Why Do We Need New Immunosuppressive Agents

Transcription

1 Why Do We Need New Immunosuppressive Agents 1

2 Reducing acute rejection rates has not transplanted into better long-term graft survival Incidence of early acute rejection episodes by era Relative risk for overall graft loss by donor type % AR months Relative Risk Decreased Donor Transplants Living Transplants Meier-Kriesche, H-U, et al. Amer J Transplant 2004;4:

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4 Cumulative graft failure yearly attrition rates of first kidney transplants Deceased SCD Living Donor 4

5 Causes of Graft Loss After First Year Death with Function 40% Other 10% Disease Recurrence 10% CAN 40% Callaghan CJ, Bradley JA. IN: Hornick P, Rose M. eds. Methods in Molecular Biology 2006; 333:1-28 5

6 Current Regimens Are Associated With Unavoidable Toxicities Nephrotoxicity NODAT Hypertension Hyperlipidema 6

7 The Problem with Current Immunosuppression Regimens More intense regimens do not address major causes of patient deaths and graft loss Nephrotoxicity and metabolic abnormalities are unavoidable and contribute to premature death and graft loss Minimization regimens are unlikely to benefit patients longer term and may contribute to the increase in chronic antibody mediated rejection as a cause of graft failure 7

8 Sellares et al AJT

9 Why The Reduction in Acute Rejection And Improved Early Graft Survival Has Not Resulted in Better Late Graft Survival Immunosuppression may have early benefits but late adverse effects on graft survival Late graft failure may occur via mechanisms unrelated to immune injury Immunosuppression may be inadequate late because of nonadherence and minimization regimens BK nephropathy, other late infections, malignancies, CVD CNI nephrotoxicity, recurrent disease, senescence Multiple and/or late acute rejection episodes, inflammation, AMR AMR = antibody-mediated rejection; CNI = calcineurin inhibitor; CVD = cardiovascular disease. Meier-Kriesche HU, et al. Am J Transplant. 2004;4(3): Magee CC, et al. Arch Intern Med. 2004;164(13): Kreis HA, et al. Transplantation. 2001;71(11 Suppl):SS5-9. 9

10 The Traditional Consensus Of Why Kidneys Fail Long-Term: Progression of Nephrotoxicity Associated with CNIs 10

11 Prevalence (%) The incidence of Calcineurin inhibitor (CNI) nephrotoxicity increases with time after transplant 100 Acute rejection Acute subclinical rejection Borderline subclinical rejection Calcineurin nephrotoxicity Years After Transplantation Nankivell BJ et al. N Engl J Med 2003;349:

12 Why Kidneys Fail in the Long Term? The balance is Tilting Towards Chronic Immunologic Injury (?humoral) As A Leading Cause of Late Graft Loss 12

13 Clinical and Translational Research Evidence for Antibody-Mediated Injury as a Major Determinant of Late Kidney Allograft Failure Robert S. Gaston, J. Michael Cecka, Bert L. Kasiske, Ann M. Fieberg, Robert Leduc, Fernando C. Cosio, Sita Gourishankar, Joseph Grande, Philip Halloran, Lawrence Hunsicker, Roslyn Mannon, David Rush, and Arthur J Matas Transplantation Volume 90:

14 Methods One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant) 7.3±6.0 years) had a baseline serum creatinine level of 1.4±0.3 mg/dl before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7 ± 16 mg/dl). 14

15 Kaplan-Meier analysis of the impact of primary or secondary local diagnosis of calcineurin inhibitor (CNI) nephrotoxicity on kidney allograft survival after for-cause biopsy 15

16 The DeKAF study also illustrates the impact of antibody-mediated injury on outcome DeKAF = Long-term deterioration of kidney allograft function; DSA = Donor-specific antibody. Gaston R et al. Am J Transplant 2009; Aug;9(8):

17 Profile of Desirable New Agents Suppresses T and B cells Lacks nephrotoxicity Does not aggravate cardiovascular risk factors Does not affect glucose metabolism Improves compliance 17

18 The New and Emerging Immunosuppression Choice Belatacept Tofacitinib 18

19 STAT STAT JAK and Cytokine Signaling JAK inhibition suppresses the signaling of multiple cytokines Cytokine α STAT β JAK P P γ JAK P Tofacitinib blocks phosphorylation of STAT and downstream activation STAT P Cytokine IL-2 IL-4 IL-7 IL-9 Effects on the immune system Stimulate the proliferation and differentiation of Th, Tc, B and NK cells Induce the differentiation of Th0 to Th2 Induce Ig switching Promote the development, proliferation and survival of T, B and NK cells Stimulate intrathymic T cell development P IL-15 Promote the proliferation, cytotoxicity and cytokine production of NK cells mrna IL-21 Enhance T and B cell function Ig, immunoglobulin; IL, interleukin; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; Th, T helper; Tc, cytotoxic T cell 19 19

20 Belatacept: A New Paradigm in Immunosuppression Chronic Intermittent Biologic Therapy Prolonged Biologic Effects (long half life) Targets Readily Saturated Lacks Immunogenicity Administered Without Acute Toxicities Potential to alter immune response to allograft 20

21 T-Cells Require Costimulation for Full Activation CD80/86-CD28 is the most important costimulatory pathway* Signal 2 Costimulation between ligands Signal 1 Antigen triggers T- cell receptor Cytokine production T-cell proliferation *Other costimulatory pathways exist that also serve this role APC=antigen-presenting cells 21

22 T-Cells Require Costimulation for Full Activation TCR signal only=no activation No Signal 2 Signal 1 only No cytokine production No cell division Becomes anergic Undergoes apoptosis APC=antigen-presenting cell; TCR=T-cell receptor; MHC=major histocompatibility complex 22

23 CTLA4 Negatively Regulates T-cell Activation CTLA4 (CD152) expression is induced by T-cell activation CTLA4 binds CD80/86 with greater avidity than CD28 CTLA4 is structurally similar to CD28 CTLA4 negatively regulates T-cell activation 23

24 Early preclinical transplant studies utilized CTLA4Ig to block B7-CD28 co-stimulation 24

25 Belatacept potently and selectively blocks T-cell activation Belatacept Selective co-stimulation blocker No cell division No cytokine production Anergy Apoptosis. 25

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27 Acute Rejection* by Year 3 Belatacept MI n = 219 Belatacept LI n = 226 CsA n = 221 Baseline Month 24 24% 17% 9% Number of cases, Month 24 Month Baseline Month 36 24% 17% 10% 4% of patients in each group had recurrent acute rejection episodes All biopsy-proven AR (BPAR) by year 3: 27% (MI); 22% (LI); 14% (CsA) Patients w/graft loss, death, lost to follow-up, or biopsy-proven AR (efficacy failure) by year 3: 32% (MI); 26% (LI); 26% (CsA) *Protocol-defined acute rejection: clinical suspicion + biopsy confirmation 27

28 Mean calculated GFR (95% CI) Mean cgfr (MDRD) Through Year Belatacept MI Slope (95% CI), ml/min/1.73 m 2 /yr Bela MI (0.106, 1.980) Bela LI Belatacept (0.309, 2.149) LI CsA (-2.994, ) Cyclosporine from CsA from CsA from CsA Month n = Belatacept MI Belatacept LI Cyclosporine ITT analysis w/ imputation. Patients with death or graft loss imputed as cgfr = 0 28

29 Percentage of patients with a functioning graft Projected Mean Graft Half-life 100% 90% 80% observed survival 70% 60% 50% 40% predicted survival half life (days) : 3,990 4,676 30% 20% 10% Belatacept LI CsA 0% Years after transplant Presented by Schnitzler et al, ATC, May 1,

30 Mean Calculated GFR (95% CI) Mean Calculated GFR (MDRD) Through Year 3 60 Belatacept MI Belatacept LI Cyclosporine from CsA from CsA Slope (95%CI), ml/min/1.73 m 2 /year Bela MI (-1.940, 0.230); Bela LI (-1.681, 0.477); CsA (-2.935, ) Months from CsA ITT analysis w/ imputation. Missing cgfr values due to death or graft loss were imputed as 0 30

31 Probability of Survival with cgfr 30 ml/min/1.73m2 (%) Time to cgfr <30 ml/min/1.73m 2, Graft Loss, or Death Belatacept MI Belatacept LI Cyclosporine Time (months) 31

32 Fellstrom B, et al. (Abstract #1301) Am J Transplant 2012; 12(Suppl 3):

33 Post-transplant Lymphoproliferative Disorders Phase II and III Kidney Studies Patients with event(s), % Belatacept MI (n = 477) Belatacept LI (n = 472) CsA (n = 476) Total PTLD cases* 8 (1.7) 7 (1.5) 3 (0.6) Renal allograft Fatal Disseminated Fatal CNS PTLD Fatal Total fatal PTLD cases *Cumulative to March

34 Patients (%) PTLD and EBV status Bela EBV (-) [n = 91] Bela EBV (+) [n = 810) CsA EBV (-) [n = 57] CsA EBV (+) [n = 399] All PTLD CNS PTLD Non-CNS PTLD * 1/48 patients in the belatacept MI group with non-cns PTLD had baseline EBV status unknown; 1/20 subject in the CsA group with non-cns PTLD had baseline EBV status unknown. 34

35 Positive cases post-transplant (%) Donor-Specific Antibodies by Year 3 (pooled data) Belatacept MI 12 Belatacept LI CsA n = 396 n = 395 n = 387 n = 384 n = 387 n = 370 n = 384 n = 387 n = 370 All DSA post-transplant De novo DSA only De novo DSA on study drug The mean fluorescence intensity of the anti-donor HLA antibodies in patients who were positive for DSA was similar between the treatment groups 35

36 Conclusion Belatacept immunosuppression represent novelty in ways that will be challenging to transplant physicians Belatacept could emerge as a transformational agent if it proves it can be administered effectively and safely in wider use 36