Clinical trial NCT00565773
Conditions: Organ Transplantation
Sponsor: Allan D Kirk, MD, PhD
Start date: 2007-12-01; Completion date: 2017-07-01
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Acute rejection is a common problem after a kidney transplant. Rejection can occur when the kidney recipient's immune system tries to attack (or reject) the new kidney. Rejection typically most often develops in the first few months after a transplant.

This single center study will seek to determine if a new combination of anti-rejection medications, including the recently FDA approved drug called Belatacept, is better than the current standard anti-rejection drug regimen at preventing rejection. Also to be determined will be whether the new combination of drugs will allow participants to wean off their oral anti-rejection medications over time.

This study will test the safety and effectiveness of a new investigational drug combination using alemtuzumab, belatacept, and sirolimus when given with or without donor bone marrow.

This combination of medicines has not been tested before in humans. Alemtuzumab (Campath) is approved for use in some types of white blood cell cancers, but is considered investigational in transplant patients. Belatacept is now FDA approved and is being studied in transplant patients. Sirolimus (Rapamune) is approved for use in transplant patients, but its use with belatacept and alemtuzumab is investigational.

In the initial 20 subjects enrolled in the study, half tested whether an infusion of bone marrow from the kidney donor would improve the effect of these drugs. This bone marrow infusion was also considered investigational.

Enrollment of 20 additional subjects began in January, 2013. The donor bone marrow infusion has been eliminated. Enrollment was open to primary living and deceased donor kidney recipients. Enrollment was closed as of 8/12/2014.

Detailed description:
This study will be a single-center, open-label,proof of concept study in non-human leukocyte antigen (HLA)-identical living and deceased donor renal transplants. The initial 20 subjects were randomized to either receive/not to receive a single donor bone marrow infusion in addition to the investigational combination of alemtuzumab, belatacept, and sirolimus. Since the bone marrow infusion has been eliminated in the second group of 20 subjects, no randomization was required. All recipients in the second group of 20 subjects will receive the same investigational combination of alemtuzumab, belatacept, and sirolimus.

At the time of transplant, participants will receive a 3-hour IV infusion of 30 mg. of alemtuzumab. Participants will receive a combination of sirolimus and belatacept for at least one year. At that time, eligible participants will consent to and begin oral immunosuppressive withdrawal or continue therapy through study close. Sirolimus will first be weaned by halving the dose and/or increasing the dosing interval over at least a 2-6 month period. After sirolimus is discontinued, participants will remain on monthly IV belatacept monotherapy indefinitely.

Follow-up will continue for at least five years. If subjects are successfully weaned from oral immunosuppression during their participation in this trial, no other alternative therapy will be warranted. Since belatacept is now FDA approved, subjects will be eligible to continue this therapy after their study participation has ended.

Arms: arm 1: Renal transplant recipients will be given an experimental combination of immunosuppressive drugs. Participants will receive a single dose of alemtuzumab on the day of transplantation and will receive belatacept and sirolimus for 1 year.

At the time of transplant, all patients will receive a single dose of 500 mg of methylprednisolone IV over 30 minutes, followed within 1 hour by an IV infusion of 30 mg of alemtuzumab over 3 hours.
Interventions: intervention 1: Belatacept intervention 2: Sirolimus intervention 3: Alemtuzumab
Intervention descriptions: intervention 1: Belatacept will be given within 24 hours of transplantation via a peripheral intravenous catheter at a dose of 10mg/kg (actual body weight) infused over 30 mins. The dose will be repeated on study days 4 (post op day 3) and 8 (post op day 7), then every 2 weeks for 5 additional doses. Thereafter, belatacept will be given once every 4 weeks (+/- 3 days) at 10mg/kg through 6 months then at 5mg/kg indefinitely. intervention 2: Sirolimus will be started on postoperative day 1 at a dose of 2 mg per day orally. Doses will be adjusted to maintain 24-hour trough levels of 8-10ng/ml until the drug is weaned. Toxicity attributable to sirolimus (e.g., mouth ulcers, arthralgias) will prompt dose reduction to address clinical concerns in this regard. If sirolimus trough levels need to be reduced below 4ng/ml to control drug side effects, the patient will be considered intolerant to the drug and will be changed to other medications. intervention 3: All participants will receive a single dose of 30 mgs of alemtuzumab on the day of transplantation.

Protocol documents:
Prot_SAP_000.pdf: 
Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 1 of 93 
 
Protocol Title:  
Use of Belatacept during Post Depletional Repopulation to 
Facilitate Tolerance in Renal Allograft Recipients  
 
 
 
 
 
Investigator:  
 
Antonio Guasch, MD 
 
 
Protocol Date: 
 
10Jul2015 
 
 
NCT Number:  
 
NCT00565773 
 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 2 of 93 
SYNOPSIS 
Title of Study: Use of Belatacept During Post Depletional Repopulation to Facilitate 
Tolerance in Renal Allograft Recipients 
Study Phase: II 
IND Sponsor: Allan Kirk, MD PhD 
Participating Site: Emory University 
Study Design: Single-center, open-label, proof-of-concept study in non-HLA-identical 
live and deceased donor renal transplants.  
Duration of Study: Subjects will be enrolled over a one-year period and followed for up 
to five years.   
Number of Subjects: Approximately 40 
Study Population: Adult, EBV seropositive patients who do not have evidence of DSA 
pretransplant and who are scheduled to receive a kidney transplant at Emory University. 
Candidacy for transplantation will be determined using the standard methods of 
evaluation active at Emory during the study period. 
Primary Objective: To determine whether lymphocyte depletion with alemtuzumab 
followed by belatacept and sirolimus will permit renal allograft function without 
rejection, and will allow for a general population of renal transplant recipients to be 
weaned to belatacept monotherapy for maintenance immunosuppression. The primary 
endpoint will be the number of patients successfully withdrawn from sirolimus for 1 year 
after their last dose of sirolimus. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 3 of 93 
Secondary Objectives:  
1) Determination of the prognostic ability of assays based on surface phenotype 
changes seen during homeostatic repopulation, including Ki67 expression, TREG 
and BTRANS cell surface phenotypes, and TM to TREG/BTRANS balance, with regard 
to the anticipation of successful immunosuppressive drug withdrawal. 
 
2) Assessment of the proposed therapies to prevent biopsy proven acute rejection at 
1, 3 and 5 years post-transplant compared to the standard reported in the SRTR 
database for similar patients. 
 
3) Assessment of the incidence of biopsy proven chronic allograft nephropathy at 1, 
3 and 5 years post-transplant compared to that reported in the SRTR database for 
similar patients. 
 
4) Assessment of the composite of occurrence of malignancies, and opportunistic 
infections by 1, 3 and 5 years compared to that reported in the SRTR database for 
similar patients. 
 
5) Long term assessment of donor-specific immune responsiveness after prolonged 
therapy with belatacept (with or without sirolimus), and during and following 
drug withdrawal as determined by in vitro alloresponsiveness in CFSE mixed 
lymphocyte reactivity and ICCS. 
 
6) Characterization of the repopulating immune system with regard to cell surface 
phenotype using MFC compared to prior experience with alemtuzumab alone or 
combined with other related regimens and, 
 
7) Comparison of the function and survival of allografts transplanted using this 
protocol to historical controls transplanted using conventional 
immunosuppression to establish an initial assessment of this approach in a general 
transplant population. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 4 of 93 
Clinical Therapy:  
 
Alemtuzumab. At the time of transplantation patients will be given a single dose of 
methylprednisolone 500 mg intravenously over 30 minutes followed by acetaminophen 
650 mg orally or rectally and diphenhydramine 50 mg intravenously, followed in one 
hour by alemtuzumab, 30mg, given intravenously over three hours.  
Transplantation. Transplantation will be performed using standard surgical techniques for 
organ engraftment. Patients will be cared for perioperatively on the transplant unit. 
Technical aspects of the postoperative management will be according to the standard of 
care.   
Belatacept. Belatacept will be given within 24 hours of transplantation via a peripheral 
intravenous catheter at a dose of 10mg/kg (actual body weight) infused over 30 mins. 
The dose will be repeated on study days 4 (post op day 3) and 8 (post op day 7), then 
every 2 weeks for 5 additional doses. Thereafter, belatacept will be given once every 4 
weeks (+/- 3 days) at 10mg/kg through 6 months then at 5mg/kg indefinitely.  
Sirolimus. Sirolimus will be started on postoperative day 1 at a dose of 2 mg per day 
orally. Doses will be adjusted to maintain 24-hour trough levels of 8-10ng/ml until the 
drug is weaned as described below.  
Toxicity attributable to sirolimus (e.g., mouth ulcers, arthralgias) will prompt dose 
reduction to address clinical concerns in this regard. If sirolimus trough levels need to be 
reduced below 4ng/ml to control drug side effects, the patient will be considered 
intolerant to the drug and will be changed to MMF (1.0 gm twice daily) and prednisone 
(starting at 30mg  - 20mg daily tapered to off over 1-3 months depending on the time 
from transplantation).  
Prophylaxis. With the exception of the immunosuppressive drugs used, perioperative 
care, including viral, bacterial and fungal infection prophylaxis will be administered in 
keeping with the current standard of care. 
 
Weaning Schedule: Weaning of immunosuppression will begin for all patients meeting 
pre-defined criteria.  Patients will be first weaned off sirolimus over at least a 2 – 6 
month period by halving the dose and/or increasing the dosing interval.   After sirolimus 
is weaned, patients will remain on belatacept monotherapy indefinitely.  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 5 of 93 
Statistical Analyses:  It is anticipated that an acute rejection rate prior to initiation of 
sirolimus withdrawal of up to 20% will exist, excluding up to four patients from 
eligibility for sirolimus withdrawal.  It also is anticipated that four additional patients will 
either not meet other criteria for withdrawal or will refuse to be withdrawn from 
immunosuppression.  The number of patients has therefore been chosen to have 
approximately 12 patients who are eligible for sirolimus withdrawal and in whom 
withdrawal is attempted, in order to establish a reasonable proof-of-concept. This target 
of 12 subjects in whom sirolimus withdrawal is attempted will allow for the detection 
approximately 6 subjects successfully withdrawn from sirolimus for one year, assuming 
the probability of a subject in whom withdrawal is attempted being successfully 
withdrawn from sirolimus for one year is 50%, a rate determined by the current cohort. 
Since there are no trials exploring monotherapy belatacept reported in the literature or 
registered with ClinicalTrials.gov, this cohort of patients withdrawn successfully will 
represent a significant finding. 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 6 of 93 
TABLE OF CONTENTS 
PROTOCOL TITLE PAGE .............................................................................................1 
SYNOPSIS ......................................................................................................................... 2 
TABLE OF CONTENTS ..................................................................................................6 
1 
INTRODUCTION ..........................................................................................9 
1.1 
Precis ................................................................................................................9 
1.2 
Background .....................................................................................................9 
1.3 
Summary Results of Belatacept Investigational Program ........................15 
1.3.1 
Preclinical Data .............................................................................................15 
1.3.2 
Clinical Pharmacology .................................................................................16 
1.3.3 
Phase 2 Study in Rheumatoid Arthritis………………….……............ .....16 
1.3.4 
Phase 2 Study in Solid Organ Transplantation .........................................17 
1.3.5 
Clinical Results of Ongoing Trial ................................................................17 
2 
STUDY OBJECTIVES ................................................................................19 
2.1 
Primary Objective ........................................................................................19 
2.2 
Secondary Objectives ...................................................................................20 
3 
STUDY DESIGN AND EVALUATION .....................................................20 
3.1 
Study Design ..................................................................................................20 
3.1.1 
Duration of Study .........................................................................................21 
3.2 
Study Population ...........................................................................................21 
3.3 
Criteria for Evaluation .................................................................................21 
3.4 
Sample Size Determination ..........................................................................21 
3.5 
Interim Analyses ...........................................................................................22 
4 
STATISTICAL METHODOLOGY ...........................................................22 
4.1 
Data Set Descriptions ...................................................................................22 
4.2 
Analyses .........................................................................................................22 
4.2.1 
Demographics and Baseline Characteristics ..............................................22 
4.2.2 
Efficacy Analyses ..........................................................................................22 
4.2.3 
Safety Analyses ..............................................................................................23 
5 
SUBJECT SELECTION CRITERIA .........................................................23 
5.1 
Inclusion Criteria ..........................................................................................23 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 7 of 93 
5.2 
Exclusion Criteria .........................................................................................23 
6 
STUDY THERAPY ......................................................................................25 
6.1 
Transplant-Specific Therapy .......................................................................25 
6.2 
Maintenance Immunosuppressive Reduction ............................................26 
6.3 
Treatment Administration ...........................................................................27 
6.3.1 
Dose Modifications ........................................................................................27 
6.4 
Discontinuation of Therapy .........................................................................28 
6.5 
Treatment Compliance .................................................................................28 
6.6 
Treatment of Rejection .................................................................................28 
6.7 
Prohibited and Restricted Therapies During the Study ...........................29 
6.8 
Withdrawal of Subjects from Study ...........................................................29 
6.9  
Stopping Rules………………………. .........................................................30 
7 
STUDY CONDUCT......................................................................................31 
7.1 
Ethics ..............................................................................................................31 
7.2 
Benefits ...........................................................................................................31 
7.3 
Costs ...............................................................................................................31 
7.4 
Risks and Discomforts ..................................................................................32 
7.5 
Risks for Women of Child Bearing Potential .............................................32 
7.6 
Immunosuppressive Therapy Specific Risks..............................................32 
7.7 
Treatment Failure .........................................................................................35 
7.8 
Phlebotomy ....................................................................................................35 
7.9 
Renal Biopsy ..................................................................................................35 
8 
STUDY OBSERVATIONS ..........................................................................38 
8.1 
Flow Charts/Time and Events Schedule .....................................................38 
9 
DETAILS OF THE RESEARCH PROCEDURES ...................................42 
9.1 
Pre transplant tissue acquisition .................................................................42 
9.2 
Post transplant monitoring ..........................................................................42 
9.3 
Specific Tests and Evaluations  ...................................................................43 
10 
INVESTIGATIONAL PRODUCT .............................................................44 
10.1  
Belatacept Preparation ................................................................................ 44 
10.2 
Other Agents .................................................................................................45 
11 
ADVERSE EVENT REPORTING .............................................................45 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 8 of 93 
11.1 
Importance of Adverse Event Reporting ....................................................45 
11.2 
Data Safety Monitoring Plan .......................................................................46 
11.3 
Collection of Safety Information .................................................................46 
11.4 
Overdose ........................................................................................................47 
11.5 
AE Follow-up ................................................................................................47 
11.6 
Reporting of AE Information Following Study Completion ....................48 
11.7 
Handling of Serious Adverse Events (SAEs) ..............................................48 
11.8 
Laboratory Test Abnormalities ...................................................................50 
11.9 
Other Safety Considerations ........................................................................50 
11.10 
Pregnancy ......................................................................................................50 
12 
ADMINISTRATIVE SECTION .................................................................51 
12.1 
Compliance with the Protocol and Protocol Revisions .............................51 
12.2 
Informed Consent .........................................................................................52 
12.3 
Informed Consent Procedures .....................................................................52 
12.4 
Subjects Unable to Give Informed Consent ...............................................53 
12.4.1 
Subjects Experiencing Acute Events or Emergencies ...............................53 
12.4.2 
Mentally Impaired or Incapacitated Subjects ...........................................53 
12.4.3 
Other Circumstances ....................................................................................53 
12.5 
Illiterate Subjects ..........................................................................................54 
12.6 
Update of Informed Consent .......................................................................54 
13 
RECORDS AND REPORTS .......................................................................54 
13.1 
Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) ......................................................................................................54 
13.2 
Records Retention .........................................................................................54 
14 
REFERENCES .............................................................................................55 
 
List of Appendices: 
 
APPENDIX A: 
Diagnosis of Graft Rejection 
APPENDIX B: 
Assays for the Determination of Alloreactivity 
APPENDIX C: 
Summary of Results of Belatacept Investigational Program  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 9 of 93 
1 
INTRODUCTION  
1.1 Précis 
Renal transplantation is the treatment of choice for most causes of end stage renal 
disease. However, current methods for transplantation rely upon the chronic use of 
immunosuppressive drugs to prevent immune rejection of the transplanted organ. These 
drugs are not completely effective such that many recipients eventually lose allograft 
function due to either acute or chronic rejection. They are also associated with metabolic, 
infectious and neoplastic side effects. Importantly, standard immunosuppressive 
approaches are also thought to inhibit adaptive immune processes promoting organ 
acceptance. 
This 
later 
effect 
makes 
transplant 
recipients 
dependent 
on 
immunosuppression for life. 
Recent clinical trials have shown that a patient’s dependence on chronic 
immunosuppression can be reduced by peri-transplant treatment with alemtuzumab, a 
monoclonal antibody that transiently depletes T-cells. Pre-clinical data have also 
indicated that, unlike conventional immunosuppressive therapy, drugs that inhibit T-cell 
costimulation, e.g. by interfering with the molecules CD80 and CD86, promote 
adaptation of the immune system such that immunosuppressive requirements diminish 
with time. In some animal models this has led to allograft tolerance, a condition in which 
a transplanted organ is accepted without the need for chronic immunosuppression and 
without recipient immuno-incompetence. This process has been shown in animal models 
to be facilitated by the mTOR inhibitor sirolimus, and to be aided by the infusion of 
donor blood or bone marrow. 
This study will combine lymphocyte depletion, mTOR inhibition, and costimulation 
blockade, in 20 renal allograft recipients of either living or live donor kidneys to 
determine whether together, these therapies will promote allograft acceptance. Peri-
transplant T-cell depletion induced by alemtuzumab will be used in combination with 
chronic therapy with sirolimus and belatacept a novel fusion protein specific for the 
costimulation molecules CD80 and CD86.  
All patients will be given a single dose of alemtuzumab on the day of transplantation. All 
patients will then be treated with belatacept and sirolimus for 1 year. Patients who remain 
rejection-free for 1 year and meet in vitro flow cytometric criteria indicating that their 
immune system has repopulated (Ki67 expression returns to baseline) will be gradually 
withdrawn from sirolimus, to determine if they can maintain a rejection-free state on 
belatacept monotherapy. In addition to clinical outcome, immune reconstitution 
following T-cell depletion and the development of donor-specific immune 
unresponsiveness will be evaluated. If successful, the trial will present an immediately 
applicable method for organ transplantation without dependence on chronic 
immunosuppressive drugs. 
1.2 Background 
 
 
Transplantation is the treatment of choice for most causes of end stage renal disease.4-6 
Approximately 17,600 patients undergo renal transplantation in the United States each 
year with one-year graft survival exceeding 92% and 96% for deceased donor and live 
donor transplants respectively.4 In 2009, the last year for which complete data are 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 10 of 93 
available, 144,180 recipients were being treated with a functioning kidney graft in the 
United States,4 making transplantation a significantly common condition, but meeting the 
FDA definition of an orphan indication per the Orphan Drug Act Amendment P.L. 98-
551, October 1984.47  
Although kidney transplantation provides superior renal replacement to dialysis in most 
cases, all renal allografts succumb to rejection without some modification of the 
recipient’s immune system. To prevent this, patients must take immunosuppressive drugs 
for life.4,7,8 In general, these drugs target some aspect of T cell activation, as T cells are 
the principal protagonists in cellular allograft rejection. A significant amount of allograft 
rejection, particularly that occurring late after transplantation, is attributable to the effects 
of B-cell mediated alloantibody production.48-50 However, alloantibody production is also 
generally considered to be T cell dependent, relying upon the effects of T cell help. Thus, 
effective control of allospecific T cells generally prevents both antibody and cellular 
mechanisms of allograft destruction.51 Indeed, a substantial cause of graft loss is 
attributable to late antibody mediated rejection driven by non-adherence with T cell-
specific drugs.52 Typical maintenance immunosuppressive regimens include a 
combination of steroids, a CNI, (cyclosprine A or tacrolimus) and/or an antiproliferative 
agent (azathioprine, MMF or sirolimus).4,7,8,58 A trend toward decreased steroid use has 
emerged in the past 5 years with approximately 30% of centers avoiding or weaning 
steroids during the first year post transplant aiming to reduce the morbidity of steroid use, 
but accepting an incremental risk of rejection.4,7  
In an effort to reduce the need for maintenance immunosuppression, over 80% of North 
American transplant centers now employ induction therapy59 with a brief course of an 
anti-T cell antibody preparation (daclizumab, basiliximab, alemtuzumab or rabbit anti-
thymocyte globulin, RATG). Indeed, most centers (58%) opt for T cell depletion with 
RATG or alemtuzumab,4,7 driven by evidence suggesting this better reduces the need for 
subsequent maintenance therapy. One induction agent that is gaining attention is 
alemtuzumab.32,33 Alemtuzumab is a CD52-specific humanized MAb indicated for the 
treatment of some lymphogenous malignancies and has been increasingly used off-label 
in transplant indications.4,7 Its advantages include a singular target (CD52) and 
monoclonal composition, both of which greatly reduce the batch-to-batch variation and 
side effects seen with polyclonal RATG. However, its use has been limited by challenges 
typical of the orphan drug status of transplantation, in that companies have opted for 
development in more profitable indications despite considerable evidence of its 
effectiveness in transplantation.60 
Historically, CNIs have emerged as the centerpiece drug of most maintenance 
immunosuppressive regimens. In the US, the predominant CNI is tacrolimus, and it is 
typically paired with MMF and steroids.4 CNIs inhibit T cell receptor (TCR) signaling in 
naïve, memory and effector T cells, and T cell dependent B-cell help through inhibition 
of calcineurin-calmodulin-dependent pathways,61-64 thereby inhibiting allograft rejection. 
CNI-based regimens are by far the most common in clinical transplantation, being used in 
over 94% of patients through 2009.4 However, CNIs also prevent viral immunity65,66 and 
impair adaptation to persistent antigens such that even after prolonged rejection-free 
survival of an allograft, removal of a CNI precipitates rejection.25,67-70  
CNI-based immunosuppression effectively prevents rejection, but its use tempers the 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 11 of 93 
substantial benefit obtained from transplantation.9-21,61-66 CNIs must be administered daily 
and are expensive, costing over $17,000 per patient per year.71-73 Both of these factors 
impair patient adherence. More importantly, they increase the risk of opportunistic 
infection and malignancy, and have many non-immune side effects that hamper their 
tolerability. Specifically, CNIs are nephrotoxic and induce secondary renal failure in up 
to 20% of chronic users, even those whose transplant is extra-renal.74 In most centers, 
CNIs continue to be paired with steroids.4,7 Steroids exacerbate osteoporosis and 
hyperlipidemia, and cause avascular osteonecrosis. Both classes of agent worsen glucose 
tolerance and hypertension and are associated with cosmetic effects fostering substantial 
non-adherence with prescribed therapies. Indeed, the long-term complications from anti-
rejection therapies become increasingly apparent over time, such that the use of 
secondary medications, such as antihypertensives, lipid lowering agents, and therapies to 
counteract advanced osteoporosis, are common. Importantly, with advances in 
immunosuppression counterbalanced by increased immunosuppressive morbidity, the 
cost effectiveness of additive maintenance immunosuppression has reached a point of 
diminished cost-effectiveness.73 As such, methods of transplantation that lessen the 
dependence on and side effects of maintenance immunosuppression stand to reduce the 
risk and expense of transplantation.   
Belatacept is a new alternative to CNI-based maintenance therapy. Belatacept is a B7-
specific fusion protein that mediates CD28-B7 costimulation blockade (CoB).34-41 Naïve 
T cells require CD28 costimulation in addition to TCR signaling to optimally activate; 
failure to receive costimulation at the time of TCR signaling not only inhibits activation, 
but also promotes antigen-specific cell anergy and/or apoptosis.22-24,34,75-78 This attenuates 
cells undergoing initial antigen engagement, but does not affect cells that are not engaged 
with antigen or those that have already been activated and moved beyond the requirement 
for costimulation. Thus, CoB has the potential to more selectively and more permanently 
influence allospecific T cells compared to CNIs. Furthermore, its precise targeting of 
costimulatory pathways avoids many of the off-target side effects associated with CNIs, 
MMF and steroids.36-41 Unfortunately, belatacept appears less able to prevent early acute 
rejection than CNIs when used as indicated: in combination with basiliximab, steroids 
and MMF.36-41 The mechanisms of this are only now becoming understood, and indeed, 
we have been actively engaged in the science of what as been termed CoB resistant 
rejection (CoBRR).79-83 It is clear that patients for whom belatacept maintenance therapy 
is effective have a significantly reduced incidence of off-target side effects, particularly 
those generally associated with prolonged CNI use: nephrotoxicity, hypertension, 
hyperlipidemia and new onset type 2 diabetes.36-41 Accordingly, belatacept has recently 
(June, 2011) been approved by the FDA as a CNI replacement. However, belatacept’s 
optimal use remains undefined. Its patients remain encumbered with the side effects of 
adjuvant agents, and accept a higher risk of rejection compared to CNI-treated patients. 
Depletional induction approaches have been shown to reduce the risk of early rejection 
post-transplant, and perhaps to reduce the needs for maintenance immunosuppression. 
Most notably, T cell depletion with alemtuzumab has been shown in several phase 2 
clinical trials to allow for transplantation using only a single immunosuppressive agent.26-
33 Specifically, studies by Calne, Knechtle, Starzl and our group have demonstrated that 
kidney transplantation can be performed in selected patients using alemtuzumab at the 
time of transplantation, followed by monotherapy with CsA, sirolimus, or tacrolimus, 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 12 of 93 
with 1, 3 and 5 year survival rates statistically equivalent to more conventional 
approaches reported in registry data. Acceptable results also have been obtained using 
polyclonal T cell depleting agents such as rabbit anti-thymocyte globulin in combination 
with monotherapy sirolimus, albeit with more side effects related to the RATG.84 Over 
the past 4 years, additional trials have emerged indicating the general efficacy, ease of 
use and tolerability or alemtuzumab-based regimens.85 Unfortunately, no development 
plans in transplantation have emerged, given the limited number of patients served and 
the remarkably low dose (generally a single dose) required in this indication. However, 
despite the ability of depletion to facilitate markedly reduced maintenance 
immunosuppression, it is clear that T cell depletion alone is not sufficient to induce 
tolerance, as patients treated with alemtuzumab alone, or who have stopped taking their 
maintenance therapy following depletion have uniformly experienced acute, albeit 
reversible, allograft rejection.27 Thus, while T cell depletion reduces immunosuppressive 
requirements, additional therapies are necessary to induce lasting graft acceptance 
without the need for immunosuppressive therapy, or allograft tolerance. 
Depletional induction approaches have been investigated and moved into the mainstream 
over the same time period as CoB;4 however, the development paths of depletional agents 
and CoB have been parallel, not complementary. The clinical trial sponsored in the first 
funding cycle of this grant has been the first to pair belatacept with alemtuzumab. An 
additional trial has paired belatacept with RATG.86 As discussed in the Preliminary 
Studies, both trials have demonstrated that depletional induction plus belatacept is well 
tolerated and efficacious, and made it apparent that an approach that takes advantage of 
the long-term benefits of a CoB-based maintenance regimen can be gained without 
increased early rejection.1,86 More importantly, we have now shown that many patients 
treated with a combined depletional/CoB therapy have diminishing donor-directed 
alloimmune responses over time. As such, we have been able to successfully reduce the 
immunosuppressive burden in many patients, avoiding CNIs and steroids from the outset, 
and eventually arriving at a maintenance regimen that consists solely of a once monthly 
dose of belatacept. These data (described below) are the first in man to systematically 
pair readily available agents and arrive upon a simple induction and maintenance regimen 
that prevents rejection (cellular and antibody medicated), avoids use of both CNIs and 
steroids, and delivers many patients to a regimen based solely on CoB. Importantly, our 
initial data suggest that the trajectory for these patients is towards lessening 
immunosuppressive requirements. Indeed, we have developed a means of assessing this 
process (see below) and now propose to incorporate this into the gradual move away 
from systemic immunosuppression.  
The biology of CoB-based immune adaptation to an existing allograft has been 
extensively studied in animal models of transplantation, but is yet to be translated into 
humans. Pre-clinical work has shown that interruption of the interaction between CD28 
and its ligands at the time of antigen exposure can prevent allograft rejection and that 
continued exposure to antigen in the presence of CoB facilitates a gradual, donor-specific 
elimination of allospecific T cells.22-24,34,75-78 Several groups, including our own, have 
shown in rigorous non-human primate transplant models that CoB can prevent rejection 
for months to years after the withdrawal of all medications.35,87-89 The durability of this 
effect depends in large part upon the precursor frequency and general activation state of 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 13 of 93 
the recipient T cell repertoire, and is synergized by mTOR inhibitors and antagonized by 
CNIs.22,23,80,82,90 In general, CoB’s influence on the immune response makes it likely to 
be most effective as a protracted therapy. Importantly, CoB is not effective in the absence 
of donor antigen.91 How mTOR inhibitors accelerate the reduction in allospecific T cells 
when used with CoB remains unproven. However, a likely mechanism relates to 
inhibition of cell maturation in the presence of donor antigen that induces impaired T cell 
activation leading to apoptosis.22-24 Stimulated cells exposed to antigen but 
simultaneously deprived of costimulation or cytokines that signal through the mTOR 
pathway typically undergo apoptosis. Over time, donor cell mediated AICD eliminates 
donor specific recipient effector T cells while leaving most of the non-allospecific T cell 
repertoire intact. In the first round of this trial, we have for the first time rigorously 
investigated the requirements regarding the source and amount of donor antigen; 
prospectively testing whether donor bone marrow is a mandatory requirement for this 
effect to occur in humans. As discussed below, we find that the allograft itself appears to 
be a sufficient source of donor antigen to mediate the desired effects. This novel finding, 
derived from the only randomized assessment of this effect as it relates to CoB in 
humans, greatly simplifies the logistical challenges to implementation of the proposed 
regimen, and eliminates the theoretical concerns regarding bone marrow induced GVHD. 
This trial, forged upon the prevailing concepts shaping our understanding of 
alloimmunity, will continue to build upon the promising clinical results obtained during 
the first funding cycle of this grant, use mechanistic insights gleaned from the study of 
existing patients, and test a refined and more generalizable form of this therapeutic 
approach to transplantation. It will continue the clinical and mechanistic follow-up of the 
first 20 patients enrolled in the study, implement the study of a second cohort of patients 
that includes broader inclusion criteria (a critical factor when considering the design of a 
adequately powered registration trial), and prospectively test a rational and biologically 
based means of guiding immunosuppressive reduction, ending in a reproducible approach 
to maintain kidney transplant recipients on a once monthly CoB-based monotherapy 
maintenance regimen, that progressively eliminates the risk of rejection and late DSA 
formation, and avoids the prevailing off-target side effects plaguing the field today. The 
resulting approach will be 1) feasible, based solely on available agents; 2) cost effective, 
eliminating drug burden with time; and 3) safer than chronic immunosuppressive drug 
exposure or induction regimens paired with rapid, empiric drug withdrawal.   
Each agent in this regimen has been chosen for its specific properties and mechanism of 
action. 
Alemtuzumab is a humanized MAb specific for CD52 with demonstrated consistent and 
reproducible lymphocyte depleting properties.32,33 CD52 is a 12-amino acid 
glycosylphosphatidylinositol (GPI) anchored glycoprotein with several characteristics 
promoting its use as a therapeutic target.92 It is a high-density molecule on T cells, B 
cells, monocytes and macrophages, but is absent on lymphoid progenitors. This facilitates 
effective but transient depletion of mature lymphocytes without myeloablation. CD52 is 
not internalized or modulated upon cross-linking and is thus a consistent target. 
Alemtuzumab recognizes the C-terminal peptide and a portion of the GPI anchor, a site in 
close proximity to the cell surface. This promotes efficient complement deposition and 
membrane attack complex formation for prompt cell lysis.93 In addition to complement-


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 14 of 93 
mediated cytotoxicity, alemtuzumab also is thought to support antibody-dependent 
cellular cytotoxicity by virtue of its IgG Fc region.94 Recent reports suggest that 
alemtuzumab may enhance lymphocyte apoptosis in vitro in the absence of complement 
or immune effector cells, leading to cell death through a non-classical caspase-
independent pathway.95 Alemtuzumab also may trigger caspase-dependent cell death.94 
Thus, alemtuzumab facilitates target cell depletion through multiple redundant 
mechanisms and this redundancy is likely a factor in its consistent clinical depleting 
effect. Its use markedly reduces the risk of early acute rejection following kidney 
transplantation.85 
Alemtuzumab is approved by the FDA for the treatment of B-cell chronic lymphocytic 
leukemia (CLL) in patients who have been treated with alkylating agents and who have 
failed fludarabine therapy.96 It also has been increasingly used for the prevention of 
kidney transplant rejection, and now is used off-label for this purpose in approximately 
7% of kidney transplant recipients in the United States.4 Alemtuzumab is well tolerated, 
particularly in the low doses planned for this trial, and in contrast to other depleting 
agents derived from mouse or rabbit sources, does not induce serum sickness or a anti-
xenogeneic protein immune response. It does not require a central line for infusion, and it 
provides rapid (<1 hour), reproducible, and gradually reversible T cell depletion in 
humans.27,28 It has been used specifically in monotherapy combination with sirolimus. It 
also has been shown to have a reduced risk of post transplant lymphoproliferative disease 
PTLD) compared to other induction strategies.97  
Sirolimus is an oral immunosuppressive agent that is approved by the FDA for the 
prophylaxis of organ rejection in patients aged 13 years or older receiving renal 
transplants.98 Phase 2 studies by the PI and others have shown that it provides sufficient 
immunosuppression in selected patients following induction with a T cell depleting 
agent.27,28,84 Unlike CNIs, sirolimus does not block T cell receptor signaling and as such, 
it does not impair the antigen signals required to mediate the salutary antigen-specific 
effects of CoB.22,23,99,100 Specifically, it does not prevent allospecific AICD.22 
Experimentally in primates, sirolimus facilitates progressive donor-specific adaptation 
particularly when used with CoB.90,101  
Belatacept is a newly approved inhibitor of T cell costimulation with superior binding 
affinity compared to other B7 specific agents.35 It has been well tolerated in the trials to 
date and importantly it, and related compounds, have been suggested in preclinical 
studies to synergize with sirolimus to promote AICD and tolerance.90,101,102 It is approved 
for the prevention of renal allograft rejection in EBV-seropositive individuals when used 
in combination with the steroids and MMF.   
This study addresses a specific need for the transplantation community and is created in 
the spirit of the Orphan Drug Act of 1983.47 Given the relatively low number of 
transplants performed annually, and the low dose of alemtuzumab required to achieve a 
therapeutic effect relative to that required for its indication, CLL, there is no economic 
incentive for a registration trial in organ transplantation. Similarly, regimens involving 
sirolimus, belatacept or other maintenance immunosuppressive drugs are typically 
developed for long-term use; there is little incentive for commercial development of 
regimens that are specifically designed to eliminate long-term drug use, and as such, no 
reasonable expectation of development without assistance. Nevertheless, all agents for 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 15 of 93 
this study are available, and are approved products available for off-label use.  
 
1.3 Summary of Results of Belatacept Investigational Program 
Given belatacept was an investigational agent when the first version of this trial began, 
comprehensive information regarding its use to date is provided in Appendix C.  A 
summary of this information is provided, in brief, below.   
1.3.1 Preclinical Data 
Both belatacept and its parent molecule CTLA4-Ig have been studied extensively in vitro 
and in non-human primates by the PI and others including Emory transplant 
investigators. A comprehensive list of the pertinent findings from pre-clinical studies is 
available in Appendix C and in the IB. These data are summarized below. 
Pre-Clinical Safety 
Although belatacept has increased binding affinity for B7 molecules in primates and 
humans compared to CTLA4Ig, the binding affinity for murine CD80 and CD86 is lower. 
Since CTLA4Ig binds more avidly than does belatacept in mice and it is very similar to 
belatacept in both its mechanism of action and its structure, CTLA4Ig is considered an 
acceptable homologue for belatacept for rodent toxicology assessments to support 
registration requirements. CTLA4Ig was not found to be mutagenic or clastogenic in 
mice but was shown to increase the risk of virally driven malignancies consistent with its 
known immunosuppressive properties.  
Non-clinical safety assessments of belatacept were performed in cynomolgus monkeys 
and showed that it was well tolerated when given intravenously to monkeys at doses up 
to 50 mg/kg every other day for 1 month (15 doses) or once weekly for 6 months. 
Belatacept was not found to be mutagenic or clastogenic in cynomolgus monkeys. The 
major non-clinical findings in monkeys with belatacept were reversible, related to the 
pharmacology of the drug, and consisted of minimal decreases in serum IgG levels and 
minimal-to-moderate lymphoid depletion of germinal centers in the spleen and/or lymph 
nodes at all dose levels. There were no solid or lymphoid malignancies noted in the 6 
month toxicity study with belatacept or in a 1 year toxicity study with CTLA4-Ig. 
Additional pertinent findings are summarized in Appendix C; a more thorough 
description of these studies is available in the IB. 
Pre-Clinical Efficacy 
Belatacept shows greater binding avidity than its parent molecule CTLA4Ig for human 
CD80 and CD86.  It is approximately 10-fold more effective in vitro on a per-dose basis 
than CTLA4Ig at inhibiting T-cell proliferation, T-cell cytokine production, and 
CD28-dependent killing of target cells by natural killer-like cells.  In an in vivo primate 
immune response model, belatacept potently blocked a primary antibody response against 
sheep red blood cells. At equivalent doses, belatacept was 3- to 11-fold more potent (by 
ID90) than CTLA4Ig at blocking specific humoral responses. 
Belatacept was found to be efficacious for the prevention of graft rejection in a 
cynomolgus monkey model of renal transplantation.37  Belatacept monotherapy was 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 16 of 93 
superior to a regimen of CsA + corticosteroids in the prolongation of graft survival in this 
stringent model.  A regimen of belatacept + MMF + corticosteroids and a regimen of 
belatacept + basiliximab prolonged graft survival superior to belatacept monotherapy as 
well as that historically observed in monkeys treated with CsA + corticosteroids.  
Analysis of pharmacokinetic (PK) data in monkeys suggested a relationship between 
trough serum drug concentrations and immunosuppressive efficacy. Additional pertinent 
findings are summarized in Appendix C; a more thorough description of these studies is 
available in the IB.  
1.3.2 Clinical Pharmacology 
Single-dose Phase 1 studies with belatacept were performed in 40 healthy volunteers 
using doses ranging from 0.1 to 20 mg/kg. No deaths or serious adverse events (SAEs) 
were reported. All reported clinical AEs were of mild or moderate intensity. No 
histamine-like peri-infusional AEs were reported. There was no evidence for the 
development of anti-belatacept antibodies. Belatacept kinetics were found to be dose-
proportional between 1 and 20 mg/kg. The half-life was adequately characterized 
between the 5 and 20 mg/kg dose levels, and ranged between 176 – 210 hours (7-9 days). 
The steady-state volume of distribution (VSS) values were small, indicating that the drug 
(with high molecular weight) was confined mainly in the plasma and extracellular space. 
Overall, the PK of belatacept appears to be linear following i.v. administration in healthy 
subjects. Additional pertinent findings are summarized in Appendix C; a more thorough 
description of these studies is available in the IB. 
1.3.3 Phase 2 Study in Rheumatoid Arthritis 
Study IM103002 was a Phase 2 pilot study that assessed the efficacy, safety, and 
immunogenicity of multiple i.v. doses of belatacept, CTLA4Ig, and placebo in 
214 subjects with RA. Eligible subjects had a diagnosis of RA for ≤ 7 years had failed at 
least 1 disease-modifying anti-rheumatic drug therapy, including etanercept, and had 
active disease (≥ 10 swollen joints, ≥ 12 tender joints, an erythrocyte sedimentation rate 
≥ 28 mm/h, and morning stiffness ≥ 45 minutes). Overall, belatacept demonstrated 
dose-dependent efficacy in this subject population, as evidenced by American College of 
Rheumatology scores. With respect to safety, no deaths were reported during the 
treatment or follow-up period (through Day 169), and no SAEs were considered drug 
related by the investigators. 
1.3.4 Phase 2 Study in Solid Organ Transplantation 
Study IM103100 was a 1-year, partially-blinded, randomized, active-controlled, multiple-
dose, multicenter (including Emory) non-inferiority study in de novo renal transplant 
recipients.36 All subjects received basiliximab induction and background maintenance 
immunosuppression with MMF and corticosteroids. Subjects were randomized in a 1:1:1 
ratio to treatment with belatacept (more intensive [MI] or less intensive [LI] regimens) or 
CsA. Belatacept was administered in a double-blind fashion, with the investigator and 
subject blinded to the identity of the belatacept dose regimen. The MI regimen most 
closely approximates that proposed in this trial. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 17 of 93 
The dosing schedule, evaluation criteria, and efficacy results for Study IM103100 study 
are presented in Appendix C.  Overall, the mean duration of exposure was comparable 
across all 3 treatment groups. Specifically, mean duration of exposure was 300, 308, and 
294 days in the belatacept MI and LI groups and the CsA group, respectively. The overall 
histological severity grade of acute rejection episodes and the average number of 
rejection episodes per subject appeared to be similar across the 3 treatment groups.  By 
month 12, chronic allograft nephropathy (CAN) was approximately 30%-50% less 
common with belatacept that with CsA.  Death and/or graft loss occurred infrequently in 
all treatment groups, and was least frequently reported in the belatacept LI group.  Most 
graft losses occurred for technical, rather than immunological reasons.  With respect to 
safety, the rate of AEs, including AEs resulting in discontinuation, was similar across the 
3 treatment groups. The rate of SAEs was somewhat higher for both belatacept treatment 
groups than for the CsA treatment group. As described in Appendix C, this difference is 
due to an increased number of reports of AEs of transplant rejection that were not 
subsequently confirmed as transplant rejection, in the belatacept treatment groups. 
Topics of special interest, including the assessment of renal function, cardiovascular and 
metabolic effects, and an exploratory analysis in an extended criteria donor population or 
in subjects with impairment of renal function post-transplant, is presented in Appendix C.   
1.3.5 Clinical Results from the Ongoing Trial. 
In keeping with the study plan proposed in the initial funding cycle, we have conducted 
and preliminarily reported1 a prospective, randomized trial to determine whether a single 
dose of alemtuzumab permits patients to avoid both CNIs and steroids, and instead be 
transplanted on a belatacept/sirolimus-based regimen. The trial was designed to offer 
patients the opportunity to wean from sirolimus at 1 year, and if stable, consider weaning 
off all immunosuppression thereafter. Randomization occurred with regard to whether 
patients received a single dose of unfractionated donor bone marrow (108 nucleated 
cells/kg) on day 7. Enrollment was completed, with 20 participants participating. All 
were non-sensitized (crossmatch negative, PRA<20%) recipients of live donor kidneys 
enrolled in an IRB-approved (IRB# 5064), prospectively registered (ClinicalTrials.gov 
Identifier: NCT00565773) trial. Induction immunosuppression consisted of intraoperative 
alemtuzumab (30mg IV), with three daily doses of methylprednisolone (500mg) followed 
by steroid elimination on day 3. All patients received and tolerated the intended induction 
dose. Maintenance immunosuppression consisted of belatacept (10mg/kg IV on days 1, 3, 
7, 14, q2w x 4, q month x 3, 5mg/kg monthly) and sirolimus (adjusted to trough levels of 
8-12ng/ml x 6 months, then 5-8ng/ml). All patients tolerated belatacept. Four patients 
developed arthalgias, edema or mouth ulcers requiring conversion from sirolimus to 
MMF.  
Twenty patients (median 45 years, range 20-69; 12 male:8 female, 16 Caucasian:4 
African American, all EBV seropositive) have been transplanted. In general, 
alemtuzumab induction followed by a belatacept-based maintenance regimen has been 
well tolerated and prevented rejection. With a mean follow-up of >700 days (102-1345 
days), all patients have excellent graft function Mean creatinine in mg/dl (range; n having 
reached that time point) at 6, 12 and 24 months is 1.1 (0.7-1.9; n=19), 1.1 (0.9-1.9; n=19) 
and 1.2 (0.6-1.8; n=11) respectively. No patient was chimeric after bone marrow 
infusion, and there have been no differences in outcome attributable to the infusion 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 18 of 93 
(discussed below). There have been no malignancies, significant infectious illnesses, nor 
CMV viremia or disease (see discussion below regarding preservation of protective 
immunity). Asymptomatic BK viremia has been detected in nine patients and in all cases 
this responded to reductions in sirolimus and/or reduced belatacept dosing. Transient, low 
level, clinically insignificant EBV viremia was detected in four patients. One patient has 
developed recurrent IgA nephropathy without a significant change in renal function. One 
patient has developed ulcerative colitis.  
Twelve patients have elected to wean to monotherapy belatacept; of these, five have been 
successfully weaned from sirolimus and maintained from 3 to 15 months on monotherapy 
belatacept. Three patients failed sirolimus weaning. Two of these patients had subclinical 
rejection detected on protocol biopsy after sirolimus weaning and by protocol received a 
oral prednisone taper and were returned to belatacept/sirolimus maintenance. Follow-up 
biopsy at 3 months confirmed resolution of sub-clinical rejection in both cases. One 
patient developed a new DSA after being weaned from sirolimus without renal 
dysfunction or biopsy findings. The patient received a single dose of IVIg (2 grams/kg), 
and was returned to sirolimus/belatacept therapy. The DSA is currently undetectable. 
Five patients are in the process of sirolimus weaning. This includes two patients deemed 
ineligible for weaning due to recurrent IgA nephropathy or ulcerative colitis. Seven 
patients have declined weaning, opting rather to continue the well tolerated belatacept 
and low dose sirolimus indefinitely. One patient is less than 1 year post transplant, and 
thus has not reached a point where weaning is offered. These preliminary data suggest 
that a subset of selected patients can be maintained on monotherapy belatacept. Indeed, 
we have mechanistic data, discussed below, that form the basis of a specific testable 
hypothesis addressing patients’ individual capacities to wean to monotherapy belatacept, 
and the optimal timing to do so. These data will serve as a major theme of the 
continuation of this protocol. 
Two patients were weaned from all immunosuppression after successful elimination of 
sirolimus for over 6 months and re-consenting to the weaning process. Remarkably, both 
patients remained rejection free off all immunosuppressive medication for 4 and 7 
months, respectively. One patient developed an asymptomatic DSA at 4 months. A 
biopsy showed no rejection. She was returned to belatacept maintenance and treated with 
a single dose of IVIg (2 grams/kg). The DSA resolved and she remains well >1 year after 
this event with normal graft function equivalent to her baseline serum creatinine of 
0.7mg/dl. The other patient developed a DSA and a concomitant clinical mixed T cell 
mediated rejection (TCMR) and antibody-mediated rejection (ABMR) 7 months after 
withdrawal of all immunosuppression. The patient was treated with RATG, 
plasmapheresis and IVIg, resolved the rejection and was, by protocol, returned to a 
standard CNI based immunosuppressive regimen. He remains stable on tacrolimus, MMF 
and prednisone with a serum creatinine of 1.5 mg/dl (baseline creatinine off all 
medication was 1.3mg/dl) over 1 year after this rejection event. From these data, we 
conclude that although patients can be weaned from immunosuppression for significant 
periods of time, that the state of tolerance in insufficiently durable, at least at this 
relatively early time point, to avoid alloimmunity. Interestingly, both DSA events 
occurred immediately following a viral upper respiratory infection, suggesting that they 
were evoked as a heterologous response to an environmental pathogen. Regardless, this 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 19 of 93 
indicates to us that complete immunosuppressive weaning offers an unacceptable risk and 
we have accordingly altered our protocol to eliminate this as an explicit goal of the trial. 
It is important to point out that our approach in this situation is substantially different 
from that taken by the investigators of a recently reported tolerance trial.2,109-111 In this 
trial performed at the Massachusetts General Hospital (MGH), several patients have been 
weaned from all immunosuppression. However, ABMR led to graft loss in 2 of 10 
patients, and DSA formed in several other patients that have been followed expectantly. 
Endothelial injury has been observed in many patients. From a statistical standpoint, it is 
not clear if the results from our regimen differ from those of this trial, as we have not 
pressed forward aggressively to continue pursing a drug-free state in the face of an 
asymptomatic DSA. We have viewed the appearance of DSA as an unacceptable risk for 
late graft loss that should be avoided, and opted not to consider immunosuppression 
elimination without some evidence that monotherapy belatatcept has some risk. We 
reason that the ultimate goal is graft function without side effects, and that risking graft 
loss in pursuit of an immunosuppressive-free state without evident benefit over a state 
maintained with a once monthly CoB-based regimen imposes risk without compensatory 
benefit. Particularly in the absence of a clear metric identifying patients at risk for ABMR 
and graft loss, we view complete drug withdrawal to be unsupportable at this time. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
This study will determine whether T-cell depletion followed by belatacept and daily 
maintenance therapy with sirolimus will permit recipients of renal allografts to avoid 
rejection and eventually be weaned to belatacept monotherapy maintenance 
immunosuppression. The primary endpoint will be the number of patients successfully 
withdrawn from sirolimus for 1 year after their last dose of sirolimus.“Successfully 
withdrawn” will be defined as a patient off sirolimus without clinical or biopsy evidence 
of rejection.   
2.2 
Secondary Objectives 
1. Determination of the prognostic ability of assays based on surface phenotype 
changes seen during homeostatic repopulation, including Ki67 expression, TREG and 
BTRANS cell surface phenotypes, and TM to TREG/BTRANS balance, with regard to the 
anticipation of successful immunosuppressive drug withdrawal. 
2. Assessment of the proposed therapies to prevent biopsy proven acute rejection at 1, 
3 and 5 years post-transplant compared to the standard reported in the SRTR 
database for similar patients; 
3. Assessment of the incidence of biopsy proven chronic allograft nephropathy at 1, 3 
and 5 years post-transplant compared to that reported in the SRTR database for 
similar patients; 
4. Assessment of the composite of occurrence of malignancies, and opportunistic 
infections by 1, 3 and 5 years compared to that reported in the SRTR database for 
similar patients; 
5. Long term assessment of donor-specific immune responsiveness after prolonged 
therapy with belatacept (with or without sirolimus), and during and following drug 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 20 of 93 
withdrawal as determined by in vitro alloresponsiveness in CFSE mixed 
lymphocyte reactivity and ICCS; 
6. Characterization of the repopulating immune system with regard to cell surface 
phenotype using MFC compared to prior experience with alemtuzumab alone or 
combined with other related regimens; and, 
7. Comparison of the function and survival of allografts transplanted using this 
protocol to historical controls transplanted using conventional immunosuppression 
to establish an initial assessment of this approach in a general transplant population. 
3 
STUDY DESIGN AND EVALUATION 
3.1 
Study Design  
This will be a single-center, open-label, non-randomized, proof-of-concept study in 
recipients of living or deceased donor renal transplants (DDRTs). Twenty renal transplant 
patients will be enrolled, at least 10 of which will be recipients of DDRTs. At the time of 
transplantation, participants will be given alemtuzumab, 30mg intravenously over three 
hours.  Participants will receive combination maintenance therapy with sirolimus and 
belatacept for at least one year. Patients’ absolute lymphocyte counts (ALCs) and percent 
expression T cell of Ki67 will be assessed monthly. After one year of therapy, 
participants may consent to and begin sirolimus withdrawal or continue therapy through 
study close. Patients wishing to withdraw from sirolimus will begin sirolimus weaning 
when their ALC has reached at least 80% of baseline and had two consecutive monthly 
assessments of their percent expression of Ki67 fall within at least one standard deviation 
of the Ki67 expression of a healthy control population. Weaning will be triggered of the 
Ki67 expression, with other surface phenotype assessments being followed 
observationally. Patients meeting these parameters will be weaned off of sirolimus by 
halving the dose and/or increasing the dosing interval over at least a three-month period. 
Each dose reduction will require stable (within 1 standard deviation) peripheral Ki67 
expression. After sirolimus is discontinued, patients will remain on belatacept 
monotherapy indefinitely. Clinical and mechanistic observation will continue for the 
duration of the study to assess the efficacy and safety of this approach. Subjects will be 
followed for at least five years. 
Duration of Study 
Subjects will be followed for at least five years. Belatacept is now approved by the FDA. 
Therefore, subjects remaining on belatacept at the conclusion of their five-year 
participation would be eligible to continue this therapy. If at the conclusion of this study 
belatacept is not commercially available to patients, the Principal Investigator will 
discuss other treatment options utilizing approved immunosuppressive therapies with the 
subject. If subjects are successfully weaned from sirolimus as a result of their 
participation in this protocol, there will be no need for consideration of alternative 
therapy. 
3.2 
Study Population 
Adult, EBV seropositive patients who do not have evidence of DSA pretransplant and 
who are scheduled to receive a kidney transplant at Emory University. Candidacy for 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 21 of 93 
transplantation will be determined using the standard methods of evaluation active at 
Emory during the study period.  
 
3.3 
Criteria for Evaluation 
1. Number of patients successfully withdrawn from sirolimus for 12 months after last 
dose of sirolimus  
2. Biopsy proven acute rejection or chronic allograft nephropathy by 1, 3 and 5 years 
3. Evidence of donor-specific hyporesponsiveness by MLR and ICCS 
4. Evidence of regulatory T cell and transitional B cell activity in the periphery and 
allograft 
5. Donor specific and third party alloantibody formation 
3.4 
Sample Size Determination 
Our prior experience with alemtuzumab, belatacept and sirolimus, in recipients of live 
donor kidneys suggests that this regimen is very effective in preventing acute rejection, 
with only one steroid sensitive, clinical rejection episode seen in the first year. However, 
with the liberalization of the inclusion criteria, it is anticipated that an acute rejection rate 
prior to initiation of sirolimus withdrawal of up to 20% will exist, excluding up to four 
patients from eligibility for sirolimus withdrawal.  It also is anticipated that four 
additional patients will either not meet other criteria for withdrawal or will refuse to be 
withdrawn from immunosuppression.  The number of patients has therefore been chosen 
to have approximately 12 patients who are eligible for sirolimus withdrawal and in whom 
withdrawal is attempted, in order to establish a reasonable proof-of-concept. This target 
of 12 subjects in whom sirolimus withdrawal is attempted will allow for the detection 
approximately 6 subjects successfully withdrawn from sirolimus for one year, assuming 
the probability of a subject in whom withdrawal is attempted being successfully 
withdrawn from sirolimus for one year is 50%, a rate determined by the current cohort. 
Since there are no trials exploring monotherapy belatacept reported in the literature or 
registered with ClinicalTrials.gov, this cohort of patients withdrawn successfully will 
represent a significant finding. 
3.5 
Interim Analyses 
No interim analysis is planned. 
4 
STATISTICAL METHODOLOGY 
4.1 
Data Set Descriptions 
A summary of all patient data will be kept in a study database developed for this study. In 
addition to the experimental data, this database will include recipient and donor 
demographics and transplant relevant medical history (comorbidities, HLA type, etc.), 
graft function, immunosuppressive medications and levels, and a running summary of the 
patient’s post transplant course. Data will be recorded and reported in accordance with 
the standards required by the United Network for Organ Sharing (UNOS). The data set 
will consist of all patients who are randomized and transplanted and will be used for all 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 22 of 93 
efficacy analyses.  The as-treated data set will consist of all patients who receive at least 
one dose of belatacept and will be used for all safety analyses.  Subgroup analyses will be 
performed for selected endpoints in subjects whom withdrawal was attempted and not 
attempted in order to provide supporting information to the main analyses. Demographic 
and baseline characteristics of patients will be summarized descriptively by treatment 
group, by means and standard deviations (SDs) for continuous variables and frequency 
distribution for categorical variables. Summaries will be performed based on the data set. 
4.2 
Analyses 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics of patients will be summarized descriptively by 
treatment group, by means and standard deviations (SDs) for continuous variables and 
frequency distribution for categorical variables. Summaries will be performed based on 
the data set. 
 
Efficacy Analyses 
No formal statistical hypothesis testing will be performed for the primary endpoint.  All 
efficacy analyses will generally be descriptive in nature. The primary efficacy analysis 
will be to assess the proportion of patients successfully withdrawn from sirolimus for one 
year.  The point estimate of this proportion and the exact two-sided 95% confidence 
interval (CI) will be provided for each treatment group.  A patient will be considered to 
be successfully withdrawn from immunosuppression for one year if the patient has been 
administered only belatacept for a period of 365 days, following successful completion of 
sirolimus, and has not experienced biopsy-proven acute rejection, formation of DSA, or 
graft loss for this same period of 365 days.   Secondary efficacy outcome measures 
involving incidences and proportions will be descriptively summarized with point 
estimates and exact, two-sided 95% CIs by treatment group. Other secondary efficacy 
outcome measures will be descriptively summarized by means and SDs for continuous 
outcomes and frequency distributions for categorical outcomes.   
Safety Analyses 
All AEs and SAEs will be summarized by treatment group. Laboratory values will also 
be descriptively summarized. 
5 
SUBJECT SELECTION CRITERIA 
For entry into the study, the following criteria MUST be met. 
5.1 
Inclusion Criteria 
1. Recipients, age 18 or older, of a kidney transplant at Emory University Hospital who 
are seropositive for the IgG antibodies specific for EBV and seronegative for IgM 
antibodies for EBV. 
2. Willingness and legal ability to give signed written informed consent. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 23 of 93 
3. For recipients of live donor kidneys, a willing renal donor who consents for donation 
of donor blood for testing throughout the follow-up period, and consents to have their 
kidney used in this experimental study. For recipients of DDRTs, access to donor 
lymphocytes for subsequent mechanistic study. 
4. Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for up to eight weeks after 
the study in such a manner that the risk of pregnancy is minimized. WOCBP must 
have a negative serum or urine pregnancy test within 72 hours prior to the start of 
study medication. 
 5.2  
Exclusion Criteria
1.  Immunosuppressive drug therapy within one year prior to enrollment. Specifically, 
candidates may not be taking or have taken prednisone, CsA, tacrolimus, 
azathioprine, MMF, cyclophosphamide, methotrexate, infliximab, etanercept, or 
other agents whose therapeutic effects are immunosuppressive in the year prior to 
transplantation and may not have conditions in which there is an anticipated need for 
these drugs during the study period. Recipients may not have taken depletional anti-
lymphocyte agents at any time. 
2. Any active malignancy or history of a malignancy within five years of enrollment, or 
any history of any hematogenous malignancy or lymphoma at any time. Patients 
with primary, cutaneous basal cell or squamous cell cancers may be enrolled 
providing the lesions are appropriately treated prior to transplant. 
3. Any known immunodeficiency syndrome (including subjects with known human 
immunodeficiency virus (HIV) infection) or other condition that, in the opinion of 
the investigators, would likely increase the risk of protocol participation or confound 
the interpretation of the data. 
4. Inability or unwillingness to comply with protocol monitoring and therapy, 
including, among others, a history of noncompliance, circumstances where 
compliance with protocol requirements is not feasible due to living conditions, travel 
restrictions, access to urgent medical services, or access to anti-rejection drugs after 
the research protocol is completed. 
5. Absence of EBV-specific IgG antibodies 
6. Absence of CMV specific antibodies in cases where the donor has evidence of CMV 
infection (CMV-specific antibodies) 
7. WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and for up to eight weeks after the study, or 
who are pregnant or breastfeeding on enrollment or prior to study drug 
administration 
8. Subjects with underlying renal disease of: Primary focal segmental 
glomerulosclerosis, Type I or II membranoproliferative glomerulonephritis, 
Hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura 
syndrome. If a subject has ESRD of unknown etiology and/or has no 
histologically-confirmed diagnosis, the subject may be enrolled into the study as 
long as there are no clinical signs or symptoms consistent with excluded clinical 
diagnoses. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 24 of 93 
9. Subjects with current or historical evidence of DSA as assessed by solid phase flow 
cytometry 
10. Subjects who are hepatitis C antibody-positive or polymerase chain reaction 
(PCR)-positive for hepatitis C, or who are hepatitis B surface antigen-positive or 
PCR-positive for hepatitis B 
11. Subjects with active tuberculosis (TB) requiring treatment within the previous 3 
years or any subject who previously required triple (or more) combination therapy 
for TB. Subjects with a known positive purified protein derivative (PPD) must have 
completed treatment for latent TB and have a negative chest x-ray at the time of 
enrollment. All patients will undergo PPD testing within 3 months of enrollment, 
have a negative CXR, and no symptoms indicative of TB 
12. Subjects with any active infection or other contraindication that would normally 
exclude transplantation including a life expectancy that is severely limited by their 
underlying medical condition 
13. Subjects with a history of substance abuse (drug or alcohol) or psychotic disorders 
that are in the opinion of a consulting psychiatrist incompatible with adequate study 
follow-up 
14. Subjects with active peptic ulcer disease, chronic diarrhea, or gastrointestinal 
malabsorption that would preclude oral drug absorption 
15. All women 40 years or older and women of any age who have first degree relatives 
with a history of breast carcinoma or who have other risk factors of breast 
carcinoma, must have a screening mammogram, or provide results of a screening 
mammogram performed within 6 months of enrollment. Subjects with a 
mammogram that is suspicious for malignancy and in whom the possibility of 
malignancy cannot be reasonably excluded following additional evaluations will be 
excluded. 
16. Subjects who have used any investigational drug within 30 days prior to their 
transplant 
17. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) will 
not be enrolled. 
6   
Study Therapy 
6.1 Transplant-specific therapies 
Alemtuzumab 
At the time of transplantation (in pre-op holding or the operating room) patients will be 
given a single dose of methylprednisolone 500 mg intravenously over 30 minutes 
followed by acetaminophen 650 mg orally or rectally and diphenhydramine 50 mg 
intravenously, followed in 1 hour by alemtuzumab, 30mg, given intravenously over 3 
hours.  
Transplantation 
Transplantation will be performed using standard surgical techniques for organ 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 25 of 93 
engraftment. An 18-gauge needle core biopsy will be obtained from the allografted 
kidney 30 minutes to 1 hour after reperfusion. These will be divided for routine histology, 
immunohistochemistry (2/3 of biopsy) and RT-PCR analysis (1/3 of biopsy) snap frozen 
on site. Patients will be cared for perioperatively on the transplant unit. Technical aspects 
of the postoperative management (Foley catheterization, ureteral stenting, etc) will be 
according to the standard of care as determined by the attending surgeon.   
Belatacept 
Belatacept will be given within 24 hours of transplantation via a peripheral intravenous 
catheter at a dose of 10mg/kg infused over 30 minutes. The dose will be repeated on 
study days 4 (post op day 3) and 8 (post op day 7), then every 2 weeks for 5 additional 
doses. Thereafter, belatacept will be given once every 4 weeks (+/- 3 days) at 10mg/kg 
through 6 months then at 5mg/kg indefinitely. 
Sirolimus 
Sirolimus will be started on postoperative day 1 at a dose of 2 mg per day orally. Doses 
will be adjusted to maintain 24 hour trough levels of 8-10ng/ml until the drug is weaned 
as described below. Sirolimus has been associated with delayed graft function in organs 
affected by acute tubular necrosis.  Therefore, in the unlikely event that patients 
experience delayed graft function (<5% of live donor transplants experience delayed graft 
function), defined as inadequate renal function to avoid dialysis by post-operative day 7, 
maintenance therapy will be changed to mycophenolate mofetil (1.5 gm twice daily) and 
prednisone (30mg daily) until graft function improves.  Patients will then be converted to 
sirolimus. 
Toxicity attributable to sirolimus (e.g. mouth ulcers, arthralgias) will prompt dose 
reduction to address clinical concerns in this regard. If sirolimus trough levels need to be 
reduced below 4ng/ml to control drug side effects, the patient will be considered 
intolerant to the drug and will be changed to mycophenolate mofetil (1.0 gm twice daily) 
and prednisone (30mg – 20mg daily tapered to off over 1-3 months depending on the 
time from transplantation). Patients on prednisone and mycophenolate will be considered 
for weaning based on the criteria described below. 
Prophylaxis 
With the exception of the immunosuppressive drugs used, perioperative care will be 
administered in keeping with the current standard of care. This will include post-
operative viral (oral valganciclovir in keeping the standard of care based on pre-operative 
donor and recipient CMV status), fungal (oral nystatin or clotrimazole), and bacterial 
prophylaxis (perioperative surgical prophylaxis transitioning to oral Pneumocystis 
prophylaxis) dosed for 6 months post transplantation. All prophylaxis agents will be 
withdrawn at 6 months unless there are specific clinical indications otherwise. 
6.2 Maintenance Immunosuppressive Reduction 
Beginning any time after year 1 (week 53), participants who are deemed eligible for 
sirolimus withdrawal as determined by clinical and flow cytometric parameters 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 26 of 93 
(described below) may be withdrawn from sirolimus. Withdrawal will proceed at a 
maximum rate of 66% of the original dose for 4 weeks, 33% of the original dose for 
another 4 weeks, then discontinued. However, each reduction in dose will be predicated 
on stable flow cytometric profile.  
Criteria for Sirolimus Withdrawal. Participants will be deemed eligible for withdrawal of 
sirolimus if they meet all of the following criteria:   
1. No episodes of steroid resistant acute rejection since transplant, and no episodes of 
steroid sensitive rejection for 12 months.  
2. Stable renal function, as defined by both of the following: 
a. GFR, using calculated CrCl (Cockcroft-Gault) of > 40ml/min. 
b. Creatinine, which in the 12 weeks preceding withdrawal has not increased more 
than 20% with respect to the lowest creatinine observed during the same period. 
c.   Absence of histologic evidence of acute or chronic rejection on pre-withdrawal 
renal biopsy according to the Banff criteria for acute, chronic and humoral 
rejection. 
3. Absence of DSA reactivity, as measured by de novo anti-donor-HLA antibodies. 
4. ALC at least 80% of the baseline ALC prior to alemtuzumab. 
5. Ki67 expression on CD3+ T cells that is within 1 standard deviation of the normal 
expression in untreated controls. Ki67 is typically seen in <3% of lymphocytes in 
health controls and a value >5% exceeds the value accepted for purposes of this 
trial.  
For determining eligibility, a renal biopsy will be obtained and creatinine clearance will 
be estimated. Requisite blood samples will be obtained within two weeks before starting 
sirolimus withdrawal.  Results of laboratory assessments of immune status will be made 
available to, and reviewed by, the investigator.  These data will be reviewed with the 
knowledge of previous results of immunosuppression withdrawal obtained in the current 
trial up to the time of review.  
Maintenance Immunosuppressive Therapy 
Patients who are weaned from sirolimus will be maintained on belatacept 5mg/kg once 
per month +/- 3 days indefinitely. In the event that patients are not successfully weaned 
from sirolimus, long-term maintenance therapy will be established on an individual basis. 
Patients with subclinical or steroid sensitive rejections can be continued using sirolimus 
and belatacept, or altered based on the individualized requirements of each patient. This 
may include the use of CNIs, anti-metabolites, steroids, biologics or other available 
medications dose to achieve the required therapeutic effect. Patients experiencing steroid 
resistant TCMR or ABMR will be converted to a CNI-based regimen. 
6.3 Treatment Administration 
Infusion of Alemtuzumab shall begin within 24 hours of surgery, and shall be given prior 
to belatacept.  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 27 of 93 
Infusion of the first belatacept dose should begin no later than 24 hours of surgery but not 
prior to the surgeon having made an initial intraoperative assessment and has concluded 
that the subject remains a transplant candidate and the transplant will proceed. Infusion 
doses will be based on the subject’s  body weight at enrollment, and will not be modified 
during the course of the study, unless there is a change of body weight ± 10%.  
Belatacept should be administered to the subject at a relatively constant rate over 30 
minutes. 
Sirolimus will begin orally within 48 hours of surgery and after both belatacept and 
alemtuzumab. 
6.3.1 Dose Modifications 
In the absence of AEs deemed at least possibly related to study drug treatment, subjects 
will complete their scheduled infusions as prescribed by protocol. In the event of new, 
serious, and unexpected toxicity potentially related to belatacept, study drug 
administration should be interrupted. The investigator must immediately notify the 
medical monitor. The subject will be considered eligible to receive further study drug 
treatment only after discussion with the medical monitor. 
Subjects who require ongoing dialysis therapy may receive the Week 4 dose of belatacept 
at the discretion of the investigator, but should receive no additional belatacept dosing, 
unless the need for dialysis has resolved by the Week 6 visit. Such subjects in whom 
belatacept dosing is discontinued should be placed on a conventional immunosuppressive 
regimen. 
Subjects who receive therapeutic plasmapheresis for the treatment of suspected humoral 
acute rejection may receive an additional dose(s) of belatacept. This decision must be 
individualized on a case-by-case basis and the investigator must discuss any dose 
modification with the BMS medical monitor in advance of such modification. 
6.4 Discontinuation of Therapy 
Belatacept therapy MUST be immediately discontinued for the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• Any clinical adverse event, laboratory abnormality or intercurrent illness which, in 
the opinion of the Investigator, indicates that continued treatment with study therapy 
is not in the best interest of the subject 
• Pregnancy 
• Missing 2 consecutive belatacept infusions, unless the subject is receiving 
lymphocyte-depleting therapy or has approval by the medical monitor to remain in 
the study 
• Subjects receiving 56 consecutive days of dialysis and the investigator has 
determined that the subject no longer requires immunosuppression as the graft is 
functionally lost 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 28 of 93 
• Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness.  
Subjects who are discontinued from study therapy must be followed for safety for 8 
weeks post-study drug discontinuation. 
6.5 Treatment Compliance 
All medications specified in this protocol must be administered as described within the 
protocol. Study medication usage is to be reviewed and compliance is to be discussed 
with subjects at each visit to assure compliance. All study medication and concomitant 
medication usage must be reported on the appropriate case report form (CRF) pages, and 
any deviations from specified administration should be clearly documented. 
Data regarding concomitant medications will be collected only if they are related to the 
treatment of  serious adverse or adverse events that are probably, possibly, or definitely 
related to study medications. 
6.6 Treatment of Rejection 
Biopsy proven acute rejection episodes will be treated based on the discretion of the 
transplant physician or surgeon. It will be permissible but not mandatory to continue 
protocol participation for patients who experience an early steroid sensitive rejection as 
described above. Presumed rejection episodes will be confirmed by biopsy as soon as 
possible after the initiation of symptoms. Biopsies will be performed at the Emory 
Transplant Clinic if at all possible. If patients are greater than a 24-hour trip from the 
center, the PI may elect to have the biopsy performed by a qualified transplant physician 
or surgeon. The Banff grade of rejection will be documented in the clinical case file and 
the date of the first episode of acute rejection will be the date the rejection is confirmed 
by biopsy. Management of rejections must be based on biopsy and clinical findings.  
Patients with suspected rejection will undergo physical exam, laboratory evaluation, 
ultrasound examination of the kidney, and percutaneous renal biopsy accompanied by 
blood collection for peripheral phenotype analysis, transcriptional analysis and evaluation 
of donor specific alloreactivity. Biopsies will be evaluated by the attending transplant 
physician and reviewed with a pathologist skilled in the evaluation of renal transplant 
biopsy material. Biopsies will be evaluated using the Banff criteria for determination of 
allograft rejection.130-132 Patients with biopsy proven rejection will be treated with 
methylprednisolone 500mg x 1-3 days. Failure to respond to methylprednisolone in no 
more than 3 days, or rapid worsening of graft function despite methylprednisolone 
therapy will prompt use of an approved antilymphocyte agent or other therapies deemed 
appropriate by the attending transplant physician or surgeon. After treatment of a steroid 
resistant rejection episode, patients will be discontinued from study 
treatment/immunosuppressive weaning and returned to a maintenance regimen 
established at the discretion of the attending transplant physician or surgeon in keeping 
with standard of care immunosuppression for renal transplantation.  After treatment of a 
steroid sensitive rejection episode, patients may be restarted on the previous level of 
immunosuppression.  The dosing and intensity of the regimen for maintenance 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 29 of 93 
immunosuppression shall be guided by the attending transplant physician or surgeon, to 
re-establish clinical stability of renal function.  This may result in patients receiving 
different doses, or restarting previously discontinued medications. Any rescue therapy 
will prompt a reinstitution of viral, fungal and PCP prophylaxis. The need for additional 
antilymphocyte agents will be carefully scrutinized by the PI prior to their administration. 
Alternative therapies will be utilized as appropriate (e.g., plasmapheresis, IVIG) unless it 
is clear (by biopsy) that the rejection is being mediated by lymphocytes. 
 
6.7 Prohibited Therapies 
Use of immunosuppressive agents and corticosteroids will be limited to those specified in 
the protocol. Vaccinations will be recommended based on the prevailing standard of care 
for transplant patients.8 Due to the risk of infection, use of live vaccines will be 
contraindicated during the course of the study. 
6.8 Withdrawal of Subjects from Study 
Subjects will be removed from the study for the following reasons: 
1. Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
2. Any clinical adverse event, laboratory abnormality or intercurrent illness which, in 
the opinion of the Investigator, indicates that continued treatment with study 
therapy is not in the best interest of the subject 
3. Pregnancy 
4. Missing 2 consecutive belatacept infusions, unless the subject is receiving 
lymphocyte-depleting therapy or has approval by the medical monitor to remain in 
the study 
5. Subjects requiring dialysis for 56 consecutive days and the investigator has 
determined that the subject no longer requires immunosuppression as the graft is 
functionally lost 
6. Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness.  
Subjects who are discontinued from study therapy will be followed for safety for 8 weeks 
post-discontinuation. 
6.9  Stopping Rules 
Specific criteria for discontinuing the trial at the time of the IRB review will be: 
treatment failure, defined as biopsy-proven, steroid-resistant acute rejection, severe 
infection, malignancy, death, or allergic response occurring in three of the first ten 
patients or five patients at any time. If two of five consecutive subjects who have 
received protocol therapy experience steroid resistant acute rejection, graft loss, 
malignancy, severe infection, and/or death in a period of three months, enrollment will be 
stopped and the study will be reassessed by the investigators and the study monitor. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 30 of 93 
7. STUDY CONDUCT 
7.1 Ethics 
This study will be conducted in accordance with the ethical principles that have their 
origin in the current Declaration of Helsinki and will be consistent with International 
Conference on Harmonization Good Clinical Practice (ICH GCP) and applicable 
regulatory requirements. 
The study will be conducted in compliance with the protocol. The protocol and any 
Amendments and the subject informed consent will receive Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) approval/favorable opinion prior to initiation 
of the study. 
Freely given written informed consent must be obtained from every subject or their 
legally acceptable representative prior to clinical trial participation, including informed 
consent for any screening procedures conducted to establish subject eligibility for the 
trial.  
The rights, safety and well-being of the trial subjects are the most important 
considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training, 
and experience to perform their respective task(s). 
This trial will not use the services of study personnel where sanctions have been invoked 
or where there has been scientific misconduct or fraud (e.g., loss of medical licensure, 
debarment). 
Systems with procedures that assure the quality of every aspect of the study will be 
implemented.  
7.2 Benefits 
If avoidance of steroids and reduced maintenance immunosuppression can be achieved, 
the patient may be freed from many of the long-term morbidities of standard 
immunosuppressive therapy. This may result in a significant improvement in quality of 
life and reduced expense for immunosuppressive medications as compared to patients on 
conventional regimens. Close monitoring of allograft recipients increases the likelihood 
of identifying potential adverse drug events or deterioration in graft function and thus 
increases the potential for intervening in a beneficial way to improve graft and patient 
survival.  
7.3 Costs  
All standard of care x-rays, diagnostic tests, medical services, hospital and clinic visits 
related to the transplant procedure and established post-transplant clinical pathway 
follow-up care, and immunosuppressive medications will be the responsibility of the 
transplant recipient and will be billed to the subject’s insurance as such. Any additional 
study specific visits, procedures, and/or blood collections for mechanistic assays will be 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 31 of 93 
provided by the study and will not be the responsibility of the study participant.   
All anti-rejection medications used in this study are available to persons outside of 
research studies. The patient will be strongly advised to seek access to support from 
existing federal, state and /or private insurance after their transplant. 
7.4 Risks and Discomforts 
Renal allotransplantation as it is currently practiced is associated with many known risks. 
These include but are not limited to risks inherent in any major vascular procedure such 
as bleeding, wound infection, pneumonia, pulmonary embolus, stroke, myocardial 
infarction and death. The current standard of care includes potent but imperfect 
immunosuppressive agents that significantly increase the risks of malignancy 
(particularly lymphomas and cutaneous malignancies), wound break-down and infection, 
cataracts, osteoporosis, hypertension, hemolytic uremic syndrome, hyperlipidemia, 
insulin requiring diabetes, and renal insufficiency and do not completely eliminate the 
risk of graft rejection. Organs transplanted from other individuals may carry infectious 
agents that may cause disease in the recipient. Organs are screened for HIV, hepatitis B 
and C viruses, EBV and CMV. Organs are not used if they are found to be positive for 
HIV or hepatitis. Prophylactic agents are used to limit infectious disease. 
All transplantation using treatment with alemtuzumab/belatacept/sirolimus instead of 
conventional immunosuppression will continue to be associated with the operative and 
general risks listed above. The experimental data suggest that the risk of wound 
complications may be less with steroid sparing protocols than with conventional therapy, 
but this remains to be proven and could still be significant or even increased in 
association with sirolimus. 
7.5 Risks for Women of Child-bearing Potential 
As of July of 2010, two healthy volunteers became pregnant at 12 months and 15 months, 
respectively, after a single dose of subcutaneous belatacept given in Phase 1 trial. Both 
pregnancies resulted in normal births. Only one woman with a kidney transplant had 
become pregnant after 7 years of belatacept treatment in a clinical trial. She has an 
induced abortion at approximately 8 weeks of pregnancy without complications.  
 
All other pregnancies in the kidney transplantation trials were in partners of subjects, 
with a total of 15 pregnancies in 12 partners treated with belatacept (10 normal births, 2 
spontaneous abortions, and 3 without neonatal outcomes reported).  
7.6 Immunosuppressive Therapy-specific risks 
Alemtuzumab 
Alemtuzumab is known to have a significant risk of cytokine release syndrome. This 
syndrome can usually be minimized by premedication with steroids but can include fever, 
chills, malaise, hypotension, tachycardia, and pulmonary edema. Lymphopenia may be 
associated with increased risk of infection. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 32 of 93 
Sirolimus 
Phase III studies of sirolimus in cyclosporine based regimens have revealed mild dose 
related thrombocytopenia and increases of serum triglycerides and cholesterol.  This 
latter finding is probably its most consistent effect and was seen in 40-50% of patients.  
Hypertriglyceridemia predominates.  HMG-CoA reductase inhibitors and fibric acid have 
been used and well tolerated to counteract the hyperlipidemia associated with sirolimus.  
Additionally, the unexpected finding of nephrotoxicity has been encountered but is likely 
attributable to sirolimus’ potentiation of CNI nephrotoxicity and thus is likely to be 
inapplicable in this trial.  Other common events reported in trials include leukopenia, 
hypertension, anemia, nausea, vomiting, elevated liver enzymes, rash and acne  [37,38]  
Other risks from the package insert for sirolimus include possible development of 
lymphoma and other malignancies, particularly of the skin, increased susceptibility to 
infection including opportunistic  infections, fatal infections, and sepsis, and lymphocele, 
a known surgical complication of renal transplantation, occurring significantly more 
often in a dose-related fashion in sirolimus-treated patients.  
Belatacept in Kidney Transplant Study  
Specific risks associated with belatacept may include those typically associated with 
transplant related immunosuppression including infection and malignancy.  
Over 1000 transplant patients have received belatacept in clinical trials. Patients in these 
trials received belatacept or cyclosporine (a marketed drug for comparison), in addition to 
basiliximab, mycophenolate mofetil (MMF also known as CellCept), which is an 
immunosuppressant, and steroids to prevent transplant rejection. In general, patients 
treated with belatacept had the same overall rate of side effects, including infections and 
cancers, as patients who received cyclosporine. In the first 36 months of follow-up in the 
three clinical trials done in kidney transplant patients, the frequency of side-effects was 
similar comparing belatacept and cyclosporine. The most commonly reported side-effects 
(in ≥ 20% of subjects) among belatacept subjects were urinary tract infection, diarrhea, 
constipation, nausea, swelling, decrease in transplanted kidney function, fever, cough, 
high blood pressure, and low white blood cells count. Some side effects were serious and 
required hospitalization.  Some were fatal. Some side effects were serious and required 
hospitalization. Some were fatal. 
 
Post-transplant Lymphoproliferative Disorder  
Post-transplant lymphoproliferative disorder (PTLD), a tumor of white blood cells that 
can occur after kidney transplantation, developed more frequently in patients who 
received belatacept (14 cases out of 949; 1.5% of subjects) than those who received 
cyclosporine (3 cases out of 476; 0.6%). In addition, more than half of the PTLD cases in 
belatacept patients involved the brain (9 cases out of 14; 65% of belatacept patients), 
which is a higher proportion than expected. A total of 11 of 17 subjects with PTLD died; 
8 out of 14 in the belatacept group and 3 out of 3 in the cyclosporine group. 
 
PTLD is known to occur after transplant in approximately 1% of adults and is almost 
always associated with the Epstein-Barr virus (EBV). NULOJIX® (belatacept) is 
contraindicated in transplant recipients who are Epstein-Barr virus (EBV) sero negative 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 33 of 93 
or with unknown EBV serostatus due to the risk of post-transplant lymphoproliferative 
disorder (PTLD), predominantly involving the central nervous system (CNS).  As the 
total burden of immunosuppression is a risk factor for PTLD, higher than the 
recommended doses or more frequent dosing of Nulojix and higher than recommended 
doses of concomitant immunosuppressive agents are not recommended. Physicians 
should consider PTLD in patients reporting new or worsening neurological, cognitive, or 
behavioral signs or symptoms.  
 
The risk of PTLD was higher in EBV sero negative patients compared to EBV 
seropositive patients. EBV seropositive patients are defined as having evidence of 
acquired immunity shown by the presence of IgG antibodies to viral capsid antigen 
(VCA) and EBV nuclear antigen (EBNA). Epstein-Barr virus serology will be 
ascertained before starting administration of Nulojix, and only patients who are EBV 
seropositive will receive Nulojix. Transplant recipients who are EBV sero negative, or 
with unknown serostatus, should not receive Nulojix.  
 
Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell-
depleting therapy. T-cell-depleting therapies to treat acute rejection should be used 
cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation.  
Patients who are EBV seropositive and CMV seronegative may be at increased risk for 
PTLD compared to patients who are EBV seropositive and CMV seropositive. Since 
CMV seronegative patients are at increased risk for CMV disease (a known risk factor for 
PTLD), the clinical significance of CMV serology for PTLD remains to be determined; 
however, these findings should be considered when prescribing Nulojix. 
 
The physician will perform tests to see if the patient has antibodies to EBV. If the patient 
does not have antibodies to the virus, they will not be allowed to enroll in the study.  If 
they do have antibodies to the virus, the physician will counsel them about their risk of 
developing PTLD.  Additional monitoring and the use of anti-viral medications may be 
prescribed by their physician to help reduce their risk. 
Post-transplant lymphoproliferative disease (PTLD) is known to be associated with the 
degree of immunosuppression. It occurs in approximately 0.7% of adults and up to 4.5% 
of children following transplantation [39-42]. This condition can give rise to lymphoma 
in over 50% of those patients in which it occurs. The relative risk of this condition 
compared to conventional therapy in humans is not known but should be reduced 
substantially by exclusion of EBV positive to negative mismatches. 
PTLD Safety Surveillance 
Special surveillance for PTLD will be considered for all subjects in this study.  The 
PTLD safety surveillance should be implemented as soon as IRB/IEC approval and 
subject consent are obtained.  
Subjects with Suspected PTLD 
CNS imaging and/or neurologic consultation should be considered for any subject with a 
new or worsening neurologic finding.  For subjects who undergo biopsy for suspicion of 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 34 of 93 
PTLD, we recommend evaluating the biopsy specimen for CD3, CD20, CD79, and 
EBER. Management of belatacept and other immunosuppressants in subjects with 
suspected PTLD should be discussed with the BMS Medical Monitor.  BMS should be 
informed of all confirmed cases of PTLD.    
Progressive Multifocal Leukoencephalopathy (PML)  
Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and 
fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma 
virus. In clinical trials with Nulojix, two cases of PML were reported in patients receiving 
Nulojix at higher cumulative doses and more frequently than the recommended regimen, 
along with mycophenolate mofetil (MMF) and corticosteroids; one case occurred in a 
kidney transplant recipient and the second case occurred in a liver transplant recipient. As 
PML has been associated with high levels of overall immunosuppression, the 
recommended doses and frequency of Nulojix and concomitant immunosuppressives, 
including MMF, should not be exceeded.  
 
Physicians should consider PML in the differential diagnosis in patients with new or 
worsening neurological, cognitive, or behavioral signs or symptoms. PML is usually 
diagnosed by brain imaging, cerebrospinal fluid (CSF) testing for JC viral DNA by 
polymerase chain reaction (PCR), and/or brain biopsy. Consultation with a specialist 
(e.g., neurologist and/or infectious disease) should be considered for any suspected or 
confirmed cases of PML.  
 
If PML is diagnosed, consideration should be given to reduction or withdrawal of 
immunosuppression taking into account the risk to the allograft.  
 
7.7 Therapy Failure  
Patients may have an increased risk of graft loss due to rejection should the primary 
therapy fail. It is not clear if the rate of rejection onset will be significantly faster for 
patients in this protocol. However, the Sponsor-investigator has extensive experience in 
managing immunosuppressive reduction trials including those with complete 
immunosuppressive withdrawal. The Sponsor-investigator and the principal investigator 
are in close and frequent contact related to the management of this trial.The monitoring 
of patients in this trial greatly exceeds that in standard practice specifically to minimize 
the likelihood of a late rapid rejection.  
7.8 Phlebotomy 
Peripheral blood draws (venipuncture); during this study, blood drawn for research will 
not exceed 450ml per six-week period. The patient may experience some discomfort at 
the site of the needle entry, and there is a risk of bruising at the site. There is a remote 
risk of fainting or local infection. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 35 of 93 
7.9 Renal Biopsy 
Renal biopsy is a standard procedure that carries a low risk for the patient of bleeding. 
The risk is minimized by guidance with real time ultrasound and decreases with time 
from the transplant procedure. Biopsies performed within one week of transplant carry a 
1-2% risk of significant bleeding (defined as requiring some intervention, either 
transfusion or surgery). This decreases to less than 0.5% after the 4th week as the kidney 
scars into place. Transplanted kidneys are easier to biopsy than native kidneys due to 
their location in the iliac fossa as opposed to in the flank.  Biopsy will not be performed 
on patients with a platelet count <80 unless clinically indicated.  A biopsy shall be 
considered clinically indicated when obtained to evaluate any abnormality and required 
by the attending physician to guide clinical care. 
During a biopsy, a patient will feel mild burning for several seconds during instillation of 
a local anesthetic agent. Thereafter, the patient will feel a pushing sensation, but usually 
little pain, as the needle enters the kidney. There may be some mild residual pain. In the 
event that significant bleeding is suspected, either through clinical observation or a 
significant decrease in hemoglobin, an ultrasound will be performed. Transfusion will be 
administered as necessary or the patient will be taken to the operating room for direct 
control of the bleeding.  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 36 of 93 
8. STUDY OBSERVATIONS 
8.1 Flow Charts/Time and Events Schedule 
Month 1 
 
 
Tests / Evaluations  
On 
Enrollment 
 
Day 7  
Post-
transplant 
(study day 8)
Day 14  
(+/- 2 days) 
post-
transplant 
Day 21  
(+/- 2 
days) 
post-
transplant 
 
 Day 28 
(+/- 3 days) 
post-
transplant 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Physical Examination 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
X 
X 
X 
Confirm Inclusion/ 
Exclusion criteria 
X 
 
 
 
 
 
CBC with Differential 
X 
 
X 
X 
X 
X 
Blood Chemistry/lipids 
X 
 
X 
X 
X 
X 
Urinalysis  
X 
 
X 
X 
X 
X 
Serum Pregnancy Test 
X 
 
 
 
 
 
Sirolimus trough (study) 
 
 
X 
X 
 
 
Donor-specific Antibody 
X 
 
 
 
 
X 
Panel Reactive Antibody 
X 
 
 
 
 
X 
Donor-specific and third 
party mixed lymphocyte 
responsiveness/ ICCS 
X 
 
 
 
 
 
Lymphocyte Subsets-
Ki67 
Xa 
 
 
 
 
Xa 
Peripheral blood 
transcription 
Xa 
 
 
 
 
Xa 
Informed Consent 
X 
 
 
 
 
 
HIV Ab 
X 
 
 
 
 
 
HBsAg and HCV Ab 
X 
 
 
 
 
 
CMV and EBV PCR 
X 
 
 
 
 
X 
BK viremia/viruria PCR 
X 
 
 
 
 
X 
Adverse Events 
X 
 
X 
X 
X 
X 
QoL 
X 
 
 
 
 
 
Immunogenicity 
Xa 
 
 
 
 
 
a These are specific study related assays for reporting purposes. 
 
 
 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 37 of 93 
 
Months 2-6 
 
 
 
 
 
 
 
 
 
Tests/Evaluations 
Every 2 
Weeks 
Monthly  
Every 3 
Months  
At 6 
Months 
With Clinical 
Biopsies 
Physical  
Examination 
 
X 
 
 
X 
Vital Signs 
 
X 
 
 
X 
CBC with 
Differential 
X 
X 
 
 
X 
Blood 
Chemistry/lipids 
X 
X 
 
 
X 
Urinalysis 
X 
X 
 
 
X 
Sirolimus trough 
x 
 
 
 
X 
Lymphocyte Subsets 
Ki67 
 
 
 
Xa 
X 
Peripheral 
transcription 
 
 
 
Xa 
X 
Donor-specific and 
third party mixed 
lymphocyte 
responsiveness/ other 
studies of 
hyporesponsiveness 
 
 
 
X 
X 
PRA 
 
 
 
X 
X 
Renal Biopsy  
 
 
 
X 
X 
Intra graft mRNA 
analysis 
 
 
 
X 
X 
 
 
 
 
X 
 
CMV and EBV PCR 
 
X 
 
 
 
BK viremia/viruria 
PCR 
 
X 
 
 
X 
Adverse Events 
X 
X 
 
 
X 
QoL 
 
 
 
X 
 
Neurologic Exam 
 
 
X 
 
 
Immunogenicity 
 
 
 
Xa 
 
=a These are specific study related assays for reporting purposes. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 38 of 93 
 
Long-Term Follow-Up Cohort 1 
 
 
Tests / 
Evaluations  
Every 
6months  
Yearly  
 
 
 
Telephone 
Reporting 
X 
 
Serum Chemistry/ 
lipids /CBC  
X 
 
Sirolimus trough 
 
X 
Lymphocyte 
subsets 
X 
 
Peripheral 
transcription 
 
X 
CMV and EBV 
PCR 
X 
 
BK viremia/viruria 
PCR 
X 
 
PRA 
 
X 
Anti-Donor 
Antibody 
 
X 
Donor-specific and 
third party mixed 
lymphocyte 
responsiveness/ 
ICCS 
 
X 
Renal Biopsy  
 
Xb 
Intragraft mRNA 
Analysis 
 
Xb 
Adverse Events 
X 
X 
QoL 
X 
 
Neurologic Exam 
X 
 
PK 
 
 
Immunogenicity 
X 
 
= 
b To be performed prior to weaning patient to monotherapy (generally at 12 months) and 
again after stable on monotherapy as clinically indicated. 
 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 39 of 93 
 
Long-Term Follow-Up Cohort 2 
 
 
Tests / 
Evaluations  
Monthly 
after 
Year 1 
Every 3 
months from 
6 - 24Months 
Every 
6mont
hs  
Yearly  
 
 
 
 
 
Telephone 
Reporting 
 
 
X 
 
Serum Chemistry/ 
lipids /CBC  
Xc 
 
X 
 
Sirolimus troughd 
X 
 
 
X 
Lymphocyte 
subsets Ki67 
 
 
X 
 
Peripheral 
transcription 
 
 
 
X 
CMV and EBV 
PCR 
 
X 
X 
 
BK 
viremia/viruria 
PCR 
 
X 
X 
 
PRA 
 
 
 
X 
Anti-Donor 
Antibody 
 
 
 
X 
Donor-specific 
and third party 
mixed lymphocyte 
responsiveness/ 
ICCS 
 
 
 
X 
Renal Biopsy  
 
 
 
Xb 
Intragraft mRNA 
Analysis 
 
 
 
Xb 
Adverse Events 
Xe 
 
 
 
QoL 
 
 
X 
 
Neurologic Exam 
 
 
X 
 
 
 
 
 
 
Immunogenicity 
 
 
X 
 
cStudy participants may have these labs drawn more or less frequently as deemed clinical necessary by the 
investigator. 
dStudy participants who are not weaning sirolimus and are on a stable, low dose can have trough levels 
monitored as frequently as a monthly basis or as clinically indicated.  
eIf study participant is on a stable dose of sirolimus, not weaning, and receiving commercial belatacept as 
an outpatient, then adverse events may be assessed every three months. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 40 of 93 
Year 1 Medication Flowchart 
 
 
 
 
 
Day of 
Transplant  
1st Dosing 
Day 1 
 
 
 
 
Mo 
1 
 
 
 
Mo 
3 
 
 
Mo 
6 
 
 
 
 
 
 
Mo 
12 
Day 
2 
 
D
a
y 
4 
Day 
8 
Day 
14 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
WK 
48 
Wk 
52 
 
 
 
 
 
Wk 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
belatacept 10 mg/kg 
X 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
belatacept 5 mg/kg 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
sirolimus 
Sirolimus will be started on post-op day 1 at a dose of 2 mg per day orally.  Doses will be adjusted to 
maintain 24-hour trough levels of 8-10 ng/ml until the drug is weaned as described below. 
methylprednisolone 
500 mg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
alemtuzumab 30 mg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylaxis 
Post-operative viral (oral valganciclovir of duration in keeping the standard of care based on pre-operative 
donor and recipient CMV status), fungal (oral nystatin or clotrimazole), and bacterial prophylaxis 
(perioperative surgical prophylaxis transitioning to oral Pneumocystis prophylaxis) dosed for 6 months 
post transplantation.  All prophylaxis agents will be withdrawn at 6 months unless there are specific 
clinical indications otherwise. 
Immunosuppression 
Withdrawal 
During year 2 (weeks 53-104), weaning of immunosuppression will begin for all patients meeting pre-
defined criteria.  Patients will be first weaned off sirolimus over at least a 2 – 6 month period.    
After sirolimus, is weaned, patients will remain on belatacept monotherapy indefinitely. 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 41 of 93 
9 Details of Research Procedures 
9.1 Pre-transplant Tissue Acquisition 
Patients will be enrolled prior to transplantation to facilitate informed consent and 
baseline sample procurement. All patients will be specifically informed that protocol 
participation will not influence their receipt of the kidney being offered. Upon 
enrollment, patients will have standard hematology, chemistry, virology, and coagulation 
samples drawn. In addition, samples will be drawn for baseline serum (from 10 ml whole 
blood) and lymphocyte harvest (from 100ml whole heparinized blood). Serum and cells 
will be separated and used for baseline assays with excess cells cryopreserved. A separate 
5 ml heparinized sample will be drawn for T cell subset phenotyping. The total amount of 
blood drawn for research purposes will not exceed 450ml in any six-week period.  
At the time of transplantation, donor samples will be obtained from 120 ml heparinized 
whole blood from live donors, and a similar amount of blood or spleen or lymph node 
from deceased donors. Lymphocytes will be procured and cryopreserved by the Emory 
Transplant Center Biorepository (see Resources). Lymphocytes will only be used for 
studies related to this protocol. After the transplant, cryopreserved serum and cell 
samples will be utilized by the Sponsor-investigator for mechanistic analysis, storage, or 
distribution to collaborating laboratories. Samples may also be sent to collaborating sites 
for study-related mechanistic analysis. 
9.2 Post-transplant Monitoring 
Post-transplant Blood Monitoring. In general, functional monitoring will proceed in 
keeping with the standard of care for kidney transplantation at the Emory Transplant 
Center. Blood for testing of renal function (creatinine, BUN, hemoglobin/hematocrit) and 
electrolytes (including sodium, potassium, chloride, bicarbonate, magnesium, calcium 
and phosphorous) will be drawn daily until discharge and at least two times weekly for 
one month. Patients will be monitored weekly for at least 3 months or until the ALC 
exceeds 500 cells/mm3, whichever is longer. Thereafter, renal function will be assessed at 
least every two weeks until they reach their one-year evaluation. Lymphocyte 
repopulation and specific Ki67 and TREG and BTRANS phenotypes will be assessed 
monthly until 1 year after sirolimus elimination, and then every 3 months through 5 years 
by analysis of 7ml of heparinized blood by flow cytometry.  
Biopsy Monitoring. A protocol biopsy will be performed following allograft reperfusion. 
Additional protocol biopsies will be performed at 6 months, and when the criteria for 
weaning to monotherapy belatacept are met (generally this will be during the second post 
transplant year) and again when the patient has been weaned to monotherapy belatacept 
for three months. An additional biopsy will be performed one year after weaning off 
sirolimus. It is assumed that histological acute allograft rejection is indicative of under-
immunosuppression. Since histological rejection has been documented to occur in the 
absence of clinical renal dysfunction (so-called sub-clinical rejection) in up to 30% of 
persons with stable allograft function, it is reasonable to assume that some patients 
studied in this trial will have sub-clinical rejection, and thus be inappropriate for further 
immunosuppressive reduction. Protocol biopsies are thus clinically indicated to pre-empt 
inappropriate immunosuppressive weaning, as well as to detect other occult pathology 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 42 of 93 
known to arise in transplanted kidneys that could confound the interpretation of the 
study.133-134 In the event that subclinical rejection is detected, the patient will receive anti-
rejection therapy in keeping with the standard of care, generally an oral steroid taper over 
30 days and reevaluation of the patient’s need for chronic immunosuppression. A follow-
up biopsy will be performed in 3 months to assess resolution of subclinical rejection. 
Subclinical rejection, once resolved, will not in and of itself remove the patient from 
consideration of weaning, if it occurs during a period of homeostatic repopulation.  
Renal biopsies also will be performed if any sustained rise in serum creatinine of greater 
than or equal to 30% of the baseline creatinine is detected. Baseline creatinine will be 
defined as the mean of five stable serum creatinine values within the first three months 
post-transplant.  Stable is defined as a variance of +/- 20% or less of any value.  Clinical 
suspicion of allograft pathology based on other grounds (urine cytology, pyuria, 
proteinuria, etc.) also will be considered grounds for biopsy at the discretion of the 
attending physician. An attending transplant physician or surgeon will perform all 
biopsies. The risks of transplant kidney biopsy will be included in the informed consent 
process for the protocol. At the time of each biopsy (protocol or clinically indicated), 
blood will be drawn for peripheral phenotyping and lymphocyte harvest (50ml 
heparinized). 
Patients will be evaluated for cellular alloreactivity, donor-specific hyporesponsiveness 
and viral specific responsiveness pre-operatively, at the time that sirolimus withdrawal 
commences, 3 months after sirolimus withdrawal, at the time of clinical rejections, and at 
study termination. This will require 50ml of heparinized blood to be drawn at these time 
points and cryopreserved for analysis.  
9.3 Specific Tests and Evaluations 
Donors 
All live donors will provide written informed consent for participation in this trial. Donor 
characteristics (deceased or living, age, race, sex, medical history, laboratory tests, and 
ischemic time) will be documented. Live donors will be specifically informed of the 
experimental nature of their recipient’s protocol. The living donor may decline to consent 
for the blood donation aspect of this protocol without affecting the recipient’s ability to 
participate in this study. However if the donor declines to sign the informed consent for 
participation in all aspects of the protocol, the recipient may not be enrolled. 
Recipient Evaluations Prior to Immunosuppressive Dosing 
After informed consent is obtained, the following tests and evaluations are to be 
conducted within 72 hours prior to randomization/study treatment unless otherwise 
specified: 
• Demographics 
• Medical history 
• Physical examination 
• Vital signs  
• Urinalysis 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 43 of 93 
• Serum pregnancy test for females of childbearing potential 
• CBC with differential  
• Lymphocyte subsets, and baseline Ki67 
• Peripheral blood transcription 
• Donor specific MLR/ ICCS and antibody titers 
• Blood chemistry: blood urea nitrogen (BUN), AST, ALT, total bilirubin, 
creatinine, sodium, potassium, calcium, bicarbonate, chloride, glucose 
• HIV antibody, HBsAg, HCV Ab 
• EBV and CMV IgG and IgM, and EBV and CMV PCR 
• BK viremia and viruria 
• Panel Reactive Antibody/ alloantibody assessment 
• Donor characteristics including ischemic time 
Evaluations During Treatment Period 
See flowcharts in Section 8 for specific tests and the timing of test to be drawn during the 
study period. In addition, a general health related quality of life measure will be collected 
from all patients. We will utilize the SF-36 questionnaire.  The instrument will be 
administered pre-transplant and at post-transplant visits in month6, 12, 18, 24, then 
annually thereafter. 
 
A neurologic assessment (exam and history) will be done every 3 months up to the year 2 
annual visit. After year two, these assessments will be done every 6 months until the end 
of participation in the study.  
 
The neurologic exam will include: 
 
A review of any new neurological symptoms of changes, such as: 
 
• Personality 
• Memory 
• Headaches 
• Pain 
• Seizures 
• Impairment of consciousness 
• Swollowing 
• Vision, hearing, and language function 
• Coordination 
• Gait 
• Weakness 
• Sensory alterations 
• Sphincter disturbances 
• Involuntary movements 
 
 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 44 of 93 
The neurologic exam will include testing of: 
 
• Mental status 
• Gait 
• Speech 
• Cranial nerves 
• Cerebral function 
• Deep tendon reflexes 
• Sensory function 
• Motor function 
 
The patient will be watched closely for any neurological changes that may develop 
throughout the study. If the patient develops a new finding or if a condition worsens, 
there will be a follow-up neurologic exam. If needed, more tests and procedures might be 
ordered and the patient might be referred to a Neurology specialist. 
 
 
10. INVESTIGATIONAL PRODUCTS 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
This trial will be conducted under an FDA Investigational New Drug application held by 
the Sponsor-investigator. All medications are approved for human use  
 
10.1 Belatacept Preparation 
A pharmacist or qualified personnel at the site will prepare the drug for i.v. 
administration.  
Care must be taken to assure sterility of the prepared solution, as the drug product does 
NOT contain any antimicrobial preservatives or bacteriostatic agents. 
All dilutions and transfers of Belatacept must be performed using polypropylene 
non-siliconized syringes (Norm-Ject) manufactured by Henke Sass Wolf in 
Germany and filtered using a 1.2 µm FILTERFLOW® filter extension set. 
NOTE: It is recommended that a separate needle and syringe be used to withdrawal the 
drug product solution from each vial. 
Glass bottles are acceptable for belatacept infusions. 
The Belatacept solution should then be diluted in D5W or NSS to a final Belatacept 
concentration as low as 1 mg/mL. The volume of the fully diluted infusion solution 
should be approximately 100 mL. 
The final Belatacept solution should be visually inspected for particulate matter prior to 
administration. 
The continuous infusion solution must be filtered upon administration using an in-line, 
sterile, non-pyrogenic, low protein-binding filter with a pore size of 1.2 µm (to be 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 45 of 93 
provided by BMS). This infusion should be administered over a period of approximately 
30 minutes. Any unused portion of the infusion solution should not be stored for reuse. 
No data are available on the compatibility of Belatacept with other i.v. substances. Other 
drug substances should not be added or infused simultaneously through the same i.v. line. 
Assure adequate, appropriate flushing between each drug substance if multiple drugs are 
administered through the same line sequentially. 
10.2 Other Agents 
Alemtuzumab will be administered in an inpatient setting and the patient will be 
monitored with pulse oximetry..  A well-described first dose effect is seen with all anti-
lymphocyte preparations though more aggressive cardiopulmonary monitoring is not 
typically necessary. Additional monitoring can be implemented as deemed necessary by 
the Principal Investigator in keeping with the standard of care. Belatacept will be 
administered as an inpatient for doses 1 and 2 and may be given as an outpatient 
thereafter.  Alemtuzumab may be administered via a central venous catheter, a vascular 
dialysis access, or peripherally and will be administered over a 3 hour period by the 
nursing or anesthetic staff. Premedication will be given as described above for 
alemtuzumab prior to drug dosing. Drug will be administered while a member of the 
attending staff is physically on-site. A member of the attending staff will physically 
examine the patient prior to the first 2 doses of Belatacept. All patients receiving 
alemtuzumab or Belatacept will have adequate vascular access to support resuscitative 
efforts should they be required.  
Patients requiring dialysis will be dialyzed prior to receiving alemtuzumab or Belatacept. 
The transplant pharmacy staff will prepare alemtuzumab and Belatacept within 6 hours of 
administration. See package insert (alemtuzumab) or Investigators’ Brochure (Belatacept) 
for how drug is supplied and prepared. 
No special precautions are warranted in handling alemtuzumab or Belatacept or solutions 
containing these agents. Empty and partially used ampules or vials should be disposed of 
according to each institution’s standard policies for disposal of biological waste. 
Sirolimus will be administered orally initially by the nursing or physician staff, and 
eventually by the patient in keeping with the package insert. 
 
11 ADVERSE EVENT REPORTING 
11.1 Importance of Adverse Event Reporting  
 
Timely and complete reporting of safety information assists in identifying any untoward 
medical occurrence, thereby allowing:  (1) protection of safety of study subjects; (2) a 
greater understanding of the overall safety profile of the investigational product; (3) 
recognition of dose-related investigational product toxicity; (4) appropriate modification 
of study protocols; (5) improvements in study design or procedures; and (6) adherence to 
worldwide regulatory requirements. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 46 of 93 
11.2 Data Safety Monitoring Plan 
The safety of interventions and treatments associated with this protocol will be under 
continuous review by the investigative team. A formal Data Safety Monitoring Board 
will be established to monitor the conduct and progress of the trial and to insure the 
prompt implementation of patient safeguards. The Board will be assembled including 
three non-trial affiliated individuals: a nephrologist, a transplant surgeon, and at least one 
other medical personnel with sufficient knowledge of transplantation to interpret the 
ongoing progress of the trial. The Principal Investigator will notify the Board of all 
Serious Adverse Events, and data pertinent to patient recruiting and outcome. The Board 
will meet annually and convey its recommendations in writing to the Sponsor-
investigator and Principal Investigator.. DSMB reports will be submitted to the 
Institutional Review Board per IRB requirements and meeting minutes will be 
disseminated to all necessary parties. 
All adverse events will be reviewed weekly in a multidisciplinary format that will involve 
review by a transplant surgeon, a transplant physician, and other members of the 
transplant staff. All Serious Adverse Events will be reviewed within the accepted 
guidelines and submitted to the appropriate regulatory bodies governing this study.  
Renal failure has many known complications. Pre-existing conditions, which progress in 
keeping with known history, will not be expeditiously reported. This protocol is not 
designed to influence those pre existing complications in any way. Therefore, only acute 
exacerbations that deviate from their natural history will be reported. 
11.3 Collection of Safety Information 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and that does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a investigational 
(medicinal) product (IP), whether or not considered related to the IP.  
During clinical trials, adverse events can be spontaneously reported or elicited during 
open-ended questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific occurrence of one 
or more adverse events.) 
Following the subject’s written consent to participate in the study, all serious AEs should 
be collected, including those thought to be associated with clinical trial procedures. The 
collection of non-serious AE information should begin at initiation of investigational 
product. Non-serious AE information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline status for the 
subjects. Following study completion, any SAE thought to be related to study drug or 
clinical trial procedures should also be reported. 
Certain adverse events occur commonly in this study population and will not be recorded 
as an adverse event, unless it is believed to be associated with the study medications 
(Alemtuzumab, Sirolimus, Belatacept) and/or it meets the definition of a serious adverse 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 47 of 93 
event. This list is inclusive of, but not limited to events noted below, and will be at the 
discretion of the Principal Investigator. 
 
 Occurrence of: 
• Post-op pain. 
• Isolated upper respiratory infection, nasopharyngitis, cough, dyspnea and 
bronchitis. 
• Isolated episodes of diarrhea, constipation, nausea, abdominal distention and 
vomiting.  
• Hypokalemia/hyperkalemia, hyponatremia/hypernatreima, hypocalcemia,/ 
hypercalcemia, hypophosphatemia/hyperphosphatemia,  
/hypomagnesemia,/hypermagnesemia, hyperuricemia and hyperglycemia 
• Peripheral edema 
• Hematuria, proteinuria, glycosuria and dysuria. 
• Headache, dizziness, tremor, insomnia, anxiety, fatigue and depression.  
• AVF thrombosis and renal artery stenosis. 
• Incontinence, hydronephrosis, hematoma, lymphocele, musculoskeletal pain, and 
atrial fibrillation.  
• Acne, facial/body rash, and folliculitis.  
 
Data on concomitant medications will be collected only if they are related to the 
treatment of a serious adverse or adverse event that is probably, possibly, or definitely 
related to study medications. All identified AEs must be recorded and described on the 
appropriate Non-serious or Serious AE page of the CRF. If known, the diagnosis of the 
underlying illness or disorder should be recorded, rather than its individual symptoms. 
The following information should be captured for all AEs: date (and time) of onset and 
resolution, severity of the event (see definitions), Investigator’s opinion of the 
relationship to investigational product (see definitions), treatment required for the AE, 
cause of the event (if known), and information regarding resolution/outcome. The 
Investigator shall supply the Sponsor and Ethics Committee with any additional 
requested information, notably for reported deaths of subjects. 
The following categories and definitions of severity should be used: 
•  
Grading Criteria  
The study site will grade the severity of adverse events experienced by the study subjects 
according to the criteria set forth in the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events Version (CTCAE). This document (referred to 
herein as the NCI-CTCAE manual) provides a common language to describe levels of 
severity, to analyze and interpret data, and to articulate the clinical significance of all 
adverse events  
 
Adverse events will be graded on a scale from 1 to 5 according to the following standards 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 48 of 93 
NCI-CTCAE manual:  
 
• Grade 1 = mild adverse event. (Awareness of event but easily tolerate.) 
• Grade 2 = moderate adverse event (Discomfort enough to cause some interferences     
with usual activity) 
• Grade 3 = severe and undesirable adverse event. (Inability to carry out usual activity). 
• Grade 4 = life-threatening or disabling adverse event..(Debilitating significantly 
incapacitates subject despite symptomatic therapy). 
• Grade 5 =Death 
 
The following categories and definitions of causal relationship to study drug should be 
used: 
• Certain:  There is a reasonable causal relationship between the study drug and the AE. 
The event responds to withdrawal of study drug (dechallenge), and recurs with 
rechallenge when clinically feasible. 
• Probable:  There is a reasonable causal relationship between the study drug and the 
AE. The event responds to dechallenge. Rechallenge is not required. 
• Possible:  There is reasonable causal relationship between the study drug and the AE. 
Dechallenge information is lacking or unclear. 
• Not likely: There is a temporal relationship to study drug administration, but there is 
not a reasonable causal relationship between the study drug and the AE.  
• Not related:  There is not a temporal relationship to study drug administration (too 
early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, concurrent disease, or circumstance and the AE. 
Adverse Events Related to Study Conditions 
If the Investigator believes that an SAE is not related to the investigational product, but is 
potentially related to the conditions of the study, (such as withdrawal of previous therapy, 
or complication of a trial procedure), the relationship should be specified in the narrative 
section of the SAE page of the CRF.  
11.4 OverdoseAn overdose is defined as the accidental or intentional ingestion of any 
dose of a product that is considered both excessive and medically important. For 
reporting purposes, BMS considers an overdose, regardless of adverse outcome, as an 
important medical event (see Serious Adverse Events). 
11.5 AE Follow-up 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious. This also applies to subjects experiencing AEs that cause interruption or 
discontinuation of investigational product, or those experiencing AEs that are present at 
the end of their participation in the study; such subjects should receive post-treatment 
follow-up as appropriate. If an ongoing AE changes in its severity or in its perceived 
relationship to study drug, a new AE entry for the event should be completed. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 49 of 93 
11.6 Reporting of AE Information Following Study Completion 
Collection of safety information following the end of investigational product 
administration is important in assisting in the identification of possible delayed toxicities 
or withdrawal effects.  All SAEs must be collected which occur within 56 days of 
discontinuation of dosing or completion of the subject’s participation in the study if the 
last scheduled visit occurs at a later time. In addition, the Investigator should report any 
SAE which may occur after this time period which they believe to be certainly, probably 
or possibly related to investigational product.  Finally, all events of death, graft loss, 
malignancy, PTLD, and serious infections (i.e., otherwise meeting SAE reporting 
requirements) must be reported for all randomized subjects until the end of the study, 
irrespective of study drug discontinuation or investigator-deemed causality. 
11.7 Handling of Serious Adverse Events (SAEs) 
A serious AE or reaction is any untoward medical occurrence that at any dose:  
• results in death,  
• is life-threatening (defined as an event in which the patient or subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe),  
• requires inpatient hospitalization or prolongation of existing hospitalization, (refer to 
note for exceptions), 
• results in persistent or significant disability/incapacity,  
• is a congenital anomaly/birth defect,  
• is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient/subject or 
may require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above.)   
NOTE: 
• Pregnancy:  Incidence of pregnancy is not considered a SAE; pregnancy must, 
however, be reported immediately using the BMS Pregnancy Surveillance Form 
• Cancer/Overdose: All cases of cancer and overdose must be reported immediately 
using the SAE Report Form.  
• Hospitalizations (exceptions):  Criteria for hospitalizations not reported as SAEs 
include admissions for: 
o Planned as per protocol medical/surgical procedure 
o Routine health assessment requiring admission for baseline/trending of health 
status documentation (e.g., routine colonoscopy) 
o Medical/surgical admission for purpose other than remedying ill health state 
(planned prior to entry into study trial; appropriate documentation required)  
o Admission encountered for other life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g. lack of 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 50 of 93 
housing, economic inadequacy, care-giver respite, family circumstances, 
administrative) 
An SAE report should be completed for any event where doubt exists regarding its status 
of seriousness. 
Adverse events classified as “serious” require expeditious handling and reporting to BMS 
to comply with regulatory requirements.  
All serious AEs whether related or unrelated to investigational product, must be 
immediately reported to BMS (or designee) by confirmed facsimile transmission.  If only 
limited information is initially available, follow-up reports are required.  The original 
SAE form must be kept on file at the study site. 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 7 
days (death or life-threatening event) or 15 days (all other SAEs) after the investigator’s 
or institution’s initial receipt of the information.  Bristol-Myers Squibb will be provided 
with a simultaneous copy via facsimile of all adverse events filed with the FDA.  SAEs 
should be reported on the MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/MedWatch/ 
MedWatch forms should be sent to the FDA online at the above internet address 
or at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD  20852-9787 
Fax:  1-800-FDA-0178 (1-800-332-0178) 
 
Cases of pregnancy must be reported on paper Pregnancy Surveillance Forms in lieu of 
SAE pages. 
Collection of complete information concerning SAEs is extremely important. Thus, 
follow-up information which becomes available as the SAE evolves, as well as 
supporting documentation (e.g., hospital discharge summaries and autopsy reports), 
should be collected subsequently, if not available at the time of the initial report, and 
immediately sent using the same procedure as the initial SAE report. 
In accordance with local regulations, Investigators will be notified of all AEs that are 
serious, unexpected, and certainly, probably, or possibly related to the investigational 
product or serious reportable adverse events which could be associated with the trial 
procedures. This notification will be in the form of an Expedited Safety Report (ESR).  
Upon receiving such notices, the Investigator must review and retain the ESR with the 
Investigator Brochure. Where required by local regulations or when there is a central 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the study, the 
Sponsor will submit the ESR to the appropriate IRB/IEC. The Investigator and IRB/IEC 
will determine if the informed consent requires revision. The Investigator should also 
comply with the IRB/IEC procedures for reporting any other safety information. Where 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 51 of 93 
required, submission of ESRs by the Investigator to Health Authorities should be handled 
according to local regulations. 
Periodically, according to the Investigator Brochure SOP, the Investigator Brochure will 
be updated and include new and relevant safety information. Until such time that an AE 
becomes identified in the Investigator Brochure, it should be considered unexpected, 
regardless of whether the AE has been the subject of a previous ESR.  
11.8 Laboratory Test Abnormalities 
At a minimum, the following laboratory abnormalities should be captured on the non-
serious or serious AE pages of the CRF as appropriate: 
• Any laboratory test result that meets the criteria for a Serious Adverse Event  
• Any laboratory abnormality that requires the subject to have investigational product 
discontinued or interrupted 
• Any laboratory abnormality that requires the subject to receive specific corrective 
therapy, that is not seen commonly in the study population as previously defined. 
It is expected that wherever possible, the clinical, rather than the laboratory term would 
be used by the reporting Investigator (e.g., anemia versus low hemoglobin value). 
11.9 Other Safety Considerations 
Any clinically significant changes noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded on the appropriate 
AE page of the CRF (i.e., NON-SERIOUS or SERIOUS). 
11.10 Pregnancy 
Sexually active women of childbearing potential must use an effective method of birth 
control during the course of the study, in a manner such that risk of failure is minimized. 
(See Section 5.1 for definition of WOCBP). 
Before enrolling women of childbearing potential (WOCBP) in this clinical trial, 
Investigators must review the guidelines about study participation for WOCBP. The 
topics include the following: 
• General Information 
• Informed Consent Form 
• Pregnancy Prevention Information Sheet 
• Drug Interactions with Hormonal Contraceptives 
• Contraceptives in Current Use 
• Guidelines for the Follow-up of a Reported Pregnancy 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion.  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 52 of 93 
All WOCBP MUST have a negative pregnancy test within 72 hours prior to receiving 
investigational product. The minimum sensitivity of the pregnancy test must be 25 IU/L 
or equivalent units of HCG. If the pregnancy test is positive, the subject must not receive 
investigational product and must not be enrolled in the study. 
Pregnancy testing must also be performed periodically throughout the study  and the 
results of all pregnancy tests (positive or negative) recorded on the case report form. 
In addition, all WOCBP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual period) at any time 
during study participation. 
If following initiation of study treatment, it is subsequently discovered that a trial subject 
is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g., dose tapering if 
necessary for subject safety). Exceptions to investigational product discontinuation may 
be considered for life-threatening conditions only after consultation with the BMS 
Medical Monitor or as otherwise specified in this protocol. The Investigator must 
immediately notify the BMS Medical Monitor of this event and record the pregnancy on 
the Pregnancy Surveillance Form. Pregnancy Surveillance Forms are forwarded to BMS.  
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
Investigator must report to BMS, on the appropriate BMS pregnancy surveillance 
forms(s), follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome. Infants should be followed for a minimum of eight 
weeks. 
 
12 ADMINISTRATIVE SECTION 
12.1 Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in this approved protocol. The Investigator 
should not implement any deviation or change to the protocol without prior review and 
documented approval/favorable opinion from the IRB/IEC of an Amendment, except 
where necessary to eliminate an immediate hazard(s) to study subjects.  
12.2 Informed Consent 
Informed consent will be obtained from each participant before enrollment. Additional 
informed consent will be obtained before beginning withdrawal of sirolimus. 
Investigators must ensure that subjects or their legally acceptable representative are 
clearly and fully informed about the purpose, potential risks and other critical issues 
regarding clinical trials in which they volunteer to participate. 
The following sections contain procedures on obtaining informed consent from subjects 
or their legally acceptable representative prior to participating in a clinical trial. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 53 of 93 
Procedures are described for all subjects, including those who are unable to give 
informed consent. The relevant procedures must be used whenever they are applicable. 
12.3 Informed Consent Procedures 
Preparation of the consent form is the responsibility of the Investigator and must include 
all elements required by ICH, GCP and applicable regulatory requirements, and must 
adhere to GCP and to the ethical principles that have their origin in the Declaration of 
Helsinki. The consent form must also include a statement that BMS and regulatory 
authorities have direct access to subject records. Prior to the beginning of the study, the 
Investigator must have the IRB/IEC’s written approval/favorable opinion of the written 
informed consent form and any other information to be provided to the subjects. 
The Investigator must provide the subject or legally acceptable representative with a copy 
of the consent form and written information about the study in the language in which the 
subject is most proficient. The language must be non-technical and easily understood. 
The Investigator should allow time necessary for subject or subject's legally acceptable 
representative to inquire about the details of the study, then informed consent must be 
signed and personally dated by the subject or the subject's legally acceptable 
representative and by the person who conducted the informed consent discussion. The 
subject or legally acceptable representative should receive a copy of the signed informed 
consent and any other written information provided to study subjects prior to subject's 
participation in the trial. 
12.4 Subjects Unable to Give Informed Consent 
12.4.1 Subjects Experiencing Acute Events or Emergencies 
A legally acceptable representative or legal guardian must provide informed consent 
when consent of the subject is not possible prior to clinical trial participation, e.g., for 
subjects experiencing an acute medical event such as myocardial infarction or stroke. 
Informed consent of the subject must additionally be obtained if they become capable of 
making and communicating their informed consent during the clinical trial. All local 
laws, rules and regulations regarding informed consent of adult subjects incapable of 
giving informed consent must be followed. 
12.4.2 Mentally Impaired or Incapacitated Subjects 
Investigators should determine whether or not a mentally impaired or incapacitated 
subject is capable of giving informed consent and should sign a statement to that effect. If 
the subject is deemed mentally competent to give informed consent, the Investigator 
should follow standard procedures. If the subject is deemed not to be mentally competent 
to give informed consent, a fully informed legal guardian or legally acceptable 
representative can be asked to give consent for, or on behalf of, the subject. All local 
laws, rules and regulations regarding informed consent of mentally impaired or 
incapacitated subjects must be followed. 
Subjects who are involuntarily hospitalized because of mental illness must not be 
enrolled in clinical trials. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 54 of 93 
12.4.3 Other Circumstances  
Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness must not be enrolled in clinical trials.  
In circumstances where a subject’s only access to treatment is through enrollment in a 
clinical trial, e.g., for subjects in developing countries with limited resources or for 
subjects with no marketed treatment options, the Investigator must take special care to 
explain the potential risks and benefits associated with the trial and ensure that the subject 
is giving informed consent. 
When a subject may be in a dependent relationship with the Investigator, a well-informed 
physician who is not engaged in the clinical trial and is completely independent of the 
relationship between the subject and Investigator should obtain the subject’s informed 
consent. 
12.5 Illiterate Subjects 
If the subject or legally acceptable representative is unable to read, a reliable and 
independent witness should be present during the entire informed consent discussion. The 
choice of the witness must not breach the subject’s rights to confidentiality. A reliable 
independent witness is defined as one not affiliated with the institution or engaged in the 
investigation. A family member or acquaintance is an appropriate independent witness. 
After the subject or legally acceptable representative orally consents and has signed, if 
capable, the witness should sign and personally date the consent form attesting that the 
information is accurate and that the subject or legally acceptable representative has fully 
understood the content of the informed consent agreement and is giving true informed 
consent.  
12.6 Update of Informed Consent 
The informed consent and any other information provided to subjects or the subject's 
legally acceptable representative, should be revised whenever important new information 
becomes available that is relevant to the subject's consent, and should receive IRB/IEC 
approval/favorable opinion prior to use. The Investigator, or a person designated by the 
Investigator should fully inform the subject or the subject's legally acceptable 
representative of all pertinent aspects of the study and of any new information relevant to 
the subject's willingness to continue participation in the study. This communication 
should be documented.  
During a subject's participation in the trial, any updates to the consent form and any 
updates to the written information will be provided to the subject. 
13 RECORDS AND REPORTS 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated with the investigational product or entered as a control in the 
investigation. Data reported on the CRF, that are derived from source documents, must be 
consistent with the source documents or the discrepancies must be explained.  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 55 of 93 
Paper CRFs must be completed legibly in ink. Subjects are to be identified by initials, 
birth date and subject number, if applicable. All requested information must be entered 
on the CRF in the spaces provided. If an item is not available or is not applicable, it must 
be documented as such; do not leave a space blank.  
The confidentiality of records that could identify subjects must be protected, respecting 
the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s). 
The completed CRF including any paper SAE CRFs must be promptly reviewed, signed, 
and dated by a qualified physician who is an Investigator or Sub-investigator. The 
Investigator must retain a copy of the CRFs including records of the changes and 
corrections. 
13.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
Before study initiation, the Investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment 
materials/process (e.g., advertisements), and any other written information to be provided 
to subjects. The Investigator or Sponsor should also provide the IRB/IEC with a copy of 
the Investigator Brochure or product labeling, information to be provided to subjects.  
The Investigator or Sponsor should provide the IRB/IEC with reports, updates and other 
information (e.g., ESR, Amendments, Administrative Letters) according to regulatory 
requirements or Institution procedures. 
13.2 Records Retention 
The Investigator must retain investigational product disposition records, copies of CRFs 
(paper or electronic files), and source documents for the maximum period required by 
applicable regulations and guidelines, or Institution procedures, or for the period 
specified by the Sponsor, whichever is longer. The Investigator must contact BMS prior 
to destroying any records associated with the study. 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (e.g., another Investigator, IRB). 
Notice of such transfer will be given in writing to BMS. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 56 of 93 
14 REFERENCES 
1. 
Kirk AD, Mead S, Xu H, Mehta A, Guasch A, Cheeseman J, Joseph J, Horan J, 
Kean L, Larsen CP, Pearson TC. Kidney Transplantation Using Alemtuzumab 
Induction and Belatacept/Sirolimus Maintenance Therapy.  Am J Transplant 2011; 
11(Suppl 2):S45. 
2. 
Kirk AD. Clinical Tolerance 2008. Transplantation 87:953-955, 2009. 
PMCID:PMC2706092 
3. 
Xu H, Mehta AK, Mead S, Cheeseman J, Stempora L, Pearson TC, Larsen C, Kirk 
AD.  Belatacept , but Not Calcineurin Inhibitors, Preserve Human CMV-specific 
Memory Cell Responses. Am J Transplant 2011; 11(Suppl 2):S44. 
4. 
Organ Procurement and Transplantation Network (OPTN) and Scientific Registry or 
Transplant Recipients (SRTR). OPTN/SRTR 2010 Annual Data Report. Department 
of Health and Human Services, Hea;th and Services Administration, Healthcare 
Systems Bureau, Division of Transplantation. Am J Transplant 2012; 
12(Suppl1):S1-154. 
5. 
Eggers PW. Effect of transplantation on the Medicare end-stage renal disease 
program.  N Engl J Med 1988; 318:223-229. 
6. 
Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the 
United States: a critical reappraisal. Am J Transplant 2011; 11:450-462. 
7. 
Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, 
Leichtman AB. Immunosuppression: evolution in practice and trends, 1994-2004. 
Am J Transplant. 2006; 6:1111-1131. 
8. 
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. 
KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J 
Transplant 2009; 9 Suppl 3:S1-155. 
9. 
Pirsch JD, D’Alessandro AM, Sollinger HW, Knechtle SJ, Reed A, Kalayoglu M, 
Belzer FO. Hyperlipidemia and transplantation: etiologic factors and therapy.  J Am 
Soc Nephrol 1992; 2:S238-S242.  
10. Shaw LM, Kaplan B, Kaufman D. Toxic effects of immunosuppressive drugs: 
mechanisms and strategies for controlling them.  Clin Chem 1996; 42:1316-1321. 
11. Boubenider S, Hiesse C, Goupy C, Kriaa F, Marchand S, Charpentier B: Incidence 
and consequences of post-transplantation lymphoproliferative disorders.  J Nephrol 
1997; 10:136-145. 
12. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 
338:1741-1751.  
13. DeMario MD, Liebowitz DN. Lymphomas in the immunocompromised patient.  
Semin Oncol 1998; 25:492-502. 
14. Sia IG, Paya CV. Infectious complications following renal transplantation.  Surg 
Clin North Am 1998; 78:95-112. 
15. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus 
(FK506) and cyclosporine for immunosuppression after cadaveric renal 
transplantation. FK506 Kidney Transplant Study Group.  Transplantation 1997; 
63:977-983. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 57 of 93 
16. Bloom RD, Crutchlow MF. New-onset diabetes mellitus in the kidney recipient: 
diagnosis and management strategies. Clin J Am Soc Nephrol 2008; 3 Suppl 2:S38-
48. 
17. Wadei HM, Textor SC. Hypertension in the kidney transplant recipient. Transplant 
Rev 2010; 24:105-120. 
18. Senzolo M, Ferronato C, Burra P. Neurologic complications after solid organ 
transplantation. Transpl Int 2009; 22:269-278. 
19. Chapman JR. Chronic calcineurin inhibitor nephrotoxicity-lest we forget. Am J 
Transplant 2011; 11:693-697. 
20. Casey MJ, Meier-Kriesche HU. Calcineurin inhibitors in kidney transplantation: 
friend or foe? Curr Opin Nephrol Hypertens 2011; 20:610-615. 
21. Dharnidharka VR, Lamb KE, Gregg JA, Meier-Kriesche HU. Associations Between 
EBV Serostatus and Organ Transplant Type in PTLD Risk: An Analysis of the 
SRTR National Registry Data in the United States. Am J Transplant 2012 Jan 6. 
[Epub ahead of print]. 
22. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. Blocking both signal 1 
and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and 
induction of peripheral allograft tolerance. Nat Med 1999; 5:1298-1302. 
23. Wells AD, Li XC, Li Y, Walsh MC, Zheng XX, Wu Z, Nuñez G, Tang A, Sayegh 
M, Hancock WW, Strom TB, Turka LA. Requirement for T-cell apoptosis in the 
induction of peripheral transplantation tolerance. Nat Med 1999; 5:1303-1307. 
24. Li XC, Wells AD, Strom TB, Turka LA. The role of T cell apoptosis in 
transplantation tolerance. Curr Opin Immunol 2000; 12:522-527. 
25. Newell KA, Larsen CP. Transplantation Tolerance. Semin Nephrol 2007; 27:487-97.  
26. Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, Bradley J, Smith K, 
Waldmann H. Prope tolerance, perioperative campath 1H, and low-dose cyclosporin 
monotherapy in renal allograft recipients. Lancet 1998; 351:1701-1702. 
27. Kirk AD, Hale DA, Mannon RB, Kleiner DE, Hoffmann SC, Kampen RL, Cendales 
LK, Tadaki DK, Harlan DM, Swanson SJ. Results from a human renal allograft 
tolerance trial evaluating the humanized CD52-specific monoclonal antibody 
Campath-1H. Transplantation  2003; 76:120-129. 
28. Knechtle SJ, Pirsch JD, Fechner Jr JH, Becker BN, Friedl A, Colvin RB, Lebeck 
LK, Chin LT, Becker YT, Odorico JS, D'Alessandro AM, Kalayoglu M, Hamawy 
MM, Hu H, Bloom DD, Sollinger HW. Campath-1H induction plus rapamycin 
monotherapy for renal transplantation: results of a pilot study. Am J Transplant 
2003; 3:722–730. 
29. Shapiro R, Basu A, Tan H, Gray E, Kahn A, Randhawa P, Murase N, Zeevi A, 
Girnita A, Metes D, Ness R, Bass DC, Demetris AJ, Fung JJ, Marcos A, Starzl TE. 
Kidney transplantation under minimal immunosuppression after pretransplant 
lymphoid depletion with Thymoglobulin or Campath. J Am Coll Surg 2005; 
200:505-515. 
30. Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, Smith KG, Thiru 
S, Jamieson NV, Hale G, Waldmann H, Calne R. Alemtuzumab (CAMPATH 1H) 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 58 of 93 
Induction Therapy in Cadaveric Kidney Transplantation-Efficacy and Safety at Five 
Years. Am J Transplant 2005; 5:1347-1353. 
31. Tan HP, Kaczorowski DJ, Basu A, Unruh M, McCauley J, Wu C, Donaldson J, 
Dvorchik I, Kayler L, Marcos A, Randhawa P, Smetanka C, Starzl TE, Shapiro R. 
Living donor renal transplantation using alemtuzumab induction and tacrolimus 
monotherapy. Am J Transplant 2006; 6:2409-2417. 
32. Morris PJ, Russell NK. Alemtuzumab (Campath-1H): a systematic review in organ 
transplantation. Transplantation 2006; 81:1361-1367. 
33. Weaver TA, Kirk AD. Alemtuzumab. Transplantation 2007; 84:1545-1547. 
34. Harlan DM, Kirk AD. The future of organ and tissue transplantation: is a new 
paradigm on the horizon? J Amer Med Assoc 1999; 282:1076-1082. 
35. Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobert E, Anderson D, 
Cowan S, Price K, Naemura J, Emswiler J, Greene J, Turk LA, Bajorath J, 
Townsend R, Hagerty D, Linsley PS, Peach RJ. Rational development of LEA29Y 
(belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive 
properties. Am J Transplant 2005; 5:443-453. 
36. Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G, Lang P, 
Grinyo J, Halloran PF, Solez K, Hagerty D, Levy E, Zhou W, Natarajan K, 
Charpentier B; Belatacept Study Group. Costimulation blockade with belatacept in 
renal transplantation. N Engl J Med 2005 353:770-781. 
37. Larsen CP, Knechtle SJ, Adams A, Pearson T, Kirk AD. A new look at blockade of 
T-cell co-stimulation: a therapeutic strategy for long-term maintenance 
immunosuppression. Am J Transplant 2006; 6:876-883. 
38. Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, 
Massari P, Mondragon-Ramirez GA, Agarwal M, Di Russo G, Lin CS, Garg P, 
Larsen CP. A phase III study of belatacept-based immunosuppression regimens 
versus cyclosporine in renal transplant recipients (BENEFIT study). Am J 
Transplant 2010; 10:535-546. 
39. Durrbach A, Pestana JM, Pearson T, Vincenti F, Garcia VD, Campistol J, Rial Mdel 
C, Florman S, Block A, Di Russo G, Xing J, Garg P, Grinyó J. A phase III study of 
belatacept versus cyclosporine in kidney transplants from extended criteria donors 
(BENEFIT-EXT study). Am J Transplant 2010; 10:547-557. 
40. Vincenti F, Larsen CP, Alberu J, Bresnahan B, Garcia VD, Kothari J, Lang P, Urrea 
EM, Massari P, Mondragon-Ramirez G, Reyes-Acevedo R, Rice K, Rostaing L, 
Steinberg S, Xing J, Agarwal M, Harler MB, Charpentier B. Three-Year Outcomes 
from BENEFIT, a Randomized, Active-Controlled, Parallel-Group Study in Adult 
Kidney Transplant Recipients. Am J Transplant 2012; 12:210-217. 
41. Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A, Grinyó J, Neumayer HH, 
Lang P, Larsen CP, Mancilla-Urrea E, Pestana JM, Block A, Duan T, Glicklich A, 
Gujrathi S, Vincenti F. Belatacept-based regimens are associated with improved 
cardiovascular and metabolic risk factors compared with cyclosporine in kidney 
transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 2011; 
91:976-983. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 59 of 93 
42. Stepkowski SM. Sirolimus, a potent new immunosuppressive drug for organ 
transplantation. Ann Transplant 1996;1:19-25. 
43. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action 
immunosuppressive effect results from blockade of signal transduction and 
inhibition of cell cycle progression. Clin Biochem 1998; 31:335-340. 
44. Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc 
Natl Acad Sci U S A 2001; 98:7037-7044. 
45. Mulay AV, Hussain N, Fergusson D, Knoll GA. Calcineurin inhibitor withdrawal 
from sirolimus-based therapy in kidney transplantation: a systematic review of 
randomized trials. Am J Transplant 2005; 5:1748-1756. 
46. Bestard O, Cassis L, Cruzado JM, Torras J, Franquesa M, Gil-Vernet S, Lucia M, 
Grinyó JM. Costimulatory blockade with mTor inhibition abrogates effector T-cell 
responses allowing regulatory T-cell survival in renal transplantation. Transpl Int 
2011; 24:451-460. 
47.http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/defa
ult.htm. Accessed January 29, 2012. 
48. Archdeacon P, Chan M, Neuland C, Velidedeoglu E, Meyer J, Tracy L, Cavaille-
Coll M, Bala S, Hernandez A, Albrecht R. Summary of FDA antibody-mediated 
rejection workshop. Am J Transplant 2011; 11:896-906. 
49. Bradley JA, Baldwin WM, Bingaman A, Ellenrieder C, Gebel HM, Glotz D, Kirk 
AD. Antibody mediated rejection-an ounce of prevention is worth a pound of cure. 
Am J Transplant 2011; 11:1131-1139. 
50. Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, Pruett TL, Bray RA, 
Gebel HM, Matas AJ. Revisiting traditional risk factors for rejection and graft loss 
after kidney transplantation. Am J Transplant 2011; 11:2132-2143. 
51. Singh N, Pirsch J, Samaniego M. Antibody-mediated rejection: treatment 
alternatives and outcomes. Transplant Rev 2009; 23:34-46. 
52. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, 
Famulski K, Matas A, Halloran PF. Understanding the Causes of Kidney Transplant 
Failure: The Dominant Role of Antibody-Mediated Rejection and Nonadherence. 
Am J Transplant 2011 Nov 14. [Epub ahead of print]. 
58. Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an 
overview. Am J Kidney Dis 2001; 38:S25-35. 
59. Kirk AD. Overview: Induction Immunosuppression. Transplantation 2006; 82:503-
602. 
60. Pondrum S. AJT Report: Alemtuzumab shows promise as off-label therapy. Am J 
Transplant 2011; 11:1761-1762. 
61. Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR. 
Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell 
activation. Science 1989;246:1617-1620. 
62. Mattila PS, Ullman KS, Fiering S, Emmel EA, McCutcheon M, Crabtree GR, 
Herzenberg LA. The actions of cyclosporin A and FK506 suggest a novel step in the 
activation of T lymphocytes. EMBO J 1990;9:4425-4433. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 60 of 93 
63. Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme 
in T-lymphocyte activation. Nature 1992;357:695-697. 
64. Bram RJ, Crabtree GR. Calcium signalling in T cells stimulated by a cyclophilin B-
binding protein. Nature 1994;371:355-358. 
65. Asberg A, Jardine AG, Bignamini AA, Rollag H, Pescovitz MD, Gahlemann CC, 
Humar A, Hartmann A; VICTOR Study Group. Effects of the intensity of 
immunosuppressive therapy on outcome of treatment for CMV disease in organ 
transplant recipients. Am J Transplant 2010; 10:1881-1888. 
66. Ekberg H, Bernasconi C, Noldeke J, Yussim A, Mjörnstedt L, Erken U, Ketteler M, 
Navrátil P. Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity 
profiles despite low doses in the Symphony study. Nephrol Dial Transplant 2010; 
25:2004-2010. 
67. Ekberg H, Grinyo J, Nashan B, Vanrenterghem Y, Vincenti F, Voulgari A, Truman 
M, Nasmyth-Miller C, Rashford M. Cyclosporine sparing with mycophenolate 
mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR 
Study. Am J Transplant 2007; 7:560-570. 
68. Gaston RS. Chronic calcineurin inhibitor nephrotoxicity: reflections on an evolving 
paradigm. Clin J Am Soc Nephrol 2009; 4:2029-2034. 
69. Nashan B. Is acute rejection the key predictor for long-term outcomes after renal 
transplantation when comparing calcineurin inhibitors? Transplant Rev 2009; 23:47-
52. 
70. Press RR, de Fijter JW, Guchelaar HJ. Individualizing calcineurin inhibitor therapy 
in renal transplantation-current limitations and perspectives. Curr Pharm Des 2010; 
16:176-186. 
71. Kasiske BL, Cohen D, Lucey MR, Neylan JF. Payment for immunosuppression after 
organ transplantation. J Am Med Assoc 2000; 283:2445-2450. 
72. Timothy F. Page, Ph.D. and Robert S. Woodward. Cost of Lifetime 
Immunosuppression Coverage for Kidney Transplant Recipients. Health Care 
Financing Rev 2008; 30:95-104. 
73. Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, Taylor RS. Clinical 
and cost-effectiveness of newer immunosuppressive regimens in renal 
transplantation: a systematic review and modeling study. Health Technol Assess 
2005; 9:1-179. 
74. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, 
Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal 
organ. N Engl J Med 2003; 349:931-940. 
75. Larsen CP, Elwood ET, Alexander DZ, Ritchie SC, Hendrix R, Tucker-Burden C, 
Cho HR, Aruffo A, Hollenbaugh D, Linsley PS, Winn KJ, Pearson TC. Long-term 
acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. 
Nature 1996; 381:434-438. 
76. Judge TA, Tang A, Spain LM, Deans-Gratiot J, Sayegh MH, Turka LA. The in vivo 
mechanism of action of CTLA4Ig. J Immunol 1996; 156:2294-2299. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 61 of 93 
77. Adams AB, Durham MM, Kean L, Shirasugi N, Ha J, Williams MA, Rees PA, 
Cheung MC, Mittelstaedt S, Bingaman AW, Archer DR, Pearson TC, Waller EK, 
Larsen CP. Costimulation blockade, busulfan, and bone marrow promote titratable 
macrochimerism, induce transplantation tolerance, and correct genetic 
hemoglobinopathies with minimal myelosuppression. J Immunol 2001; 167:1103-
1111. 
78. Vermeiren J, Ceuppens JL, Van Ghelue M, Witters P, Bullens D, Mages HW, 
Kroczek RA, Van Gool SW. Human T cell activation by costimulatory signal-
deficient allogeneic cells induces inducible costimulator-expressing anergic T cells 
with regulatory cell activity. J Immunol 2004; 172:5371-5378. 
79. Trambley J, Bingaman AW, Lin A, Elwood ET, Waitze SY, Ha J, Durham MM, 
Corbascio M, Cowan SR, Pearson TC, Larsen CP. Asialo GM1(+) CD8(+) T cells 
play a critical role in costimulation blockade-resistant allograft rejection. J Clin 
Invest 1999; 104:1715-1722. 
80. Ford ML, Koehn BH, Wagener ME, Jiang W, Gangappa S, Pearson TC, Larsen CP. 
Antigen-specific precursor frequency impacts T cell proliferation, differentiation, 
and requirement for costimulation. J Exp Med 2007; 204:299-309. 
81. Ford ML, Larsen CP. Overcoming the memory barrier in tolerance induction: 
molecular mimicry and functional heterogeneity among pathogen-specific T-cell 
populations. Curr Opin Organ Transplant 2010; 15:405-410. 
82. Ford ML, Wagener ME, Hanna SS, Pearson TC, Kirk AD, Larsen CP. A critical 
precursor frequency of donor-reactive CD4+ T cell help is required for CD8+ T cell-
mediated CD28/CD154-independent rejection. J Immunol 2008; 180:7203-7211. 
83. Lo DJ, Weaver TA, Stempora L, Mehta AK, Ford ML, Larsen CP, Kirk AD. 
Selective targeting of human alloresponsive CD8+ effector memory T cells based on 
CD2 expression. Am J Transplant 2011; 11:22-33. PMCID:PMC3057516. 
84. Swanson SJ, Hale DA, Mannon RB, Kleiner DE, Chamberlain CE, Polly S, Harlan 
DM, Kirk AD. Kidney transplantation with rabbit antithymocyte globulin induction 
and sirolimus monotherapy. Lancet 2002; 360:1662-1664. 
85. Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy 
R, Holman J; INTAC Study Group. Alemtuzumab induction in renal transplantation. 
N Engl J Med 2011; 364:1909-19. 
86. Ferguson R, Grinyó J, Vincenti F, Kaufman DB, Woodle ES, Marder BA, Citterio F, 
Marks WH, Agarwal M, Wu D, Dong Y, Garg P. Immunosuppression with 
belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant 
recipients. Am J Transplant 2011; 11:66-76. 
87. Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS, Hong X, 
Thomas D, Fechner JH Jr, Knechtle SJ. CTLA4-Ig and anti-CD40 ligand prevent 
renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94:8789-8794. 
88. Kirk AD. Transplant Tolerance: a look at the non-human primate literature in the 
view of modern tolerance theories. Crit Rev Immunol 1999; 19:349-88. 
89. Kirk AD, Tadaki DK, Celniker A, Batty DS, Berning JD, Colonna JO, Cruzata F, 
Elster EA, Gray GS, Kampen RL, Patterson NB, Szklut P, Swanson J, Xu H, Harlan 
DM. Induction Therapy with Monoclonal Antibodies Specific for CD80 and CD86 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 62 of 93 
Delays the Onset of Acute Renal Allograft Rejection in Non-human Primates. 
Transplantation 2001; 72:377-84. 
90. Preston EH, Xu H, Dhanireddy KK, Pearl, JP, Leopardi FV, Starost MF, Hale DA, 
Kirk AD. Synergy between IDEC-131 (anti-CD154), sirolimus, and donor-specific 
transfusion facilitates operational tolerance following renal transplantation in non-
human primates. Am J Transplant 2005; 5:1032-41. 
91. Wells AD, Walsh MC, Bluestone JA, Turka LA. Signaling through CD28 and 
CTLA-4 controls two distinct forms of T cell anergy.  J Clin Invest 2001; 108:895-
903.  
92. Xia MQ, Tone M, Packman L, Hale G, Waldmann H. Characterization of the 
CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an 
unusually small peptide backbone. Eur J Immunol 1991; 21:1677-1684.  
93. Xia MQ, Hale G, Lifely MR, Ferguson MA, Campbell D, Packman L, Waldmann H. 
Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored 
glycoprotein which is an exceptionally good target for complement lysis. Biochem J 
1993; 293:633-640.  
94. Nuckel H, Frey UH, Roth A, Duhrsen U, Siffert W. Alemtuzumab induces enhanced 
apoptosis in vitro in B-cells from patients with chronic lymphocytic leukemia by 
antibody-dependent cellular cytotoxicity. Eur J Pharmacol 2005; 514:217-224.  
95. Stanglmaier M, Reis S, Hallek M. Rituximab and alemtuzumab induce a nonclassic, 
caspase-independent apoptotic pathway in B-lymphoid cell lines and in chronic 
lymphocytic leukemia cells. Ann Hematol 2004; 83:634-645.  
96. Alemtuzumab package insert. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/alemmil050701LB.htm. 
Accessed January 29,2012. 
97. Kirk AD, Cherikh WS, Ring R, Burke G, Kaufman D, Knechtle SJ, Potdar S, 
Shapiro R, Dharnidharka VR, Kauffman HM. Dissociation of Depletional Induction 
and Post Transplant Lymphoproliferative Disease in Kidney Recipients Treated 
With Alemtuzumab. Am J Transplant 2007; 7:2619-2625. 
98. Rapamune package insert. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021083s033,021110s043
lbl.pdf. Accessed January 29,2012. 
99. Li Y, Zheng XX, Li XC, Zand MS, Strom TB. Combined costimulation blockade 
plus rapamycin but not cyclosporine produces permanent engraftment. 
Transplantation 1998; 66:1387-1388. 
100. Gao W, Lu Y, El Essawy B, Oukka M, Kuchroo VK, Strom TB. Contrasting effects 
of cyclosporine and rapamycin in de novo generation of alloantigen-specific 
regulatory T cells. Am J Transplant. 2007; 7:1722-1732. 
101. Xu H, Montgomery SP, Preston EH, Tadaki DK, Hale DA, Harlan DM, Kirk AD. 
Studies investigating pre-transplant donor specific blood transfusion, rapamycin, and 
the CD154-specific antibody IDEC-131 in a non-human primate model of skin 
allotransplantation. J Immunol 2003; 170:2776-2782. 
102. Weaver TA, Charafeddine AH, Agarwal A, Turner AP, Russell M, Leopardi FV, 
Kampen RL, Stempora L, Song M, Larsen CP, Kirk AD. Alefacept Promotes 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 63 of 93 
Costimulation Blockade Based Allograft Survival in Primates. Nat Med 15:746-749, 
2009. PMCID:PMC2772128 
103. Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, Swanson SJ, 
Mannon RB, Roederer M, Kirk AD. Immunocompetent T-cells with a memory-like 
phenotype are the dominant cell type following antibody-mediated T-cell depletion. 
Am J Transplant 2005; 5:465-474. 
104. Kirk AD, Mannon RB, Kleiner DE, Swanson SJ, Kampen RL, Cendales LK, Elster 
EA, Wakefield T, Chamberlain C, Hoffmann SC, Hale DA. Results from a Human 
Renal Allograft Tolerance Trial Evaluating T-Cell Depletion with Alemtuzumab 
combined with Deoxyspergualin. Transplantation 2005; 80:1051-1059. 
105. Montgomery SP, Mog SR, Xu H, Tadaki DK, Hale D, Hirshberg B, Berning JD, 
Leconte J, Harlan DM, Kirk AD. Efficacy and Toxicity of a Protocol Using 
Sirolimus, Tacrolimus, and Daclizumab in a Nonhuman Primate Renal 
Allotransplant Model. Am J Transplant 2002; 2:381-385. 
106. Hale DA, Kirk AD. mTOR Inhibitors in Transplantation-Novel Immunosuppressive 
Strategies with Sirolimus. Curr Opin Org Transplant 2004; 9:400-405. 
107. Kirk AD, Mannon RB, Swanson SJ, Hale DA. Strategies for minimizing 
immunosuppression in kidney transplantation. Transplant Int 2005; 18:2-14. 
108. Kirk AD, Hale DA, Ford E, Kleiner DE, Kampen RL, Elster EA, Swanson SJ, 
Cendales L, Cropper T, Hale L, Jordan S, Koussis T, Peretti J, Sloane A, Salaita C, 
Ring M, Chamberlain C, Mannon RB. Solid Organ Transplantation at the National 
Institutes of Health: Development of a Research Based Transplantation Practice. in 
Clinical Transplants 2005. Cecka and Terasaki (Eds), UCLA Tissue Typing 
Laboratory, Los 131-144, 2006. 
109. Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, 
Shaffer J, Preffer FI, Ding R, Sharma V, Fishman JA, Dey B, Ko DS, Hertl M, Goes 
NB, Wong W, Williams WW Jr, Colvin RB, Sykes M, Sachs DH. HLA-mismatched 
renal transplantation without maintenance immunosuppression. N Engl J Med 2008; 
358:353-361. 
110. Porcheray F, Wong W, Saidman SL, De Vito J, Girouard TC, Chittenden M, Shaffer 
J, Tolkoff-Rubin N, Dey BR, Spitzer TR, Colvin RB, Cosimi AB, Kawai T, Sachs 
DH, Sykes M, Zorn E. B-cell immunity in the context of T-cell tolerance after 
combined kidney and bone marrow transplantation in humans. Am J Transplant 
2009; 9:2126-2135. 
111. Farris AB, Taheri D, Kawai T, Fazlollahi L, Wong W, Tolkoff-Rubin N, Spitzer TR, 
Iafrate AJ, Preffer FI, Locascio SA, Sprangers B, Saidman S, Smith RN, Cosimi AB, 
Sykes M, Sachs DH, Colvin RB. Acute renal endothelial injury during marrow 
recovery in a cohort of combined kidney and bone marrow allografts. Am J 
Transplant 2011; 11:1464-1477.  
112. Wu Z, Bensinger SJ, Zhang J, Chen C, Yuan X, Huang X, Markmann JF, Kassaee 
A, Rosengard BR, Hancock WW, Sayegh MH, Turka LA. Homeostatic proliferation 
is a barrier to transplantation tolerance. Nat Med 2004; 10:87-92. 
113. Li XC, Turka LA. An update on regulatory T cells in transplant tolerance and 
rejection. Nat Rev Nephrol 2010; 6:577-583. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 64 of 93 
114. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, Burlingham 
WJ, Marks WH, Sanz I, Lechler RI, Hernandez-Fuentes MP, Turka LA, Seyfert-
Margolis VL; Immune Tolerance Network ST507 Study Group. Identification of a B 
cell signature associated with renal transplant tolerance in humans. J Clin Invest 
2010; 120:1836-1847. 
115. Le Texier L, Thebault P, Lavault A, Usal C, Merieau E, Quillard T, Charreau B, 
Soulillou JP, Cuturi MC, Brouard S, Chiffoleau E. Long-term allograft tolerance is 
characterized by the accumulation of B cells exhibiting an inhibited profile. Am J 
Transplant 2011; 11:429-438. 
116. Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noël C, Pillebout E, 
Brouard S, Soulillou JP. Clinical operational tolerance after kidney transplantation. 
Am J Transplant 2006; 6:736-746. 
117. Bohne F, Martínez-Llordella M, Lozano JJ, Miquel R, Benítez C, Londoño MC, 
Manzia TM, Angelico R, Swinkels DW, Tjalsma H, López M, Abraldes JG, 
Bonaccorsi-Riani E, Jaeckel E, Taubert R, Pirenne J, Rimola A, Tisone G, Sánchez-
Fueyo A. Intra-graft expression of genes involved in iron homeostasis predicts the 
development of operational tolerance in human liver transplantation. J Clin Invest 
2012; 122:368-382. 
118. Belatacept package insert. http://packageinserts.bms.com/pi/pi_nulojix.pdf. 
Accessed January 29,2012. 
119. Bloom DD, Hu H, Fechner JH, Knechtle SJ. T-lymphocyte alloresponses of 
Campath-1H-treated kidney transplant patients. Transplantation 2006; 81:81-87. 
120. Stapler D, Lee ED, Selvaraj SA, Evans AG, Kean LS, Speck SH, Larsen CP, 
Gangappa S. Expansion of effector memory TCR Vbeta4+ CD8+ T cells is 
associated with latent infection-mediated resistance to transplantation tolerance. J 
Immunol 2008; 180:3190-200. 
121. Coley SM, Ford ML, Hanna SC, Wagener ME, Kirk AD, Larsen CP. IFN-gamma 
dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell 
responses. J Immunol 2009; 182:225-233. 
122. Kean LS, Adams AB, Strobert E, Hendrix R, Gangappa S, Jones TR, Shirasugi N, 
Rigby MR, Hamby K, Jiang J, Bello H, Anderson D, Cardona K, Durham MM, 
Pearson TC, Larsen CP. Induction of chimerism in rhesus macaques through stem 
cell transplant and costimulation blockade-based immunosuppression. Am J 
Transplant 2007; 7:320-335. 
123. Larsen CP, Page A, Linzie KH, Russell M, Deane T, Stempora L, Strobert E, Penedo 
MC, Ward T, Wiseman R, O'Connor D, Miller W, Sen S, Singh K, Kean LS. An 
MHC-defined primate model reveals significant rejection of bone marrow after 
mixed chimerism induction despite full MHC matching. Am J Transplant 2010; 
10:2396-2409. PMCID:  PMC2980834. 
124. Hoffmann SC, Kampen RL, Amur S, Sharaf MA, Kleiner DE, Hunter K, Swanson 
SJ, Hale DA, Mannon RB, Blair PJ, Kirk AD. Molecular and immunohistochemical 
characterization of the onset and resolution of human renal allograft ischemia-
reperfusion injury. Transplantation 2002; 74: 916-23.  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 65 of 93 
125. Hoffmann SC, Hale DA, Kleiner DE, Mannon RB,  Kampen RL, Jacobson L,  
Cendales LC, Swanson SJ, Becker BN, Kirk AD. Functionally significant renal 
allograft rejection is defined by transcriptional criteria. Am J Transpl 2005; 5:573-
581.  
126. Mannon RB, Hoffmann SC, Ryschkewitsch C, Curfman B, Kampen RL, Cheng OC, 
Hale DA, Major E, Kleiner DE, Kirk AD. Molecular Evaluation of BK 
Polyomavirus Nephropathy. Am J Transplant 2005; 5:2883-93.  
127. Meuwese CL, Stenvinkel P, Dekker FW, Carrero JJ. Monitoring of inflammation in 
patients on dialysis: forewarned is forearmed. Nat Rev Nephrol 2011; 7:166-176. 
128. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Experimental 
Cell Research 1965; 37:614-636. 
129. Pascual J, Zamora J, Pirsch JD. A systematic review of kidney transplantation from 
expanded criteria donors. Am J Kidney Dis 2008; 52:553-586.  
130. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, Croker BP, 
Demetris AJ, Drachenberg CB, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz 
D, Goldberg JC, Grande J, Halloran PF, Hansen HE, Hartley B, Hayry PJ, Hill CM, 
Hoffman EO, Hunsicker LG, Lindblad AS, Yamaguchi Y. The Banff 97 working 
classification of renal allograft pathology.  Kidney Int 1999; 55:713-723. 
131. Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, 
Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, 
Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, 
Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, 
Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ. Banff '05 
Meeting Report: differential diagnosis of chronic allograft injury and elimination of 
chronic allograft nephropathy ('CAN'). Am J Transplant 2007; 7:518-526. 
132. Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, Solez K, Baldwin 
WM 3rd, Bracamonte ER, Broecker V, Cosio F, Demetris AJ, Drachenberg C, 
Einecke G, Gloor J, Glotz D, Kraus E, Legendre C, Liapis H, Mannon RB, 
Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, 
Rodriguez ER, Seron D, Seshan S, Suthanthiran M, Wasowska BA, Zachary A, 
Zeevi A. Banff '09 meeting report: antibody mediated graft deterioration and 
implementation of Banff working groups. Am J Transplant 2010; 10:464-471. 
133. Rush DN, Henry SF, Jeffery JR, Schroeder TJ, Gough J. Histological findings in 
early routine biopsies of stable renal allograft recipients. Transplantation 1994; 
57:208-211. 
134. Nickerson P, Jeffery J, Rush D. Long-term allograft surveillance: the role of protocol 
biopsies. Curr Opin Urol 2001; 11:133-137. 
135. Henderson LK, Nankivell BJ, Chapman JR. Surveillance protocol kidney transplant 
biopsies: their evolving role in clinical practice. Am J Transplant 2011; 11:1570-
1575.  
136. Aitchison J. The Statistical Analysis of Compositional Data. J Royal Stat Soc. Series 
B (Methodological) 1982; 44:139-177. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 66 of 93 
APPENDIX  A:  DIAGNOSIS OF GRAFT REJECTION 
Clinical 
Assessment – 
Signs & 
Symptoms of 
Rejection 
 
 
 
 
 
 
 
 
-  A presumptive diagnosis of an acute episode of rejection 
will be based on the following finds 
 
Fever > 102, orally 
 
Graft swelling 
 
Graft tenderness 
 
> 0.3 mg/dl rise in serum creatinine or a 15% rise in 
serum creatinine 
Oliguria 
Reduced flow in perfusion, 
 
extraction or excretion profile on renal scan 
Ultrasound findings consistent with rejection 
Clinical Assessment 
– Onset of Rejection 
-  The clinical diagnosis of rejection will be confirmed at the 
time additional immunosuppressive therapy is initiated.  The 
date of the first episode of acute rejection will be the date 
additional immunosuppressive medication is initiated 
Clinical Assessment 
– Therapeutic 
Response 
-  Complete Resolution – return of clinical 
parameters to baseline.  
-  Partial Resolution –improvement in clinical parameters, but 
failure to return to baseline within 5 days following start of 
corticosteroid pulses. 
-  No Response - no improvement in clinical parameters within 
5 days following start of corticosteroid pulses. 
Clinical Assessment 
– Severity Grade of 
Rejection 
-  Mild – complete resolution within 5 days following 
corticosteroid pulses. 
-  Moderate - partially responsive to one treatment of 
corticosteroid pulses, but requires additional steroid therapy. 
-  Severe  - unresponsive to > 2 corticosteroid pulses, and 
requires aggressive therapy with OKT3. 
Histologic 
Assessment – Renal 
Biopsy 
-  Results of renal biopsy provide histologic confirmation of 
diagnosis as per Banff criteria 
NOTE: It is expected that activated lymphocytes may be encountered in the grafts of patients in 
the absence of a detrimental immune response. However, any evidence of immune injury will 
prompt more aggressive functional monitoring, and a heightened index of suspicion in 
considering additional immunosuppressive therapy. 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 67 of 93 
 
APPENDIX B: ASSAYS FOR THE DETERMINATION OF ALLOREACTIVITY 
The following assays will be performed to assess the recipients’ general ability to mount 
an alloreactive response, and the specific ability to mount a response toward the donor. 
The development of assays for determining alloresponsiveness is an ongoing process and 
other assays may be considered as they become available.  
We will use multiparameter flow cytometry (MFC) panels (see table below) that we have 
established and standardized as part of the original trial, and also harmonized in support 
of the NIH-sponsored CTOT (NCT00308802 and NCT01436305) and CTOTC-02 
(NCT00951353) transplant consortia. Our standardization of these MFC panels allows 
our unique patients to be placed in the context of multiple other immunosuppressive 
regimens including standard CNI-based approaches. The panels are designed to 
determine the degree to which patients’ T cells are predominantly naïve (CD45RA+, 
CCR7+), effector memory (TEM; CD45RA-, CCR7-), central memory (TC; CD45RA-, 
CCR7+), terminal effector (TEFF; CD45RA+, CCR7-), exhausted (TEX; CD57-, PD-1+) or 
senescent (TSEN; CD57+, PD-1-). In addition to phenotypic markers distinguishing naïve 
from more differentiated cells, our flow panels include surface and intracellular 
molecules that regulate T cell migration (CCR7 and CCR5), cytotoxic potential (perforin, 
granzyme), recent thymic emigration (RTE; CD103, CCR5), activation status (CD38, 
HLA-DR, CD45RA/RO, CD28), susceptibility to apoptosis (BCL-2), proliferation (Ki-
67), association with regulatory functions (FoxP3 and CD103), and B cell maturation 
(IgD, IgM, CD19, CD27). TREGS will be defined as CD3+CD4+,CD25+, FoxP3+ cells 
derived from the live cell, lymphocyte forward and side scatter gate. BTRANS will be 
defined as CD3-, CD19+, IgD+, CD38hi cells derived from the live cell, lymphocyte 
forw
ard 
and 
side 
scatt
er 
gate. 
Perce
ntage 
data 
will be derived directly and absolute cell counts will be extrapolated using the 
simultaneously drawn complete blood counts with differential accessed through merger 
of the Laboratory Information Management Software (LIMS) file with data from the 
Clinical Data Warehouse (see Resources). Assessments of baseline and subsequent 
values will be based on percentage data rather than absolute cell count, hypothesizing that 
ratios are more relevant after 1 year when the absolute cell count has normalized. This 
data stream is an established SOP and links all samples to clinical data through a HIPAA-
compliant data merger. All flow panels are in daily use in support of this trial and the 
CTOT and CTOTC trials. 
T cell assays assessing the peripheral T cell repertoire with regards to alloimmunity and 
protective immunity. Recognizing that diminished alloreactivity is relevant only if it is 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 68 of 93 
specific for the allograft and does not come at the expense of protective immunity, we 
have and will continue to follow our patients for their capacity to protect themselves from 
opportunistic infection. In addition to clinical parameters (rejection, viremia), we will 
continue to evaluate alloreactive potential against donor and third party alloantigens, and 
viral specific T cell reactivity against CMV and EBV in vitro at time points indicated in 
the experimental plan above. This is vital to gain insight into the antigen specificity of 
any treatment effect. As discussed in the Preliminary Studies section, we are beginning to 
see elimination of donor allo-responsiveness but maintenance of non-donor 
responsiveness and CMV responsiveness. Quantitative in vitro measures of this repertoire 
migration are vital to understanding the durability of any observed clinical phenotype that 
emerges.   
We will continue to measure the proliferation of CFSE-loaded CD4 and CD8 T cells 
responding to antigenic stimulation by donor and third party alloantigens (in the form of 
T cell depleted lymphocytes), and immuno-dominant peptide pools for CMV and EBV as 
shown in the Preliminary Studies. Briefly, frozen recipient PBMC will be thawed and 
labeled with CFSE (Renovar Inc., Madison, WI) as per the manufacturer’s instructions. 
Responder CFSE-labeled PBMC will be co-cultured with mitomycin-c treated donor or 
3rd party allogeneic stimulators.  After 4-days, cells will be stained with fluorescence-
labeled antibodies or tetramers and analyzed by MFC to identify the populations of 
interest.  This technique, compared to thymidine incorporation, avoids radiation, better 
identifies proliferating subsets, and measures proliferative intensity (the number of 
rounds of proliferation to distinguish between limited versus extensive proliferation).119 
Using MFC, the proliferative potential of responding cells will be determined by 
quantifying the number of cell divisions that occur in immunosuppressed patients as 
compared to controls.  We have established the CFSE proliferation assay in our lab in 
combination with Ki-67 staining, which marks proliferating cells, to identify the 
proliferative capacity of antigen-specific T cells.  
For viral-specific responses, we use MHC defined tetramers containing immuno-
dominant viral peptides for common CMV and EBV epitopes. We will continue to define 
the activation status of these cells, determine their cross-reactivity for donor and third 
party alloantigens, and relate this in vitro to proliferative capacity, effector function, and 
relationship to maintenance immunosuppressive regimen. We make use of two 
approaches to determine the phenotype and function of virus-specific T cells over time 
after renal transplantation.  First, we have made CMV tetramers (A2-restricted 
NLVPMVATV and B7-restricted TPRVTGGGAM) and EBV-specific tetramers (A2-
restricted GLCTLVAML, B7-restricted RPPIFIRRL, and B8-restricted FLRGRAYGL 
and RAKFKQLL peptides) to assess CD8 responses. By gating on the tetramer positive 
cells and making use of flow analysis, it is possible to determine the phenotype of the 
virus-specific T cells and quantify them to a sensitivity of 0.03% of CD8 T cells. Second, 
we analyze the function (CD107a/degranulation) and cytokine expression (IFN-γ, TNF-α 
and IL-2) of antigen-specific CD4 and CD8 T cells as we have previously 
described.120,121 Prior studies have shown that TCM proliferate better and are more 
protective against viral infection than TEM. As such, we hypothesize that maintaining a 
high proliferative potential is critical for immunosuppressed patients to combat infection, 
and that the selective resistance of TM will allow this to persist post alemtuzumab 
treatment. To determine if the fluctuations in T cell phenotype associate with quantitative 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 69 of 93 
changes in alloreactivity or viral-specific immunity, we continue to quantify changes in 
the frequency, phenotype, and function of alloreactive T cells over time after 
transplantation, and merge these analyses with the viral specific approaches described 
below and data from the Clinical Data Warehouse denoting outcome specifically related 
to the development of acute rejection and viremia. Allospecific cells will be evaluated 
using both CFSE proliferation and ICCS using donor- or third-party allogeneic 
stimulators. This technique allows the assessment of proliferating subsets by division 
cycle and has been used extensively by our group.83,122,123  
Transcriptional Studies. Peripheral blood (7.5 ml) will continue to be drawn into EDTA 
tubes at the times indicated in the protocol (Appendix A). Cells will be ficol separated 
and placed in 100 µl of RNAlater (Ambion) in a sterile, RNAase-free 2.5 ml freezing 
tube, placed on ice at 4°C and frozen at -80°C within four hours. We routinely process 
microarray-grade RNA from peripheral blood with a typical yield of 5-10 mcg/2.5mls 
blood. Renal biopsies will be obtained at the times indicated in the protocol as two 18-
gauge needle core biopsies. The cores will be split with two halves sent for histological 
processing and two halves immediately transferred into 100 µl of RNAlater in a sterile, 
RNAase-free 2.5 ml freezing tube, placed on ice at 4°C and frozen at -80°C within four 
hours. These samples will be stored for batched analysis. Two halves of the core biopsies 
will be processed locally for diagnostic purposes. Two stained (H/E, PAS) slides will be 
forwarded to pathology for centralized light microscopic analysis and quantitative Banff 
scoring. Four unstained slides will be forwarded to the Emory pathology lab for 
immunohistochemistry (CD3, CD20, CD56, and C4d).  
In the first iteration of the trial, we proposed transcriptional analysis of blood and biopsy 
material and indeed have collected samples that we will evaluate as described n the initial 
study. These assays have been batched for analysis at the completion of the study as 
batch variation markedly alters interpretation of array-type transcriptional analysis. We 
will continue collection of samples as per our established protocol. Briefly, clinical 
samples will be procured and processed to RNA and PCR LDAs will be performed in the 
PI’s lab. These arrays will be prospectively evaluated for their ability to segregate clinical 
outcomes in protocol patients and related to previously studied patients transplanted 
under standard of care immunosuppression. We have ample published experience with 
RT-PCR (TaqMan) in transplantation.124-126 Total RNA will be reverse transcribed to 
cDNA using TaqMan reverse transcription kit (Applied Biosystems) and amplified (50oC 
for 2min, 99oC for 10min, 40 cycles at 99oC for 15sec and 60oC for 1min) using 384-well 
LDAs (Applied Biosystems) or as individual target assays as necessary. Each 
amplification will be performed in quadruplicate and the mean values of quadruplicate 
assays will serve as the reported value. All samples will be compared to a pooled sample 
of cDNA from our established homogenous reference for normal kidney (pre-
procurement live donor biopsy). Data will be analyzed and reported as described.124-126 
We will construct a custom 384 well LDAs for these studies. These arrays will contain 
targets that we have shown to discriminate between subclinical and clinical acute 
rejection,125 BK nephropathy,126 and reperfusion injury.124 These LDAs will allow for the 
validation of 98 genes in quadruplicate and will amply accommodate RT-PCR validation 
of 15 genes per condition and 20 known control genes for validation of results. Individual 
biopsy gene transcript data will be normalized by log transformation, and compared 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 70 of 93 
between biopsy and blood samples with one-way analysis of variance (ANOVA). Post-
hoc inter-group comparisons for different conditions will be made using a Bonferroni 
correction to appropriately account for multiple comparisons with significance defined as 
a two-tailed p<0.05. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 71 of 93 
APPENDIX C: SUMMARY OF RESULTS OF BELATACEPT 
INVESTIGATIONAL PROGRAM 
Given that the investigational agent used in this trial is belatacept, comprehensive 
information is provided regarding its use to date. 
Preclinical Data 
Belatacept binds weakly to murine B7 molecules, and therefore, cannot be studied in 
rodent models of immune-mediated diseases or transplantation. The parent molecule of 
belatacept, CTLA4Ig, was therefore utilized in various rodent, non-human primate, and 
ex vivo T-cell proliferation assay human experiments to determine the potency of 
belatacept compared with CTLA4Ig. A more extensive description of these studies is 
available in the IB; the pertinent findings are summarized below. 
Efficacy: 
• Belatacept shows ~ 2-fold greater binding avidity than CTLA4Ig for human CD80 
and ~ 4-fold greater binding avidity than CTLA4Ig for human CD86 
• Belatacept is approximately 10-fold more effective in vitro on a per-dose basis than 
CTLA4Ig at inhibiting T-cell proliferation, T-cell cytokine production, and 
CD28-dependent killing of target cells by natural killer-like cells 
• In an allogeneic mixed-leukocyte culture assay under secondary allostimulation 
conditions, belatacept was approximately 5- to 7-fold more potent than CTLA4Ig at 
blocking interleukin (IL)-2, IL-4, and interferon- T-cell cytokine production 
• In an in vivo primate immune response model, belatacept potently blocked a primary 
antibody response against sheep red blood cells. At equivalent doses, belatacept was 
3- to 11-fold more potent (by ID90) than CTLA4Ig at blocking specific humoral 
responses 
• Belatacept was found to be efficacious for the prevention of graft rejection in 
cynomolgus monkeys, a non-human primate model of renal transplantation 
• Belatacept monotherapy was superior to a regimen of CsA + corticosteroids in the 
prolongation of graft survival in a stringent primate renal transplant model 
• A regimen of belatacept + MMF + corticosteroids and a regimen of belatacept + 
basiliximab demonstrated efficacy (ie, prolongation of graft survival) superior to 
belatacept monotherapy as well as that historically observed in monkeys treated with 
CsA + corticosteroids 
• Analysis of pharmacokinetic (PK) data in monkeys suggested a relationship between 
trough serum drug concentrations and immunosuppressive efficacy 
• Treatment with belatacept, alone or in combination with basiliximab, did not result in 
long-term tolerance to the donor graft. Therefore, it appears likely that chronic 
intermittent dosing of belatacept is required for optimal long-term prophylaxis of 
rejection 
• In an islet cell transplant model, treatment of 5 pancreatectomized macaques with a 
belatacept-based regimen yielded islet cell allograft survival of 56, 190, 204, 216, and 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 72 of 93 
> 220 days. In contrast, a control regimen of sirolimus and anti-IL-2 receptor yielded 
islet cell allograft survival of only 7 days. 
 
Safety: 
The nonclinical safety assessment of belatacept was performed in the cynomolgus 
monkey. As noted previously, belatacept is a 2-amino acid variant of CTLA4Ig. 
Although the mutations in belatacept increase binding affinity in primates compared to 
CTLA4Ig, the binding affinity for murine CD80 and CD86 is lower with belatacept than 
it is with abatacept, and belatacept has approximately 10% of the activity of CTLA4Ig in 
an in vitro murine spleen cell bioassay. Since CTLA4Ig, which is active in mice, binds 
more avidly than does belatacept in mice and it is very similar to belatacept in both its 
mechanism of action and its structure, CTLA4Ig is considered an acceptable homologue 
for belatacept for rodent toxicology assessments to support registration requirements. A 
more thorough description of these studies is available in the IB; the pertinent findings 
are summarized below. 
• No drug-related toxicity was observed in a single-dose intravenous (i.v.) toxicity 
study using cynomolgus monkeys given belatacept at doses of up to 90 mg/kg 
• Belatacept was well tolerated when given i.v. to monkeys at doses up to 50 mg/kg 
every other day for 1 month (15 doses) or once weekly for 6 months (26 doses). The 
major nonclinical findings in monkeys with belatacept were reversible, related to the 
pharmacology of the drug, and consisted of minimal decreases in serum IgG levels 
and minimal-to-moderate lymphoid depletion of germinal centers in the spleen and/or 
lymph nodes at all dose levels. Similar observations were noted for CTLA4Ig when 
administered to monkeys at doses up to 50 mg/kg once weekly for 1 year (52 doses) 
• No adverse cardiovascular, respiratory, or neurological effects have been detected in 
any of the single- or repeat-dose toxicity studies of belatacept when given to monkeys 
for up to 6 months. In addition, no belatacept-related changes were observed in 
plasma or serum levels of histamine, complement (C3a), tumor necrosis factor-α, or 
IL-6 (mediators associated with hemodynamic changes and anaphylactoid responses) 
• CTLA4Ig was not found to be mutagenic or clastogenic when tested at maximum 
concentrations recommended by international guidelines or maximal achievable 
concentration 
• In studies conducted with CTLA4Ig, the major safety concern identified relates to the 
potential for an increased incidence of virally-induced tumors in the presence of 
long-term immunomodulation. In a mouse carcinogenicity study, increases in the 
incidence of lymphoma and mammary gland tumors were observed at human 
exposure multiples of 0.8- and 1.9-fold, respectively. In mice, murine leukemia virus 
and mouse mammary tumor virus have been reported to cause lymphomas and 
mammary tumors, respectively. The presence of these viruses was confirmed in mice 
from this study based upon electron microscopy and immunohistochemistry. Data 
collected from these studies strongly support the conclusion that the increased 
malignancies in this study are secondary to long-term CTLA4Ig-induced 
immunomodulation and the immunological control of these specific viruses 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 73 of 93 
• No evidence of lymphoma, other solid tumors, or preneoplastic morphological 
changes such as lymphoid hyperplasia were observed in the 6-month monkey toxicity 
study conducted with belatacept or in the 1-year monkey toxicity study conducted 
with CTLA4Ig despite the presence of lymphocryptovirus in the CTLA4Ig study, 
which could mediate these changes 
• In i.v. embryo-fetal development studies with CTLA4Ig, no maternal or embryo-fetal 
toxicity was observed at doses up to 200 mg/kg/day in rats, 300 mg/kg/day in mice, 
or 200 mg/kg/3 days in rabbits (human exposure multiple of 30- and 29-fold for rats 
and rabbits, respectively; human exposure multiples not determined for mice). In the 
rat and rabbit studies, CTLA4Ig was shown to cross the placenta, indicating that 
fetuses from CTLA4Ig-treated dams were exposed to drug. On the basis of these data, 
CTLA4Ig was considered not teratogenic in mice, rats, or rabbits, supporting the 
administration of CTLA4Ig and belatacept to women of childbearing potential 
(WOCBP) 
• In a fertility and early embryonic development study with CTLA4Ig in rats, there 
were no effects on reproductive function in male or female rats, and no effect on early 
embryonic development at doses up to 200 mg/kg administered i.v. every 3 days 
(human exposure multiple of 11-fold) 
• In a pre- and post-natal development study with CTLA4Ig in rats, there were no 
effects on the F0-generation dams at doses up to 200 mg/kg administered i.v. every 3 
days (human exposure multiple of 11-fold), and no effects on the F1-generation rats at 
≤ 45 mg/kg (human exposure multiple of 3-fold). At 200 mg/kg, drug-related changes 
in the F1-generation were limited to females, and consisted of an increase (9-fold) in 
the T-cell-dependent antibody response to keyhole limpet hemocyanin and moderate 
diffuse inflammation of the thyroid gland of 1 rat. These findings are considered to 
represent the lower threshold limit for effects of CTLA4Ig on immune parameters in 
the F1-generation rats, as these changes were either limited to only 1 sex or 1 animal, 
and no other immune parameters were affected (splenic-lymphocyte and natural-killer 
cell phenotypes, serum Ig levels, and presence of antinuclear antibodies). 
 
Clinical Pharmacology 
A single-dose Phase 1 study with belatacept was performed in 40 healthy volunteers. 
Subjects received single i.v. infusions of either 0.1, 1, 5, 10, or 20 mg/kg belatacept. At 
each dose level, 6 subjects received active drug and 2 received placebo. Analysis of the 
safety data indicates that single i.v. doses were well tolerated. No deaths or serious 
adverse events (SAEs) were reported. All reported clinical AEs were of mild or moderate 
intensity. No histamine-like peri-infusional AEs were reported. No clinically significant 
changes in vital signs or laboratory parameters were observed. There was no evidence for 
the development of anti-belatacept antibodies. When the dose increased in a ratio of 
1: 5: 10: 20, the geometric mean area under the concentration-time curve from time zero 
extrapolated to infinity values increased in a ratio of 1: 4.6: 9.9: 18.5; therefore, 
belatacept kinetics were found to be dose-proportional between 1 and 20 mg/kg. The 
half-life was adequately characterized between the 5 and 20 mg/kg dose levels, and 
ranged between 176 – 210 hours (7-9 days). Following a single i.v. infusion of 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 74 of 93 
1-20 mg/kg, total body clearance (CLT) values ranged from 0.45-0.49 mL/h/kg. The 
steady-state volume of distribution (VSS) values were small, indicating that the drug 
(with high molecular weight) was confined mainly in the plasma and extracellular space. 
Both CLT and VSS appeared to be dose independent between the 1 and 20 mg/kg dose 
levels. Overall, the PK of belatacept appears to be linear following i.v. administration in 
healthy subjects. 
Phase 2 Study in Rheumatoid Arthritis 
Study IM103002 was a Phase 2 pilot study that assessed the efficacy, safety, and 
immunogenicity of multiple i.v. doses of belatacept, CTLA4Ig, and placebo in 
214 subjects with RA. Eligible subjects had a diagnosis of RA for ≤ 7 years had failed at 
least 1 disease-modifying anti-rheumatic drug therapy, including etanercept, and had 
active disease (≥ 10 swollen joints, ≥ 12 tender joints, an erythrocyte sedimentation rate 
≥ 28 mm/h, and morning stiffness ≥ 45 minutes). Overall, belatacept demonstrated 
dose-dependent efficacy in this subject population, as evidenced by American College of 
Rheumatology scores. With respect to safety, no deaths were reported during the 
treatment or follow-up period (through Day 169), and 12 subjects reported SAEs, 
although no SAEs were considered drug related by the investigators. 
Phase 2 Study in Solid Organ Transplantation 
Study Design 
Study IM103100 was a 1-year, partially-blinded, randomized, active-controlled, multiple-
dose, multicenter non-inferiority study in de novo renal transplant recipients. All subjects 
received basiliximab induction and background maintenance immunosuppression with 
MMF and corticosteroids. Subjects were randomized in a 1:1:1 ratio to treatment with 
belatacept (more intensive [MI] or less intensive [LI] regimens) or CsA (open-label dosed 
twice daily to achieve a specified trough serum concentration range). Belatacept was 
administered in a double-blind fashion, with the investigator and subject blinded to the 
identity of the belatacept dose regimen. 
Belatacept subjects were dosed with 10 mg/kg on Days 1, 5, 15, 29, 43, 57, 71, 85, 113, 
141, and 169 (MI regimen) or 10 mg/kg on Days 1, 15, 29, 57, and 85 (LI regimen). 
Subjects were reallocated on Days 85 (LI regimen) and 169 (MI regimen) to a 5 mg/kg 
dose of the drug every 4 or 8 weeks through Day 365. 
Evaluation Criteria 
The primary efficacy variable was the incidence of clinically-suspected and 
biopsy-proven acute rejection (CSBPAR) at 6 months post-transplantation. CSBPAR was 
defined as an increase in serum creatinine (SCr) of at least 0.5 mg/dL compared to the 
baseline value in the absence of other factors known to adversely affect renal function 
that led the investigator to suspect acute rejection, which was then confirmed by 
centrally-assessed biopsy. Secondary efficacy variables were the incidence of all 
biopsy-proven acute rejections, including those without an increase in SCr of at least 
0.5 mg/dL, as well as the composite endpoints of CSBPAR or presumed acute rejection 
and biopsy-proven acute rejection or presumed acute rejection at 6 months and 1 year, 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 75 of 93 
and death and/or graft loss at 1 year. ‘Presumed acute rejection’ was defined as an 
elevation in SCr (at least 0.5 mg/dL compared to the baseline value in the absence of 
other factors known to adversely affect renal function) that led the investigator to suspect 
and treat the subject for acute rejection without a biopsy to confirm the diagnosis, or 
despite a biopsy that did not confirm acute rejection. All biopsies were assessed in a 
blinded fashion by a central pathologist. The primary cause of graft loss and death was 
also adjudicated. 
The safety evaluation included AEs (including infections), vital signs, physical 
examinations, electrocardiograms (ECGs), and laboratory parameters (hematology, 
biochemistry, and urinalysis). Topics of special interest were renal function (glomerular 
filtration rate [GFR], as determined by iohexol clearance, SCr, and calculated creatinine 
clearance or GFR at 1, 6, and 12 months), blood pressure (BP) parameters (systolic 
pressure [SBP] and diastolic blood pressure [DBP], presence of hypertension), fasting 
serum cholesterol and triglycerides (TGs), and the presence of post-transplant diabetes 
mellitus (PTDM). 
Efficacy Results 
The efficacy results for Study IM103100 study are presented in the following sections. 
Overall, the mean duration of exposure was comparable across all 3 treatment groups. 
Specifically, mean duration of exposure was 300, 308, and 294 days in the belatacept MI 
and LI groups and the CsA group, respectively. 
Acute Rejection 
The primary endpoint, CSBPAR at 6 months, occurred infrequently in all treatment 
groups (Table 1.3.4.3A). The incidence rate was slightly lower in the belatacept groups 
than in the CsA group. The criteria for non-inferiority to CsA were easily satisfied for 
both belatacept groups; however, the number of events was too small to support any 
further conclusions regarding the relative efficacy of the 3 regimens. The distribution of 
events by severity (as indicated by histological grade) was similar across the 3 treatment 
groups. Identical results were observed at 12 months. 
The secondary endpoint of biopsy-proven acute rejection occurred 2 to 4 times more 
frequently than the primary endpoint of CSBPAR, indicating that most biopsy-proven 
acute rejection episodes were subclinical (ie, not associated with an increase in 
SCr ≥ 0.5 mg/dL). These episodes of subclinical rejection were observed on biopsies 
taken to satisfy the protocol requirements, according to local practice, or for other reasons 
than an increase in SCr ≥ 0.5 mg/dL. 
Biopsy-proven acute rejection occurred most frequently in the belatacept LI group. As 
the rate of CSBPAR was comparable across treatment groups, the difference in the rate of 
biopsy-proven acute rejection was due to an increase in the number of subclinical 
rejection episodes in the belatacept LI arm. Reallocation to 8-week treatment was 
associated with an increased frequency of subclinical rejection. 
Overall, the histological severity grade of acute rejection episodes appeared to be similar 
across the 3 treatment groups. While Grade IIB rejection, as assessed by Banff 97 
criteria, occurred more frequently in the belatacept groups, the number of such events 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 76 of 93 
was small, and the confidence intervals (CIs) around the incidence rates broadly 
overlapped (belatacept MI: 1.0.%-12.5%; belatacept LI: 1.1%-13%; and CsA: 0%-6.5%). 
Table 1.3.4.3A: 
Acute Rejection - Study IM103100 
Banff Grade for Acute Rejections 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
CSBPAR (ITT Analysis) by Month 6 (Primary Endpoint)a 
Mild Acute (IA) 
2 (2.7%) 
0 
1 (1.4%) 
Mild Acute (IB) 
0 
0 
1 (1.4%) 
Moderate Acute (IIA) 
2 (2.7%) 
3 (4.2%) 
2 (2.7%) 
Moderate Acute (IIB) 
1 (1.4%) 
1 (1.4%) 
2 (2.7%) 
Total 
5 (6.8%) 
4 (5.6%) 
6 (8.2%) 
Difference in Event Rates (LEA29Y - 
CsA) with Asymptotic 95% CI (%) 
-1.5 
(-10.0, 7.0) 
-2.6 
(-10.9, 5.7) 
--- 
BPAR (ITT Analysis) by Month 6 
Mild Acute (IA) 
2 (2.7%) 
3 (4.2%) 
3 (4.1%) 
Mild Acute (IB) 
0 
1 (1.4%) 
1 (1.4%) 
Moderate Acute (IIA) 
6 (8.1%) 
8 (11.3%) 
7 (9.6%) 
Moderate Acute (IIB) 
3 (4.1%) 
5 (7.0%) 
2 (2.7%) 
Total 
11 (14.9%) 
17 (23.9%) 
13 (17.8%) 
Difference in Event Rates (LEA29Y - 
CsA) with Asymptotic 95% CI (%) 
-2.9 
(-14.9, 9.0) 
6.1 
(-7.1, 19.4) 
--- 
BPAR (ITT Analysis) by Month 12 
Mild Acute (IA) 
3 (4.1%) 
4 (5.6%) 
3 (4.1%) 
Mild Acute (IB) 
1 (1.4%) 
4 (5.6%) 
1 (1.4%) 
Moderate Acute (IIA) 
5 (6.8%) 
8 (11.3%) 
7 (9.6%) 
Moderate Acute (IIB) 
5 (6.8%) 
5 (7.0%) 
2 (2.7%) 
Total 
14 (18.9%) 
21 (29.6%) 
13 (17.8%) 
Difference in Event Rates (LEA29Y - 
CsA) with Asymptotic 95% CI (%) 
1.1 
(-11.4, 13.6) 
11.8 
(-2.0, 25.5) 
--- 
a 
The results for CSBPAR were the same for all treatment groups at Month 12. 
BPAR = biopsy-proven acute rejection, CI = confidence interval, CSBPAR = clinically-suspected and biopsy-proven acute rejection, 
and ITT = intent to treat. 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 77 of 93 
Recurrent Acute Rejection 
Recurrent acute rejections are summarized in Table 1.3.4.3B. Overall, the average 
number of rejection episodes per subject (~1.2) was similar among the 3 treatment 
groups. 
Table 1.3.4.3B: 
Frequency of Biopsy-proven Acute Rejections - Study 
IM103100 (Intent-to-Treat Analysis) 
 
LEA29Y MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
No. of  Subjects with Acute 
Rejection 
14 
21 
13 
 
1 Episode 
11/14 (78.6%) 
18/21 (85.7%) 
12/13 
(92.3%) 
 
2 Episodes 
2/14 (14.3%) 
3/21 (14.3%) 
0 
 
3 Episodes 
1/14 (7.1%) 
0 
1/13 (7.7%) 
 
Chronic Allograft Nephropathy (CAN) 
Biopsy specimens were also examined for CAN by an independent blinded central 
histopathologist using Banff 97 working classification of kidney transplant pathology.i 
By Month 12, CAN was approximately 30%-50%, in relative terms, less common with 
belatacept than with CsA (Table 1.3.4.3C). 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 78 of 93 
Table 1.3.4.3C: 
Biopsy-proven Chronic Allograft Nephropathy - Study 
IM103100 
 
Biopsy-proven Chronic Allograft 
Nephropathy 
LEA29Y MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
Month 3 
3 (4.1%) 
2 (2.8%) 
9 
(12.3%) 
Difference in Event Rates (LEA29Y - CsA) 
with Asymptotic 95% CI (%) 
-8.3 
(-17.1, 0.5) 
-9.5 
(-18.0, -1.0) 
--- 
Month 6 
6 (8.1%) 
3 (4.2%) 
11 
(15.1%) 
Difference in Event Rates (LEA29Y - CsA) 
with Asymptotic 95% CI (%) 
-7.0 
(-17.3, 3.3) 
-10.8 
(-20.3, -1.4) 
--- 
Month 12 
15 (20.3%) 
11 (15.5%) 
22 
(30.1%) 
Difference in Event Rates (LEA29Y - CsA) 
with Asymptotic 95% CI (%) 
-9.9 
(-23.8, 4.1) 
-14.6 
(-28.1, -1.2) 
--- 
Note: Biopsy-proven chronic allograft nephropathy was assessed by the central 
pathologist; Day 1  
 
 
baseline biopsies were included. In an analysis restricted to subjects with at least 1 
post-baseline  
 
 
biopsy, the rates of biopsy-proven chronic allograft nephropathy at 12 months 
were 29%, 20%,  
 
 
and 44% for the LEA29Y MI, LEA29Y LI, and CsA groups, respectively. 
CI = confidence interval. 
 
Subject and Graft Survival 
Death and/or graft loss occurred infrequently in all treatment groups, and was least 
frequently reported in the belatacept LI group (Table 1.3.4.3D). Most graft losses 
occurred for technical, rather than immunological reasons. 
Five deaths (4 in the CsA group and 1 in the belatacept MI group) appear in 
Table 1.3.4.3D, which was analyzed according to the intent-to-treat (ITT) principle. Two 
of these deaths – both in the CsA group – occurred on therapy or within 56 days of the 
last dose of study therapy. Accordingly, these deaths also are counted under the 
prespecified safety conventions, and appear in the safety summaries in Section 1.3.4.4. 
Three other deaths qualify under the ITT principle, but not under the safety conventions 
because they either never received study drug or the death was an event subsequent to the 
discontinuation of study drug + 56 days. These deaths appear in Table 1.3.4.3D, but not 
in the safety summaries in Section 1.1.4.4. One death in the CsA group, and 1 in the 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 79 of 93 
belatacept MI group, occurred > 56 days after the last dose of study therapy. One death in 
the CsA group occurred in a subject who was randomized, but never treated. 
Table 1.3.4.3D: 
Subject Death and Graft Loss by Month 12 - Study IM103100 
 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
Deaths by Month 12 (ITT Analysis)a 
Total No. of Deaths 
1 (1.4%) 
0 
4 (5.5%) 
Reasons: 
 
 
 
 
Cardiac 
0 
0 
2 (2.7%) 
 
Infection / Sepsis 
1 (1.4%) 
0 
0 
 
Pulmonary Embolism 
0 
0 
1 (1.4%) 
 
Other - Unknown 
0 
0 
1 (1.4%) 
Graft Loss by Month 12 (ITT Analysis) 
Total No. of Graft Losses 
3 (4.1%) 
1 (1.4%) 
3 (4.1%) 
Reasons: 
 
 
 
 
Renal Vein or Renal Artery 
Thrombosis 
1 (1.4%) 
1 (1.4%) 
2 (2.7%) 
 
Other - Infarction (Etiology 
Unknown,  
 
Possibly Ongoing Rejection) 
 
1 (1.4%) 
 
0 
 
0 
 
Other - PTLD as Treatment of 
PTLD 
1 (1.4%) 
0 
0 
 
Other - Combination - Persistent 
DGF; 
 
Acute Rejection; Infection 
 
0 
 
0 
 
1 (1.4%) 
Error! Bookmark not defined. Includes all deaths reported up to 12 months post-randomization, 
by treatment group assigned. 
DGF = delayed graft function, ITT = intent to treat, and PTLD = post-transplant lymphoproliferative disorder. 
 
Adverse Events 
Overall Adverse Events 
The overall incidence of AEs is summarized in Table 1.3.4.4A. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 80 of 93 
Table 1.3.4.4A: 
Overall Incidence of Adverse Events Through Day 56 After 
Double-blind Period (Randomized, Transplanted and Treated 
Population) - Study IM103100 
 
No. (%) of Subjects 
 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=71) 
Adverse Events 
73 (98.6) 
69 (97.2) 
68 (95.8) 
Discontinued Due to Adverse Events 
13 (17.6) 
15 (21.1) 
14 (19.7) 
Related Adverse Events 
43 (58.1) 
40 (56.3) 
50 (70.4) 
Serious Adverse Events 
50 (67.6) 
52 (73.2) 
41 (57.7) 
Related Serious Adverse Events 
20 (27.0) 
23 (32.4) 
21 (29.6) 
Deathsa 
0 
0 
2 (2.8) 
a Includes all deaths up to 56 days after last dose of study therapy, by therapy received. 
 
The rate of AEs, including AEs resulting in discontinuation, was similar across the 3 
treatment groups. The rate of SAEs was somewhat higher for both belatacept treatment 
groups than for the CsA treatment group. As described below, this difference is due to an 
increased number of reports of AEs of transplant rejection, not subsequently confirmed as 
transplant rejection, in the belatacept treatment groups. 
The incidence of AEs, by Medical Dictionary for Drug Regulatory Activities (MedDRA) 
system organ class and preferred term, is summarized in Table 1.3.4.4B. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 81 of 93 
Table 1.3.4.4B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
Through Day 56 After Double-blind Period (Randomized, 
Transplanted and Treated Population) - Study IM103100 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=71) 
Subjects with Any Adverse Events 
73 (98.6) 
69 (97.2) 
68 (95.8) 
Blood & Lymphatic System Disorders 
29 (39.2) 
28 (39.4) 
40 (56.3) 
 
Leukopenia 
14 (18.9) 
12 (16.9) 
21 (29.6) 
 
Anemia 
13 (17.6) 
12 (16.9) 
21 (29.6) 
Cardiac Disorders 
10 (13.5) 
10 (14.1) 
10 (14.1) 
Endocrine Disorders 
4 (5.4) 
8 (11.3) 
9 (12.7) 
Gastrointestinal Disorders 
45 (60.8) 
45 (63.4) 
42 (59.2) 
 
Nausea 
19 (25.7) 
18 (25.4) 
16 (22.5) 
 
Diarrhea 
17 (23.0) 
18 (25.4) 
17 (23.9) 
 
Constipation 
16 (21.6) 
22 (31.0) 
20 (28.2) 
 
Vomiting 
11 (14.9) 
14 (19.7) 
11 (15.5) 
General Disorders & Administration Site 
Conds. 
43 (58.1) 
40 (56.3) 
42 (59.2) 
 
Edema Peripheral 
23 (31.1) 
20 (28.2) 
21 (29.6) 
 
Pyrexia 
15 (20.3) 
19 (26.8) 
15 (21.1) 
 
Pain 
7 (9.5) 
6 (8.5) 
9 (12.7) 
 
Fatigue 
6 (8.1) 
6 (8.5) 
9 (12.7) 
 
Edema 
6 (8.1) 
7 (9.9) 
11 (15.5) 
Immune System Disorders 
22 (28.7) 
29 (40.8) 
16 (22.5) 
 
Transplant Rejection 
19 (25.7) 
23 (32.4) 
11 (15.5) 
Infections & Infestations 
54 (73.0) 
52 (73.2) 
53 (74.6) 
 
Urinary Tract Infection 
17 (23.0) 
17 (23.9) 
22 (31.0) 
 
Cytomegalovirus Infection 
11 (14.9) 
10 (14.1) 
13 (18.3) 
 
Nasopharyngitis 
9 (12.2) 
10 (14.1) 
11 (15.5) 
Injury, Poisoning & Procedural 
Complications 
44 (59.5) 
45 (63.4) 
45 (63.4) 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 82 of 93 
Table 1.3.4.4B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
Through Day 56 After Double-blind Period (Randomized, 
Transplanted and Treated Population) - Study IM103100 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=71) 
 
Incision Site Complication 
17 (23.0) 
16 (22.5) 
13 (18.3) 
 
Post Procedural Pain 
14 (18.9) 
17 (23.9) 
15 (21.1) 
 
Graft Dysfunction 
9 (12.2) 
10 (14.1) 
10 (14.1) 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 83 of 93 
Table 1.3.4.4B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
Through Day 56 After Double-blind Period (Randomized, 
Transplanted and Treated Population) - Study IM103100 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=71) 
Investigations 
26 (35.1) 
22 (31.0) 
29 (40.8) 
 
Blood Creatinine Increased 
13 (17.6) 
10 (14.1) 
13 (18.3) 
Metabolism & Nutrition Disorders 
36 (48.6) 
35 (49.3) 
42 (59.2) 
 
Hypophosphatemia 
14 (18.9) 
24 (33.8) 
15 (21.1) 
 
Hyperlipidemia 
9 (12.2) 
8 (11.3) 
6 (8.5) 
 
Hypercholesterolemia 
6 (8.1) 
4 (5.6) 
9 (12.7) 
 
Hypokalemia 
5 (6.8) 
5 (7.0) 
9 (12.7) 
Musculoskeletal & Connective Tissue 
Disorders 
26 (35.1) 
20 (28.2) 
20 (28.2) 
 
Arthralgia 
8 (10.8) 
6 (8.5) 
4 (5.6) 
 
Back Pain 
8 (10.8) 
3 (4.2) 
6 (8.5) 
Nervous System Disorders 
26 (35.1) 
20 (28.2) 
26 (36.6) 
 
Headache 
13 (17.6) 
10 (14.1) 
8 (11.3) 
 
Tremor 
8 (10.8) 
10 (14.1) 
14 (19.7) 
Psychiatric Disorders 
18 (24.3) 
27 (38.0) 
20 (28.2) 
 
Insomnia 
12 (16.2) 
19 (26.8) 
17 (23.9) 
Renal & Urinary Disorders 
28 (37.8) 
27 (38.0) 
25 (35.2) 
Reproductive System & Breast Disorders 
7 (9.5) 
12 (16.9) 
7 (9.9) 
Respiratory, Thoracic & Mediastinal 
Disorders 
23 (31.1) 
24 (33.8) 
29 (40.8) 
 
Cough 
7 (9.5) 
8 (11.3) 
11 (15.5) 
 
Dyspnea 
5 (6.8) 
6 (8.5) 
9 (12.7) 
Skin & Subcutaneous Tissue Disorders 
26 (35.1) 
18 (25.4) 
18 (25.4) 
Vascular Disorders 
27 (36.5) 
29 (40.8) 
29 (40.8) 
 
Hypertension 
16 (21.6) 
17 (23.9) 
22 (31.0) 
Note:  
The number of adverse events for transplant rejections includes investigator-reported transplant rejections, 
 
 
often obtained at the time of biopsy, irrespective of central blinded histological evaluation and/or local  


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 84 of 93 
 
 
evaluation. All cases of centrally-confirmed clinically-suspected and biopsy-proven acute rejection and  
 
 
biopsy-proven acute rejection are reported in Table 1.3.4.3.A. 
MedDRA = Medical Dictionary of Drug Regulatory Activities. 
Transplant rejection was reported more commonly with both doses of belatacept than 
with CsA. Subsequent evaluation revealed that these reports reflected episodes of 
suspected acute rejection later disproven by central biopsy, as well as episodes that 
resolved spontaneously without treatment. All reported AEs of transplant rejection that 
were subsequently confirmed by biopsy have been counted in the efficacy summaries 
provided above. AEs commonly observed during CsA treatment, such as anemia, 
leukopenia, hirsutism, tremor, hypomagnesemia, and hypertension, were reported less 
frequently with belatacept than with CsA in this study. Infectious complications occurred 
with comparable frequency. Pulmonary edema and proteinuria were reported more 
frequently with belatacept than with CsA. The significance of these events requires 
further evaluation. 
Serious Adverse Events 
The most frequent SAEs are summarized by MedDRA system organ class and preferred 
term in Table 1.3.4.4C. As noted above, SAEs were reported somewhat more frequently 
in the belatacept treatment groups than in the CsA group. This difference is accounted for 
by an increased frequency of reporting acute rejection as an AE in the belatacept groups. 
Subsequent evaluation revealed that these reports reflected episodes of suspected 
rejection later disproven by central biopsy, as well as episodes that resolved 
spontaneously without treatment. All reported AEs of transplant rejection that were 
subsequently confirmed by biopsy have been counted in the efficacy summaries provided 
above in Section 1.1.4.3. 
Three subjects treated with the belatacept MI regimen developed PTLD. One case 
occurred on treatment and the others occurred 2 months and > 1 year after 
discontinuation of the study drug. The subject that developed PTLD on treatment was 
Epstein-Barr virus (EBV) negative and received an EBV positive allograft. This subject 
was diagnosed with PTLD 9 months after transplantation from a biopsy of a lesion near 
the basal ganglia, and belatacept was discontinued. The subject died 5 months later from 
Pneumocystis carinii pneumonia and recurrent Cytomegalovirus (CMV) infection while 
receiving dexamethasone and sirolimus. A second subject was diagnosed with PTLD 4 
months after transplantation and 2 months after discontinuation of belatacept with 
initiation of tacrolimus. The diagnosis was based upon a renal allograft biopsy performed 
for suspected acute rejection. The tumor tissue and urine tested positive for EBV, and 
retrospective analysis of stored sera from the recipient tested negative for EBV. This 
subject underwent a transplant nephrectomy. A final subject received 4 doses of 
belatacept before discontinuation for a Grade IIB rejection, which was treated with a 
10-day course of OKT3. PTLD was diagnosed from an excisional biopsy of an anterior 
cervical lymph node 12 months after discontinuation of study drug. Additional 
information on these cases is provided in the IB. 
One subject treated with the belatacept MI regimen developed breast cancer after 
12 months of treatment. In retrospect, the baseline mammogram for this subject was 
abnormal. No subjects treated with the belatacept LI regimen developed malignancies. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 85 of 93 
Two subjects treated with CsA developed malignancies – squamous cell carcinoma of the 
skin and thyroid cancer – while a third subject developed a parathyroid nodule not yet 
confirmed to be malignant. 
Table 1.3.4.4C: 
Most Frequent (At Least 5% in Any Group) Serious Adverse 
Events Through Day 56 After Double-blind Period 
(Randomized, Transplanted and Treated Population) - Study 
IM103100 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=71) 
Subjects with Any Serious Adverse 
Events 
50 (67.6) 
52 (73.2) 
41 (57.7) 
Blood & Lymphatic System Disorders 
2 (2.7) 
3 (4.2) 
4 (5.6) 
Gastrointestinal Disorders 
7 (9.5) 
7 (9.9) 
5 (7.0) 
General Disorders & Administration Site 
Conds. 
5 (6.8) 
8 (11.3) 
7 (9.9) 
 
Pyrexia 
4 (5.4) 
8 (11.3) 
6 (8.5) 
Immune System Disorders 
20 (27.0) 
23 (32.4) 
13 (18.3) 
 
Transplant Rejection 
18 (24.3) 
20 (28.2) 
9 (12.7) 
Infections & Infestations 
17 (23.0) 
12 (16.9) 
18 (25.4) 
 
Cytomegalovirus 
5 (6.8) 
4 (5.6) 
7 (9.9) 
 
Pyelonephritis 
4 (5.4) 
1 (1.4) 
2 (2.8) 
 
Urinary Tract Infection 
2 (2.7) 
0 
4 (5.6) 
Injury, Poisoning & Procedural 
Complications 
8 (10.8) 
6 (8.5) 
9 (12.7) 
Investigations 
8 (10.8) 
2 (2.8) 
4 (5.6) 
 
Blood Creatinine Increased 
8 (10.8) 
2 (2.8) 
4 (5.6) 
Metabolism & Nutrition Disorders 
1 (1.4) 
2 (2.8) 
4 (5.6) 
Renal & Urinary Disorders 
9 (12.2) 
11 (15.5) 
9 (12.7) 
Respiratory, Thoracic & Mediastinal 
Disorders 
6 (8.1) 
3 (4.2) 
4 (5.6) 
Vascular Disorders 
3 (4.1) 
5 (7.0) 
8 (11.3) 
MedDRA = Medical Dictionary of Drug Regulatory Activities. 
 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 86 of 93 
Topics of Special Interest 
Renal Function 
Renal function was assessed by measurement of iohexol using a plasma disappearance 
method. As iohexol is a true glomerular filtration marker, measurement of iohexol 
clearance may be regarded as a ‘gold standard’ technique. Because iohexol clearance 
measures are relatively difficult to perform, renal function was also assessed by 
measurement of SCr and application of several SCr-based formulas for prediction of 
renal function. Unlike iohexol, creatinine is not a true glomerular filtration marker, and is 
relatively insensitive to changes in renal function in subjects with GFRs > 50-60 mL/min. 
Iohexol clearance was greater in the belatacept treatment groups than in the CsA group at 
all time points (Table 1.3.4.5A). Data collection was not complete, however, and it is 
difficult to predict the impact of missing data on the observed results. SCr and 
creatinine-based estimates of renal function, which were obtained more consistently than 
iohexol clearance, also generally favored belatacept, although to a lesser degree. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 87 of 93 
Table 1.3.4.5A: 
Renal Function - Study IM103100 
 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
Mean (SD) Measured Serum Creatinine (mg/dL) (ITT Analysis) 
Month 1 
n=68 
1.3 (0.46) 
n=69 
1.3 (0.52) 
n=65 
1.6 (1.02) 
Month 6 
n=62 
1.2 (0.41) 
n=66 
1.2 (0.33) 
n=54 
1.4 (0.69) 
Month 12 
n=60 
1.2 (0.46) 
n=59 
1.2 (0.55) 
n=50 
1.4 (1.29) 
Mean (SD) Iohexol Clearance Rate (mL/min/1.73 m2) (ITT Analysis) 
Month 1 
n=53 
59.7 (17.34) 
n=51 
60.2 (14.45) 
n=48 
54.0 (19.33) 
Month 6 
n=41 
62.2 (25.60) 
n=41 
64.5 (19.48) 
n=31 
56.0 (19.54) 
Month 12 
n=32 
66.3 (20.71) 
n=37 
62.1 (15.90) 
n=27 
53.5 (16.43) 
Mean (SD) Calculated GFR (mL/min/1.73 m2) Using Levey Formula (ITT 
Analysis) 
Month 1 
n=68 
65.3 (21.43) 
n=69 
65.6(20.61) 
n=65 
56.9 (20.92) 
Month 6 
n=62 
70.1 (21.09) 
n=65 
69.9 (20.04) 
n=54 
63.3 
(26.496) 
Month 12 
n=60 
72.4 (22.53) 
n=59 
73.2 (22.54) 
n=50 
68.0 (28.06) 
GFR = glomerular filtration rate, ITT = intent to treat, and SD = standard deviation. 
Renal Function Following Biopsy-proven Acute Rejection 
In general, based on the last available SCr values, renal function following biopsy-proven 
acute rejection (including clinically-suspected and subclinical events) was similar among 
subjects in the 3 treatment groups (belatacept MI: 1.9 mg/dL; belatacept LI: 1.6 mg/dL; 
CsA: 2.3 mg/dL). 
Mean SCr values for subjects who had recurrent acute rejections are summarized in 
Table 1.3.4.5B. Subjects with recurrent acute rejection had similar or better most recent 
mean SCr at last follow-up in the belatacept treatment groups as compared to the CsA 
treatment group. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 88 of 93 
Table 1.3.4.5B: 
Most Recent Mean Serum Creatinine Values Post Acute 
Rejection - Study IM103100 (Intent-to-Treat Analysis) 
 
Mean Serum Creatinine (mg/dL) 
LEA29Y MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
1 Episode of Acute Rejection 
1.7 
1.6 
2.3 
> 1 Episode of Acute Rejection 
2.5 
1.6 
2.7 
 
 
 
 
Non-Grade IIB Acute Rejection 
1.7 
1.6 
2.3 
Grade IIB Acute Rejection 
2.2 
1.5 
2.2 
 
Mean SCr values for subjects with more severe acute rejections (moderate - Grade IIB) 
are also summarized in Table 1.3.4.5B. Grade IIB rejections were observed in 5 subjects 
in both belatacept groups and 2 subjects in the CsA group. The mean SCr values at last 
follow-up were comparable between the belatacept MI and CsA groups, but lower in the 
belatacept LI group. 
Cardiovascular and Metabolic Effects 
Mean SBP was 3-4 mm Hg higher with CsA than with belatacept by Month 12, despite a 
somewhat higher rate of antihypertensive medication use in the CsA group 
(Table 1.3.4.5C). Total cholesterol was slightly lower with belatacept than with CsA, as 
were both the non-high-density lipoprotein (non-HDL) and 
HDL fractions 
(Table 1.3.4.5D). Lipid-lowering medications were used more frequently with CsA 
(53%) than with belatacept (32%-36%). HbA1c and the incidence of PTDM were slightly 
lower with belatacept than with CsA (Table 1.3.4.5E). 
Table 1.3.4.5C: 
Blood Pressure - Study IM103100 
 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
Mean (SD) Diastolic Blood Pressure (mm Hg) (ITT Analysis) 
Month 1 
n=58 
81 (11.0) 
n=63 
79 (11.3) 
n=57 
82 (9.9) 
Month 6 
n=49 
79 (9.4) 
n=50 
77 (10.2) 
n=41 
81 (8.2) 
Month 12 
n=52 
78 (9.2) 
n=47 
75 (11.7) 
n=39 
78 (7.6) 
Mean (SD) Systolic Blood Pressure (mm Hg) (ITT Analysis) 
Month 1 
n=58 
135 (15.6) 
n=63 
136 (17.0) 
n=57 
135 (14.4) 
Month 6 
n=49 
n=50 
n=41 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 89 of 93 
Table 1.3.4.5C: 
Blood Pressure - Study IM103100 
 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
130 (16.3) 
129 (16.3) 
136 (17.1) 
Month 12 
n=52 
130 (17.3) 
n=47 
129 (15.7) 
n=39 
133 (18.7) 
Incidence of Hypertension (ITT Analysis) 
Months 0 - 1 
72 (97.3%) 
68 (95.8%) 
71 (97.3%) 
Months 1 - 3 
n=73 
65 (89.0%) 
n=70 
58 (82.9%) 
n=72 
66 (91.7%) 
Months 3 - 6 
n=73 
65 (89.0%) 
n=70 
57 (81.4%) 
n=71 
66 (93.0%) 
Months 6 - 9 
n=72 
64 (88.9%) 
n=69 
57 (82.6%) 
n=67 
61 (91.0%) 
Months 9 - 12 
n=72 
63 (87.5%) 
n=69 
58 (84.1%) 
n=64 
59 (92.2%) 
Antihypertensive Medication Use at 12 months (ITT Analysis) 
Subjects on Antihypertensive 
Medications 
63 (87.5%) 
57 (82.6%) 
59 (92.2%) 
No. of Classes 
 
 
 
 
1 
17 (27.0%) 
20 (35.1%) 
9 (15.3%) 
 
2 
20 (31.8%) 
22 (38.6%) 
24 (40.7%) 
 
3 
16 (25.4%) 
10 (17.5%) 
18 (30.5%) 
 
≥ 4 
10 (15.9%) 
5 (8.8%) 
8 (13.6%) 
Note: Hypertension was defined as diastolic blood pressure ≥ 90 mm Hg and/or systolic 
blood pressure  ≥ 140 mm Hg or use of any antihypertensive medication. 
ITT = intent to treat and SD = standard deviation. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 90 of 93 
Table 1.3.4.5D: 
Lipids - Study IM103100 
 
LEA29Y 
MI 
(N=74) 
LEA29Y LI 
(N=71) 
CsA 
(N=73) 
Mean (SD) Total Cholesterol (mg/dL) (ITT Analysis) 
Month 1 
n=69 
222 (64.7) 
n=69 
210 (45.6) 
n=65 
239 (53.7) 
Month 6 
n=63 
204 (40.4) 
n=65 
202 (47.7) 
n=54 
224 (54.8) 
Month 12 
n=60 
198 (41.4) 
n=58 
201 (40.0) 
n=50 
212 (44.2) 
Mean (SD) non-HDL Cholesterol (mg/dL) (ITT Analysis) 
Month 1 
n=68 
159 (62.7) 
n=68 
142 (40.2) 
n=64 
169 (51.5) 
Month 6 
n=62 
150 (39.4) 
n=64 
143 (42.1) 
n=51 
165 (55.1) 
Month 12 
n=59 
145 (36.7) 
n=56 
144 (35.8) 
n=48 
151 (43.4) 
Mean (SD) HDL Cholesterol (mg/dL) (ITT Analysis) 
Month 1 
n=68 
64 (19.4) 
n=68 
68 (21.7) 
n=64 
70 (21.6) 
Month 6 
n=62 
54 (14.8) 
n=65 
56 (19.0) 
n=52 
62 (20.1) 
Month 12 
n=60 
53 (15.7) 
n=57 
56 (13.5) 
n=48 
59 (18.5) 
Subjects on Lipid-lowering Medications (ITT Analysis) 
Months 0 - 1 
21 (28.4%) 
10 (14.1%) 
23 (31.5%) 
Months 1 - 3 
n=73 
16 (21.9%) 
n=70 
15 (21.4%) 
n=72 
26 (36.1%) 
Months 3 - 6 
n=73 
22 (30.1%) 
n=70 
20 (28.6%) 
n=71 
30 (42.3%) 
Months 6 - 9 
n=72 
24 (33.3%) 
n=69 
22 (31.9%) 
n=67 
31 (46.3%) 
Months 9 - 12 
n=72 
26 (36.1%) 
n=69 
22 (31.9%) 
n=64 
34 (53.1%) 
ITT = intent to treat and SD = standard deviation. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 91 of 93 
 
Table 1.3.4.5E: 
Diabetes - Study IM103100 
 
LEA29Y MI 
(N=74) 
LEA29Y 
LI 
(N=71) 
CsA 
(N=73) 
Mean (SD) HbA1c (%) (ITT Analysis) 
Month 1 
n=67 
5.7 (0.83) 
n=69 
5.7 (0.78) 
n=67 
5.9 (0.95) 
Month 6 
n=61 
5.9 (0.95) 
n=58 
5.9 (0.84) 
n=53 
6.1 (1.09) 
Month 12 
n=60 
5.8 (0.83) 
n=57 
5.8 (0.67) 
n=52 
6.2 (0.84) 
New-onset PTDM / Treated for Hyperglycemia (ITT Analysis) 
Total No. Subjects Without Pre-transplant 
Diabetes 
67 
65 
60 
Month 1 
0 
0 
1 (1.7%) 
Month 6 
0 
0 
2 (3.3%) 
Month 12 
2 (3.0%) 
0 
3 (5.0%) 
Note: PTDM was defined as the need for treatment of hyperglycemia with either an oral 
agent or insulin for a total of ≥ 4 weeks in a subject not known to be diabetic prior 
to transplant. 
HbA1c = hemoglobin A1c, ITT = intent to treat, PTDM = post-transplant diabetes 
mellitus, and SD = standard deviation. 
 
Immunogenicity 
No immunogenicity was observed in Study IM103100. 
Exploratory Analysis in an Extended Criteria Donor Population or in Subjects with 
Impairment of Renal Function Post-transplant 
ECD criteria were not prospectively defined in Study IM103100. An analysis of subjects 
who received an allograft with possible impaired renal function at the time of 
transplantation was explored in a retrospective fashion. Criteria for this analysis were 
donor age ≥ 60 years and CIT ≥ 24 hours. In addition, subjects who experienced either 
DGF (defined as dialysis treatment within first week of transplantation) or slow graft 
function (defined as SCr at Day 5 ≥ 3 mg/dL without dialysis) were also analyzed. 
Tables 1.3.4.6A and 1.3.4.6B show key efficacy and safety data, retrospectively, from 
these respective analyses. 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 92 of 93 
Table 1.3.4.6A: 
Evaluation of Subjects from Study IM103100 with Donor Age 
≥ 60 Years or Cold-ischemic Time ≥ 24 Hours 
 
LEA29Y MI 
(N=17) 
LEA29Y LI 
(N=16) 
CsA 
(N=10) 
Subject Death or Graft Loss by Month 12, 
n (%) 
0 
1 (6.3%) 
0 
Acute Rejection (Clinically-suspected) by 
Month 6,  
n (%) 
1 (5.9%) 
0  
0 
Acute Rejection (Clinically-suspected and 
Subclinical) by Month 6, n (%) 
1 (5.9%) 
3 (18.8%) 
1 (10.0%) 
Chronic Allograft Nephropathy by Month 
12, n (%) 
4 (23.5%) 
2 (12.5%) 
5 (50.0%) 
Median Glomerular Filtration Rate by 
Month 12  
(mL/min/1.73 m2) 
(n=11) 
61.5 
(n=10) 
57.4 
(n=4) 
48.0 
Malignancies, n 
0 
0 
0 
 
Table 1.3.4.6B: 
Evaluation of Subjects from Study IM103100 with Slow or 
Delayed Graft Function 
 
LEA29Y MI 
(N=32) 
LEA29Y LI 
(N=32) 
CsA 
(N=30) 
Subject Death or Graft Loss at Month 12, n 
(%) 
2 (6.3%) 
0 
4 (13.3%) 
Acute Rejection (Clinically-suspected) at 
Month 6,  
n (%) 
5 (15.6%) 
2 (6.3%) 
4 (13.3%) 
Acute Rejection (Clinically-suspected and 
Subclinical) at Month 6, n (%) 
7 (21.9%) 
8 (25.0%) 
9 (30.0%) 
Chronic Allograft Nephropathy at Month 
12, n (%) 
8 (25.0%) 
5 (15.6%) 
12 (40.0%) 
Median Glomerular Filtration Rate at 
Month 12  
(mL/min/1.73 m2) 
(n=11) 
56.0 
(n=20) 
56.4 
(n=10) 
48.0 
Malignancies, n 
1 
0 
1 


Belatacept 
Confidential 
Post-Depletion Revised v.7.0  Protocol: 1FD003539 
Version: 10Jul2015                            IM103-036 
Page 93 of 93 
In these analyses, belatacept demonstrated results consistent with the results in the overall 
study population. Of note, there were favorable trends with respect to GFR and CAN 
with comparable acute rejection rates between the belatacept and CsA treatment groups.