpoint: No AR occurred in any group after 6 months Safety Adverse effects significantly higher in CsA vs. belatacept: Hypertrichosis and diabetes mellitus Infection rates were similar among groups (73% belatacept groups vs. 75% CsA) No infusion-related reactions occurred Malignancy: 2 Intensive (1 breast, 1 PTLD), 0 LI, and 2 CsA (1 skin, 1 thyroid) PTLD: 2 additional cases 2-13 months after intensive belatacept replaced by tacrolimus o Of the 3 cases, 2 had a primary EBV infection and the third received 10 days of muromonab-CD3 for AR At 6 months, belatacept was found to be non-inferior to CsA Both belatacept regimens demonstrated improved measured GFR vs. CsA Belatacept may have an improved cardiovascular/metabolic side effect profile Although not statistically significant, belatacept had lower rates of CAN 3 cases of PTLD were reported in Intensive belatacept regimen; all had risk factors (primary EBV infection and lymphocyte-depleting therapy) Well-designed study Evaluated several parameters which will help determine when to utilize belatacept in transplantation Helped develop primary endpoints for Phase III trials Utilized CsA as a comparator Wide non-inferiority range Partially blinded, which may have contributed to ~10% higher biopsy rate in belatacept DGF rates not reported; CAN reported, but post-hoc analysis Only designed to establish noninferiority of belatacept to CsA in regards to AR rates Limited number of patients had measured GFR (58.5% who completed 12 months) High dropout rate Infection prophylaxis protocol not established Overall, low AR rates

B. Five-year Phase II extension data37 i. Of those in long-term extension, 78/102 patients in belatacept groups and 16/26 patients in CsA group completed 5 years of treatment ii. Patients were self-selected population who did well during first 12 months iii. Mean calculated GFR (mL/min/1.73m2) a. 12 months: 75.8 20.1 with belatacept; 74.4 22.7 with CsA b. 60 months: 77.2 22.7 with belatacept; 59.3 15.3 with CsA iv. Deaths: 3 belatacept (2 with functioning graft, 1 with graft loss); 2 CsA (both with functioning graft) v. Graft loss only: 1 belatacept, 0 CsA vi. BPAR: 6 belatacept (4 on 8-week dosing and 2 on 4-week dosing), 0 CsA vii. PTLD: 0 belatacept, 0 CsA

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X. Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) Phase III A. One-year BENEFIT data30
Vincenti F, Charpentier B, Vanreterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT Study). Am J Transplant 2010;10(3):535-46. To assess the efficacy of a belatacept-based regimen compared to a cyclosporine-based regimen in adult Purpose kidney transplant recipients receiving a living or standard criteria donor (SCD) organ at 12 months Three year, randomized, parallel-group, active-controlled, multicenter (100 centers) Phase III study with Design enrollment beginning January 2006 and primary endpoints assessed June 2008 Enrollment Inclusion 18 years of age; living or SCD kidney transplant with anticipated cold ischemia time of < 24h Exclusion ECD [Age 60 or 50 with 2 additional risk factors (cerebrovascular accident, hypertension, or serum creatinine > 1.5 mg/dL)] anticipated cold ischemia time of 24 hours, DCD, prior or concurrent non-renal solid organ transplant, and PRA 50% for first time transplants or PRA 30% in re-transplants Methods Randomized to one of three treatment arms Belatacept More Intensive (MI) 0-3 months: 10 mg/kg/dose on day 1, day 5, and then week 2, 4, 6, 8, 10, & 12 4-6 months: 10 mg/kg/dose on week 16, 20, & 24 7-12 months: 5 mg/kg every 4 weeks Belatacept Less Intensive (LI) 0-1 month: 10 mg/kg/dose on day 1, day 5, and then week 2 & 4 2-3 months: 10 mg/kg/dose on week 8 & 12 3-12 months: 5 mg/kg every 4 weeks Cyclosporine (CsA) Initial dose: 4-10 mg/kg/day 0-1 month: Dose adjusted to trough CsA concentration of 150 300 ng/mL 2-12 months: Dose adjusted to trough CsA concentration of 100 250 ng/mL All patients received basiliximab (20 mg on day 0 and day 4), MMF 2 g/day, and corticosteroid taper Protocol recommended at least 3 months of antiviral prophylaxis and 6 months of PCP prophylaxis Patients in CsA group with DGF could receive T-cell depleting therapy Outcomes Coprimary endpoints Composite patient and graft survival Composite renal impairment Measured GFR < 60 mL/min/1.73m2 at month 12 (iothalamate); OR Decrease in measured GFR 10 mL/min/1.73m2 from month 3 to month 12 Incidence of AR: Protocol-defined clinical suspicion and biopsy-proven Secondary endpoints at month 12 Mean calculated GFR (MDRD) and measured GFR, CAN on protocol biopsy at week 52, mean systolic and diastolic blood pressure, NODAT, mean change in non-HDL cholesterol from baseline to month 12, and DGF Statistics Intention to treat with randomized patients who received transplant Primary endpoint sequential testing procedure 1.) Patient and graft survival using 10% noninferiority 2.) Superiority of belatacept on renal function with a continuity-corrected chi-squared test 3.) AR using 20% noninferiority Two-sided alpha = 2.7% for each belatacept arm vs. CsA (to account for multiple comparisons), alpha = 5% overall for the entire study Measured GFR analyzed using ANOVA Projected 220 patients per treatment arm with 93% power that met all coprimary endpoints Absolute difference between belatacept and CsA could not exceed 3% for graft/patient survival Results Randomized 666 patients (MI = 219, LI = 226, CsA = 221) 527 patients completed 12 month phase (MI = 173, LI = 181, CsA = 173; dropout rates = 21%, 20%, and 22%, respectively) Baseline donor and recipient characteristics similar

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Composite patient/graft survival Difference from CsA 97.3% CI Composite renal impairment Difference from CsA 97.3% CI Mean measured GFR (mL/min/1.73m2) Difference from CsA 97.3% CI

Belatacept MI 95% 2.2% -2.9%,7.5% 55% -22.9% -32.6%,-12.9% (p < 0.0001) 65.0

Belatacept LI 97% 3.2% -1.5%,8.4% 54% -23.7% -33.3%,-13.7% (p < 0.0001) 63.4 12.9 7.2,18.6 (p < 0.0001) 17% 10.0% 3.3%,17.1% 14% 24% -8.5% -17.9%,0.9% 8.0 (p = 0.010) 4% (p = 0.069) 26% (p = 0.0223)

CsA 93% 78% 50.4 7% 18% 32% 18.3 10% 35% -

14.6 8.8,20.3 (p < 0.0001) AR incidence* 22% Difference from CsA 15.1% 97.3% CI 7.9%,22.7% DGF incidence 16% CAN incidence 18% Difference from CsA -14.2% 97.3% CI -23.2%,-5.0% Increase from baseline in non-HDL 8.1 (mg/dL) (p = 0.012) 7% Incidence of NODAT (p = 0.483) Percent requiring 3 29% antihypertensive agents (p = 0.089) *AR endpoint: 82% of AR occurred within first 3 months

Conclusions

Strengths

Limitations

Safety Acute infusion reactions occurred in 4 patients in each belatacept MI and LI groups Overall, infections were similar among groups; TB reported in 1 CsA patient Adverse reactions similar between groups except tremor (16% CsA vs. 4% MI, 5% LI) Malignancy: 5 MI, 4 LI, and 1 CsA PTLD Belatacept MI Belatacept LI CsA During 12 month study 1 2 1 After 12 month study 2 0 0 Total 3 2 1 o 2 PTLD infections in MI group involved CNS o 1/6 had only EBV negative serology pretransplant o 1/6 had only lymphocyte-depleting therapy for rejection o 2/6 had both lymphocyte-depleting therapy and EBV negative serology pretransplant At 12 months, belatacept provided similar efficacy to CsA and superior renal function Higher rates of malignancy, including PTLD, were observed with belatacept MI belatacept group did not meet AR noninferiority criteria, while LI belatacept group did AR episodes tended to occur within 3 months of transplantation Belatacept provided improved cardiovascular/metabolic adverse effect profile MI belatacept demonstrated significantly lower CAN; LI belatacept trended towards lower CAN One of the largest prospective transplant studies conducted to date Evaluated several parameters which will help determine when to utilize belatacept in transplantation Measured GFR collected from 88% of patients Protocol biopsies at 12 months completed in 79% of patients Utilized CsA as comparator CsA patients allowed lymphocyte-depleting therapy if DGF or renal impairment occurred Open-label for CsA vs. belatacept Bristol-Meyers Squibb sponsored study Only preliminary 1 year data

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B. Two-year BENEFIT data (abstract)40

Larsen CP, Grinyo J, Charpentier B, et al. Belatacept vs. cyclosporine in kidney transplant recipients: twoyear outcomes from the BENEFIT study. American Transplant Congress 2010.
Results 493/666 patients completed 2 years of treatment (MI = 164, LI = 176, CsA = 153) Belatacept MI (n=164) Composite patient/graft survival Additional AR episodes from year 1 to 2 Number of AR episodes occurring during 1st year from BENEFIT 94% 4 49 (22%) Belatacept LI (n=176) 95% 0 39 (17%) CsA (n=153) 91% 4 16 (7%)

Conclusions

Renal endpoint: Mean measured GFR for both belatacept MI and LI ~ 15-17 mL/min higher vs. CsA (p < 0.0001) CV/Metabolic endpoints: Additional effects regarding lower LDL with both belatacept groups vs. CsA (p 0.002) Safety: Overall safety results remained similar between groups Malignancy and serious infection rates remained comparable between groups PTLD occurred in two belatacept MI patients from year 1 to 2 At 24 months, belatacept continued to provide similar efficacy and superior renal function No additional efficacy with MI vs. LI belatacept Majority of AR with belatacept occurred early Additional cases of PTLD occurred between year 1 and year 2 Belatacept demonstrated beneficial effects on LDL cholesterol

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XI. Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial from EXTended Criteria Donors (BENEFIT-EXT) Phase III A. One-year BENEFIT-EXT data31
Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT Study). Am J Transplant 2010;10(3):547-57. To assess the efficacy and safety of a belatacept-based regimen compared to a cyclosporine-based regimen in Purpose adult kidney transplant recipients receiving an extended criteria donor organ at 12 months Three year, randomized, parallel-group, active-controlled, multicenter (79 centers) Phase III study with Design enrollment beginning March 2005 Enrollment Inclusion: At least 18 years of age and extended criteria donor (EXT) [Age 60 or 50 with 2 additional risk factors (cerebrovascular accident, hypertension, or serum creatinine > 1.5 mg/dL); anticipated cold ischemia time of 24 hours; or donation after cardiac death] Methods Methods and randomization design identical to BENEFIT trial Outcomes Coprimary endpoints* Composite patient and graft survival Composite renal impairment Measured GFR < 60 mL/min/1.73m2 at month 12 (iothalamate); OR Decrease in measured GFR 10 mL/min/1.73m2 from month 3 to month 12 Secondary endpoints at month 12 Mean measured and calculated GFR ( MDRD), CAN on protocol biopsy at week 52, incidence of protocol defined clinically-suspected, biopsy-proven AR, mean systolic and diastolic blood pressure, NODAT, and change in serum cholesterol from baseline to month 12 * Note: AR not primary endpoint in BENEFIT-EXT due to anticipated high rates of DGF Intention to treat with randomized patients who received transplant Primary endpoint sequential testing procedure 1.) Patient and graft survival using 10% noninferiority 2.) Superiority of belatacept on renal function using a continuity-corrected chi-squared test Two-sided alpha = 2.7% for each belatacept arm vs. cyclosporine (to account for multiple comparisons), although alpha = 5% for overall study Measured GFR analyzed using ANOVA Projected 180 patients per arm with 80% power to meet all coprimary endpoints at the 0.05 significance level Enrolled 543 patients (MI = 184, LI = 175, CsA = 184) 387 patients completed 12 month phase (MI = 133, LI = 129, CsA = 125; dropout rates = 28%, 26%, 30%, respectively) Baseline donor and recipient characteristics similar; major cause of donor mortality was CVA (69.8%) Belatacept MI Composite patient/graft survival Difference from CsA 97.3% CI Composite renal impairment Difference from CsA 97.3% CI Mean measured GFR (mL/min/1.73m2) Difference from CsA 97.3% CI 86% 1.6% -6.6%,9.9% 70.5% -14.4% -24.0%,-4.7% (p = 0.0018) 52.1 Belatacept LI 89% 3.8% -4.3%,11.9% 76.5% -8.4% -17.8%,1.0% (p = 0.0656) 49.5 4.3 -1.5,10.1 (p = 0.1039) 17.7% 3.6% -5.0%,12.3% CsA 85% 84.8% 45.2 14.1% -

Statistics

Results

6.9 1.1,12.7 (p = 0.0083) AR incidence* 17.9% Difference from CsA 3.8% 97.3% CI -4.7%,12.4% *AR endpoint: 81% of AR occurred within first 3 months

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DGF incidence CAN incidence Difference from CsA 97.3% CI Increase from baseline in non-HDL (mg/dL) Incidence of NODAT Percent requiring 3 antihypertensive agents

Belatacept MI 47% 45% -6.8% -18.2%,4.7% 12.6 (p = 0.002) 2% (p = 0.031) 39 - 43%

Belatacept LI 47% 46% -5.7% -17.2%,6.0% 11.2 (p = 0.001) 5% (p = 0.295)

CsA 49% 52% 29.3 9% 52%

Conclusions

Strengths

Limitations

Safety Acute infusion reactions occurred in 7 patients in MI group and 9 patients in LI group Overall, infections were similar among groups; except TB reported in 2 MI and 2 LI patients Adverse reactions similar between groups Malignancy: 4 MI (1 PTLD, 1 Kaposis sarcoma, 1 breast cancer, 1 colon cancer), 4 LI (2 PTLD, 1 myelodysplastic syndrome and 1 breast cancer), and 6 CsA developed malignancies (1 breast cancer, 1 renal neosplasm, 1 thyroid neoplasm, 1 transitional cell carcinoma, and 2 Kaposis sarcoma) PTLD Belatacept MI Belatacept LI CsA During 12 month study 1 2 0 After 12 month study 1 1 0 Total 2 3 0 o 4/5 PTLD infections involved CNS o 2/5 had CMV disease o 3/5 had EBV negative serology pretransplant o None had used lymphocyte-depleting therapy o 3/5 died as of March 2009 At 12 months, belatacept provided similar efficacy to cyclosporine and resulted in improved renal function in patients receiving an EXT kidney Higher rates of PTLD, specifically CNS PTLD, were observed in patients receiving belatacept The belatacept groups also appeared to have an improved cardiovascular/metabolic adverse effect profile compared with cyclosporine Well-designed, large, multicenter trial Specifically analyzed EXT concerns, which included DCD donors and extended cold ischemia times Measured GFR Protocol biopsies at 12 months completed in 73% of patients Analyzed risk factors for developing PTLD Utilized cyclosporine as a comparator Only preliminary 1 year data T-cell depleting therapy for DGF only permitted in CsA group (15% CsA group received) Open label for CsA vs. belatacept Sponsored by Bristol-Meyers Squibb

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B. Two-year BENEFIT-EXT data (abstract)41

Durrbach A, Larsen CP, Pestana JM et al. Belatacept vs cyclosporine in ECD kidney transplants: two-year outcomes from the BENEFIT-EXT study. American Transplant Congress 2010.
Results 347 patients completed 2 years of treatment (MI = 116, LI = 119, CsA = 112) Belatacept MI Composite patient/graft survival Mean measured GFR (mL/min/1.73m2) Additional AR episodes from year 1 to 2 Number of AR episodes occurring during 1st year from BENEFIT 83% 52 (p = 0.028) 0 33 (18%) Belatacept LI 84% 50 (p = 0.108) 1 31 (18%) CsA 83% 45 2 26 (14%)

Conclusions

CV/Metabolic endpoints: Benefits on lipids and blood pressure maintained Safety: Overall safety results remained similar between groups Malignancy and serious infection rates remained comparable between groups PTLD occurred in one of each belatacept MI and LI groups from year 1 to 2 At 24 months, belatacept continued to have benefit on renal function and cardiovascular endpoints, with comparable graft/patient survival vs. CsA No additional efficacy with MI vs. LI Additional cases of PTLD occurred between year 1 and year 2 Minimal additional AR occurred

XII. Pooled Safety Data of Belatacept Phase II and Phase III Trials42 A. Analysis of data to July 2009 with median follow-up of approximately 2.4 years Table 3: Safety Profile of Belatacept from Phase II and III Studies42
Incidence of death (%) Serious adverse events (%) Overall malignancy (%) Overall PTLD (#)* CNS PTLD Serious infections (%) Polyoma (%) Fungal infections (%) PML (#) Tuberculosis (#) Belatacept MI (n = 477) 83% 71% 10% 8 6 37% 7% 22% 1 5 Belatacept LI (n = 472) 84% 68% 6% 5 2 32% 3% 17% 0 4 CsA (n = 476) 83% 69% 7% 2 0 36% 6% 21% 0 1

*No cases of PTLD occurred after 18 months in belatacept groups

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XIII. Belatacept EBV+, LI Subgroup Analysis44 A. 85% of patients who were enrolled in the Phase II and Phase III belatacept trials were EBV+

Figure 4: Benefit-Risk Profile of the Belatacept LI at 2 Years in EBV+ Kidney Transplant Recipients vs. CsA (CI 97.3% or 95%)44 i. Outcome data includes only Phase III trials and safety data includes Phase II and III trials ii. PTLD: 4 cases in EBV+, LI belatacept (2 renal, 2 CNS) vs. 0 in CsA EBV+ recipients XIV.Summary of Phase II and Phase III Studies A. Pros of belatacept i. No added benefit with MI vs. LI belatacept recipients ii. Improved renal function at least 2 years post-transplant with belatacept LI in SCD kidney transplants with increase in GFR of ~15 mL/min/1.73m2 vs. CsA

a. EXT kidney transplants had an increase in GFR of 5 mL/min/1.73m2 with LI belatacept vs. CsA (not significant)
iii. Improved patient/graft survival with EBV+ belatacept LI at 2 years vs. CsA in SCD recipients iv. Improved metabolic/cardiovascular profile with belatacept vs. CsA B. Cons of belatacept i. Increased AR with belatacept EBV+, LI group in SCD kidney transplants ii. PTLD: 4 episodes in EBV+, LI belatacept group (1%) vs. 0 in EBV+ CsA group iii. PML: 1 case in MI belatacept group XV. Other Active Phase II Studies Involving Belatacept A. Switch from CNI in stable kidney transplant patients45 B. Comparison of belatacept- with tacrolimus-based, steroid-avoiding regimens46 C. Belatacept in liver transplant recipients vs. tacrolimus47

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STATUS AND SUMMARY

XVI.Status A. FDA Approval27,48 i. March 2010, FDA Cardiovascular and Renal Drugs Advisory Committee recommended FDA approval of belatacept for renal transplant recipients ii. May 2010, FDA reviewed two-year data from Phase III belatacept trials and requested an additional one year of data before approval in renal transplant iii. Manufacturer of belatacept, Bristol-Myers Squibb, intends to seek approval for LI regimen as indicated dosage in adult renal transplant recipients a. Will be contraindicated in EBV-negative or EBV-unknown patients iv. Timing of presentation of 3 year data to FDA unknown XVII. Summary A. Although 1-year graft survival rates in renal transplant exceed 90%, long term outcomes remain challenged with nephrotoxicity and metabolic/cardiovascular risks B. New immunosuppressive agents must balance successful graft outcomes with overall costs and over-immunosuppression C. Belatacept a novel biologic maintenance immunosuppressant which potentially may be FDAapproved in the following months XVIII. Recommendations A. Population for use i. EBV+ adult renal transplant recipients at low risk for acute rejection ii. Patients able to receive IV infusions every 4 weeks after the first 3 months of therapy B. Population most likely to BENEFIT from belatacept i. Patients who are adherent with clinic visits, but may have adherence issues with taking medications (difficult to predict at time of transplant) ii. Patients at risk for developing metabolic/cardiovascular complications with CNIs a. Obese patients b. Hispanic ancestry c. Family history of diabetes d. Patient age > 40 e. Previous cardiovascular event C. Possible future niche populations in renal transplant i. Patients experiencing severe toxicity associated with CNIs, including nephrotoxicity and neurotoxicity ii. Patients with difficulty maintaining therapeutic drug levels with CNIs D. Further precautions with use of belatacept i. Only use LI dosing regimen ii. Avoid in EBV-negative and EBV-unknown recipients iii. Avoid use in patients at high risk for AR iv. Avoid use of lymphocyte-depleting therapy if possible v. Avoid use in patients with PRA 50% for first time transplants or PRA 30% in retransplants vi. Utilize appropriate antiviral prophylaxis49

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Lorber MI, Mulgaonkar S, Butt K, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: A 3-year randomized, multicenter, phase III study. Transplantation 2005;80(2):244-52. 29 Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353(8):770-81. 30 Vincenti F, Charpentier B, Vanreterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT Study). Am J Transplant 2010;10(3):535-46. 31 Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT Study). Am J Transplant 2010;10(3):547-57. 32 American Transplant Congress. Congress wrap-up: transplant, FDA sectors debate clinical trial approaches. Available at http://atc-365.ascendeventmedia.com/Highlight.aspx?id=653&p=50. Accessed September 3, 2010. 33 SRTR. OPTN/SRTR 2008 Annual Report: Table 5.6d. Scientific Registry of Transplant Recipients Web site. Available at http://www.ustransplant.org/annual_reports/current/506d_ki.htm. Accessed September 3, 2010. 34 Hunt SA, Haddad F. The changing face of heart transplantation. J Am Coll Cardiol 2008;52(8):587-98. 35 Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005;5(3):443-53. 36 Latek R, Fleener C, Lamian V, et al. Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation. Transplantation 2009;87(6):926-33. 37 Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol 2010 Jul 15. (Epub ahead of print). 38 Zhou Z, Shen J, Kaul S, Pfister M, Roy A. Belatacept Population Pharmacokinetics in Renal Transplant Patients. American Transplant Congress 2010:abstract 1505. 39 Bremer S, Vethe NT, Rootwelt H. Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. J Transl Med 2009;7(64):1-14. 40 Larsen CP, Grinyo J, Charpentier B, et al. Belatacept vs. cyclosporine in kidney transplant recipients: two-year outcomes from the BENEFIT study. American Transplant Congress 2010:abstract 142. 41 Durrbach A, Larsen CP, Pestana JM et al. Belatacept vs cyclosporine in ECD kidney transplants: two-year outcomes from the BENEFIT-EXT study. American Transplant Congress 2010:abstract 143. 42 Grinyo J, Charpentier B, Medina Pestana J, et al. Safety profile of belatacept in kidney transplant recipients from a pooled analysis of Phase II and Phase III studies. American Transplant Congress 2010:abstract 144. 43 Goring S, Eyawo O, Mills EJ, et al. A mixed treatment comparison of efficacy and cardiometabolic safety of belatacept, cyclosporine and tacrolimus for immunosuppression therapy in adult renal transplant recipients. XXIII International Congress of the Transplantation Society 2010:abstract MO04.12. 44 Vincenti F, Grinyo J, Larsen C, et al. Benefit-risk profile of the belatacept LI regimen at 2 years in EBV(+) kidney transplant recipients. XXIII International Congress of the Transplantation Society 2010:abstract P15.07. 45 Rostaing L, Nainan G, del C Rial M et al. Switch from a CNI- to a belatacept-based immunosuppressive regimen in kidney transplant recipients is safe and results in better renal function: 12 month results from a phase II study. American Transplant Congress 2010:abstract 166. 46 Ferguson R, Vincenti F, Kaufman DB et al. Immunosuppression with belatacept-bassed, CNI-avoiding and steroid-avoiding regimens vs. a tacrolimus based, steroid-avoiding regimen in kidney transplant patients: Results of a 1-year randomized study. American Transplant Congress 2010:abstract 372. 47 US National Institutes of Health. NIH Clinical Trials Web site. Available at http://www.clinicaltrials.gov. Accessed September 3, 2010. 48 Reuters. Bristol-Myers say FDA issues letter on belatacept. Reuters website. Available at http://www.reuters.com/article/idUSTRE64136D20100502. Accessed September 3, 2010. 49 Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010;10(5):1228-37.

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Appendix A Abbreviations APC: Antigen presenting cell AR: Acute rejection BENEFIT: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial BENEFIT-EXT: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial EXTended criteria Donors BPAR: Biopsy-proven acute rejection CAN: Chronic allograft nephropathy CI: Confidence interval CMV: Cytomegalovirus CNI: Calcineurin inhibitor CNS: Central nervous system CsA: Cyclosporine CTLA-4: Cytotoxic T-lymphocyte antigen-4 CV: Cardiovascular DGF: Delayed graft function EBV: Epstein-Barr virus ECD: Expanded criteria donor EXT: Extended criteria donor FDA: Food and Drug Administration GFR: Glomerular filtration rate HDL: High-density lipoprotein HHV-8: Human herpes virus 8 HLA: Human leukocyte antigen HSV: Herpes simplex virus IFTA: Interstitial fibrosis and tubular atrophy IL-2: Interleukin 2 LEA29Y: Belatacept LDL: Low-density lipoprotein LI: Less intensive MDRD: Modification of diet in renal disease MI: More intensive MMF: Mycophenolate mofetil mTOR: Mammalian target of rapamycin NODAT: New-onset diabetes after transplant PCP: Pneumocystis jiroveci pneumonia PML: Progressive multifocal leukoencephalopathy PRA: Panel of reactive antibodies PTLD: Post transplant lymphoproliferative disorder SCD: Standard criteria donor SCr: Serum creatinine TDM: Therapeutic drug monitoring TB: Tuberculosis UNOS: United Network for Organ Sharing VZV: Varicella zoster virus

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