Innovation In Transplantation:

Innovation In Transplantation: Improving outcomes Thomas C. Pearson Department of Surgery Emory Transplant Center CHOA Symposium October 22, 2016

Disclosures Belatacept preclinical and clinical trial were supported by Bristol-Myers Squibb I have served on an Advisory Board for Bristol- Myers I will discuss studies of off-label use of belatacept 2

Innovation in Transplantation: improving outcomes Current status of clinical transplantation: how we got here Stimulation blockade: concept, mechanism of action and rationale design Belatacept: Pre-Clinical Development Pathway Belatacept: Lessons from Clinical Trials New Opportunities and Unmet Needs

Saints Cosmas and Damian The Miracle of the Black Leg 348 AD

Nobel Prize in Medicine 1912 Alexis Carrell developed methods for sewing blood vessels together.

Sir Peter Medawar The Nobel Prize in Physiology or Medicine 1960 "for discovery of acquired immunological tolerance"

Innovations in Transplantation: Circa 1950 Basic surgical techniques defined Transplants are lost due to an immune response

First Kidney Transplant- Dec 1954

First Kidney Transplant- Dec 1954 Joseph Murray

The Era of Immunosuppression Tweedledee Sir Roy Calne Gertrude Elion George Hitchings Titus Lollipop

Evolution of transplant immunosuppression Zand MS. Semin Dial. 2005;18:511-519 Improved Immunosuppression Results in Reduced Rejection and Improved Graft Survival

Current Agents Calcineurin inhibitors Mycophenolate Mofetil Sirolimus Azathioprine Steroids IL-2R antagonists Anti-lymphocyte antibody preparations alemtuzumab Co-stimulation blockade Leflunomide

100 90 80 70 Kidney Graft Survival Rates 94.7 93 88.6 90.5 90.7 81.6 84.8 80 75.2 78.1 67 66.1 60 50 40 30 20 10 0 PCKD Glomerular Diabetes Hypertension 1 year graft 3 year graft 5 year graft UNOS: National Registry Data Kaplan-Meier Analysis of 1997-2004 (Data as of 09/02/2016) 15

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Kidney Transplants Performed American Journal of Transplantation pages 11-46, 11 JAN 2016 DOI: 10.1111/ajt.13666 http://onlinelibrary.wiley.com/doi/10.1111/ajt.13666/full#ajt13666-fig-0022 SRTR

Region 3 Deceased and Living Donors, 7/1/2006-6/30/2016 1800 Number of Donors 1500 1200 900 600 300 Deceased Donor 0 Living Donor 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 NOTE: 2007=7/1/2006-6/30/2007; 2008=7/1/2007-6/30/2008; 2009=7/1/2008-6/30/2009; 2010=7/1/2009-6/30/2010; 2011=7/1/2010-6/30/2011; 2012=7/1/2011-6/30/2012; 2013=7/1/2012-6/30/2013; 2014=7/1/2013-6/30/2014; 2015=7/1/2014-6/30/2015; 2016=7/1/2015-6/30/2016 Year

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Adult Kidney Transplant Wait List American Journal of Transplantation pages 11-46, 11 JAN 2016 DOI: 10.1111/ajt.13666 http://onlinelibrary.wiley.com/doi/10.1111/ajt.13666/full#ajt13666-fig-0001 SRTR

Kidney Median Time to Transplant American Journal of Transplantation pages 11-46, 11 JAN 2016 DOI: 10.1111/ajt.13666 http://onlinelibrary.wiley.com/doi/10.1111/ajt.13666/full#ajt13666-fig-0007 SRTR

Immunosuppression for Renal Transplantation Basiliximab Thymoglobulin Calcineurin Inhibitor Mycophenolate Steroids Time

Lodhi and Meier-Kriesche, 2011

Improving long-term outcomes and healthspan: a daunting but worthy goal 100 80 Graft Survival (%) 60 40 50% Survival (Half Life) Highly complex regimens Demanding follow-up 20 Mechanism-based toxicity 0 0 2 4 6 8 Years High blood pressure Diabetes Nephrotoxicity Risk of DSA Non-adherence Meier-Kriesche AJT 2004; 4: 1289

Causes of Graft Loss Causes of Graft Loss >6 Months Glomerulonephritis 6% Other 5% Chronic rejection 36% Death with function 50% Reference: Ojo AO. Kidney Int 2000;57:307-313. 26

Causes of Death with a Functioning Graft USRDS 2009 Adult Renal Transplants 2003 2007

Improving Long-term Outcomes a daunting but worthy goal 100 Graft Survival (%) 80 Why is 60it so hard to improve long-term survival and healthspan? 50% Survival (Half Life) 40 Highly complex regimens Long-term trials are logistically and financially impractical. Demanding follow-up SRTR, CMS and Centers of Excellence drive improvement in short-term outcomes 20 0 0 2 4 6 8 Years Meier-Kriesche AJT 2004; 4: 1289 Mechanism-based toxicity Pressures to reduce acute care cost can compete with strategies to improve long-term outcomes. High blood pressure Diabetes Nephrotoxicity Much (most) of long care is given outside of transplant centers Non-adherence Drug-sparing risk of DSA And yet, we the transplant community must design and deliver the solutions

Innovations in Transplantation: Circa 2000 Short-term results are very good Long-term results not improving The wait list is long and getting longer

Immunosuppression: Goals Maintain efficacy acute rejection Improve toxicity profile Improved long-term outcomes

Transplant Immunology 101 T cells play a central role in graft rejection Co-stimulation pathways critical for T cell function

CD28 a Critical Costimulatory Pathway B7-1 (CD80) B7-2 (CD86) CD28 CTLA4 Enhanced T cell survival Activate bioenergetics MHC TCR Cytokine synthesis

Discovery of Co-stimulation Maturation renders DC 100-fold more potent T cell activators Nobel Prize in Medicine, 2011

Development of CTLA4-Ig Structure and Function of B7, CD28, and CLTA4 begin to be elucidated CLTA4-Ig in born Peter Linsley Ed Clark Craig Thompson Jeff Bluestone

Development of a CTLA-4 Fusion Protein to Block CD28 Costimulation CTLA-4 CTLA-4 Ig CTLA-4 Ig Human IgG1 37

Costimulation moves from biology to therapeutic target CTLA4-Ig Drug candidate Costimulation blocker

Rhesus Kidney Transplant Model Yerkes Primate Research Center

CD28 Blockade: Pre-clinical model 100 75 50 CTLA4-Ig Control 25 0 0 10 20 30 40 50 Time (days) CTLA4-Ig minimal effect on survival

Effective for treatment of rheumatoid arthritis T cell-mediated autoimmune disorder Large safety experience with long-term administration

Belatacept: Rational Design A29 L104 CTLA4 Extracellular Domain Silent IgG1 Tail High affinity CTLA4-Ig variant Increased biologic potency Larsen, Pearson et al AJT 2005

10-fold greater inhibition of T cell responses in vitro Serum Cr Prolonged Transplant survival in CNI-inhibitor-free regimens Basilximab Basiliximab Belatacept Larsen et al Am J Trans 2005 Treatment ends

Belatacept Core Development Program Renal Transplant (N = 1427) Phase II IM103100 (N=218) Proof of concept Potential alternative to CNI Phase III IM103008 BENEFIT (N=666) Standard criteria donors IM103027 BENEFIT-EXT (N=543) Extended criteria donors >900 renal transplant recipients received belatacept

BENEFIT and BENFIT-EXT Study Design De Novo therapy in Kidney Transplant recipients Prospective, randomized, international, multi-center Superior renal function, non-inferior rejection control Primary endpoint Secondary endpoints Randomization 6 months 12 months 24 months 36 months Belatacept MI 10 mg/kg 5 mg/kg every 4 weeks DAY 1 5 14 28 42 56 70 84 112 140 168 Belatacept LI 10 mg/kg 5 mg/kg every 4 weeks DAY 1 5 14 28 56 84 112 Cyclosporine 150 300 ng/ml 100 250 ng/ml DAY 1 28 All patients received basiliximab induction, mycophenolate mofetil, and corticosteroids Only CsA patients: T-cell depleting agents permitted for anticipated DGF 47

Belatacept Maintains Superior Renal Function BENEFIT: cgfr Slope Bela MI +1.043 Bela LI +1.229 CsA -2.046 from CsA 15.1 15.3 from CsA 17.5 17.6 from CsA 20.8 21.4 ITT analysis w/ imputation. Patients with death or graft loss imputed as cgfr = 0 008- BENEFIT 48

Belatacept Improves Cardiovascular & Metabolic Profiles Lower Blood Pressure with fewer medications Favorable lipid profiles with fewer medications New Onset Diabetes lower at 12 mo, not significant at 24 or 36 months

Allograft Rejection and its consequences

Acute Rejection by Year 3 Belatacept MI Belatacept LI CsA BENEFIT 24% 17% 10% BENEFIT-EXT 18% 19% 16% 52

Comprehensive Benefit-Risk Assessment Absolute Difference between Belatacept LI and CsA (%) Death/Graft Loss -008-027 Belatacept better -3.2 CsA better Death -3.8-1.4 Rejection Rejection w/ckd 4/5 CKD Stage 4/5 NODAT Uncontrolled HTN Uncontrolled Dyslipidemia Serious Infections Malignancy PTLD (EBV+) Pooled Core Studies -2.1 10.0 3.6 1.3-5.2-9.6-16.4-5.7-4.2-10.6-15.4-9.6-12.4-4.8 0.04 1.0-30 -25-20 -15-10 -5 0 5 10 15 20

Belatacept: path to approval Concept: Belatacept evaluated as alternative to cyclosporine Program Objectives Maintain short-term survival Non-inferior for control of rejection Superiority for renal function Phase III Trials begin 2005 FDA Panel Review 2009 Belatacept FDA Approval June 15, 2011 First Recipient receives Belatacept standard of care July 26, 2011 Phase II Transplant Trial 2001

Belatacept 1.0/1.1 Protocol (2011) Belatacept Intensity of Exposure Maintenance Induction Mycophenolate Prednisone (5) Basiliximab Time

Belatacept 1.0 We have a problem! 100 Freedom from Rejection 100 Graft Survival 80 60 % 40 Bela 1.0/1.1 (N=98) Tac (N=206) 80 60 40 *p=0.57 Bela 1.0/1.1 (N=98) Tac (N=206) 20 20 0 0 180 360 540 720 Days 0 0 365 12 730 24 1095 36 1460 48 Months

egfr of Tac and Bela 1.0/1.1 Intent-to-Treat Patients 70 65 60 egfr 55 50 Tac Bela 1.0/1.1 45 40 0 12 24 36 48 Month 1 mo 2 mo 3 mo 6 mo 9 mo 12 mo 24 mo 36 mo 48 mo Bela(N=97) 96 97 97 96 95 94 95 94 53 Tac(N=205) 205 205 204 203 202 201 196 190 175

Continuous improvement cycle Belatacept 2.0-2.5 Adjust Protocol Design 50-100 patient cycles Monitor Implement

Risk of Rejection Tacrolimus Induction Patients at risk of early post-transplant rejection Belatacept 3 6 12 24 months post-transplant

Belatacept 2.0-2.5 Protocols Intensity of Exposure Maintenance Induction Belatacept De-intensified Mycophenolate Prednisone (5) Basiliximab Tacrolimus Time

Freedom from Rejection 100 Belatacept Belatacept/Tac short Belatacept/Tac extended 100 100 80 80 80 60 % 60 % 60 40 40 40 20 20 20 0 0 180 360 540 720 0 0 180 360 540 720 0 0 180 360 540 720

Belatacept vs Tacrolimus: All Patients 100 Graft Survival 70 Renal Function (egfr) Tac 80 Bela 60 60 Bela (N=518) 40 Tac (N=205) 50 20 0 0 365 1 730 2 1095 3 Years 40 0 12 24 36 48 Months

Belatacept associated with lower rates donor-specific Antibody *p=0.002 % Freedom from DSA 100 95 90 85 80 Belatacept 1.0-2.4 Tacrolimus 75 0 365 12 730 24 1095 36 Months

January J January 28, 2016

Rates of Death or Graft Loss

Kidney Graft Function

Innovation in transplantation: Circa 2016 Better safety profile Improved renal function Higher acute rejection rate More severe rejection pathology Acute Rejection Rates Percent Patients with Acute Rejection Cyclosporine Belatacept

Belatacept On Going Clinical Trials Conversion Trial Thymoglobulin Induction

Moving forward: The next generation of costimulation blockers How can we optimize CD28-based costimulation blockade? Improve upon current CD28 costimulation blockade reagents Combine current CD28 blockers with novel therapeutics to improve efficacy

Krummey and Ford Frontiers Immunol 2012

Genetically Engineered Donor Organs Normally organs from other species are promptly rejected due to key protein differences Making Pig Organs more human-like by Knocking Out key rejection molecules Previous reports average time to rejection 2-3 weeks Emory Xeno-Kidney Project- >300 days, longest ever reported

Doube Knockout Donor Pig Gal -/-, β4gal -/-

Needs Clinical Application Application Discovery Discovery Translation Translation

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