Why we need a new paradigm in immunosuppression USHERING A NEW ERA OF IMMUNOSUPPRESSION. Causes of death and graft loss after kidney transplantation

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1 USHERING A NEW ERA OF IMMUNOSUPPRESSION Flavio Vincenti AR 3 (%) Why we need a new paradigm in immunosuppression Incidence of early acute rejection episodes ( 6 months) Relative risk Overall graft loss by donor type Living transplants Deceased donor Reduced acute rejection rates have not translated into better long-term graft survival Meier-Kriesche et al. Am J Transplant 4;4: Why We Need Novel IS Significant Kidney Allograft Attrition Regardless of Immunosuppressive Regimen Collaborative Transplant Study Results Causes of death and graft loss after kidney transplantation Current regimens do not address causes of graft loss Death Graft loss CTS Database N=51,33 recipients of deceased donor organs Opelz G, Döhler B. Transplantation 9;87: Years Following Transplantation 3 USRDS adult, 1st kidney-only transplants, , who died with functioning graft (n=,648) Callaghan & Bradley. In: Hornick, Rose, eds. Methods in Molecular Biology 6; 333:1-28 1

2 Profile of Desirable New Agents A NEW PARADIGM IN IMMUNOSUPPRESSION IS NEEDED TO PRESERVE RENAL FUNCTION, DECREASE CARDIOVASCULAR TOXICITIES AND IMPROVE LONG TERM OUTCOME Suppresses T and B cells Lacks nephrotoxicity Does not aggravate cardiovascular risk factors Does not affect glucose metabolism Improves compliance Prototype of Novel Drugs That Represent A Paradigm Shift in Immunosuppressive Regimens Costimulation blockade with Belatacept JAK3 inhibition with A Paradigm Shift in Biologic Immunosuppression Biologics for maintenance therapy: required profile No acute toxicities associated with administration Can be delivered in a peripheral vein or subcutaneously Lack immunogenicity Modulation preferable to depletion 7 8 2

3 T-Cells Require Costimulation for Full Activation CD8/86-CD28 is the most important costimulatory pathway T-Cells Require Costimulation for Full Activation TCR signal only=no activation Signal 2 Costimulation between ligands No Signal 2 Signal 1 Antigen triggers T- cell receptor Cytokine production T-cell proliferation Signal 1 only No cytokine production No cell division Becomes anergic Undergoes apoptosis Other costimulatory pathways exist that also serve this role APC=antigen-presenting cell 9 9 APC=antigen-presenting cell; TCR=T-cell receptor; MHC=major histocompatibility complex CTLA4 Negatively Regulates T-cell Activation CTLA4 (CD152) expression is induced by T-cell activation CTLA4 binds CD8/86 with greater avidity than CD28 Early preclinical transplant studies utilized CTLA4Ig to block B7-CD28 costimulation CTLA4 is structurally similar to CD28 CTLA4 negatively regulates T-cell activation 12 3

4 Belatacept potently and selectively blocks T-cell activation Belatacept Selective co-stimulation blocker Belatacept: Phase 3 Studies in de novo Renal Transplantation IM3-8 8 (BENEFIT; Belatacept Evaluation of Nephroprotection and Efficacy as First- line Immunosuppression Trial) Living or deceased donor First-time time recipient: PRA < % Retransplant: PRA < 3% No cell division No cytokine production Anergy Apoptosis. 14 Belatacept: Phase 3 Studies in de novo Renal Transplantation Treatment Regimen BENEFIT -8 and BENEFIT-EXT EXT -27 Transplantation 6 months IM (BENEFIT-EXT; EXT; Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) rial) Deceased donor meeting extended criteria donor (ECD) criteria First-time time kidney transplants PRA < 3% Cyclosporine (7±3 mg/kg daily) Belatacept MI (More Intensive) Belatacept LI (Less Intensive) ng/ml ng/ml 1 28 mg/kg 5 mg/kg mg/kg 5 mg/kg Month 1 Month 2 Month 6 After Month 6 All patients received basiliximab induction, mycophenolate mofetil, and corticosteroid-tapertaper 16 4

5 Phase 3 Studies Co-primary Endpoints 12 Months Composite patient and graft survival (non-inferiority; % margin) Belatacept Phase 3 Clinical Trials Primary Endpoint: Composite Renal Impairment mgfr <6 ml/min/1.73m 2 OR Decreased mgfr ml/min/1.73m 2 between months 3 and 12 Composite renal impairment (superiority) Acute rejection (Study -8: non-inferiority, % margin) P<.1 P<.1 P=.18 P=.6 17 Vincenti F et al Am J Transplant 9; 9(Suppl 2):191; Abstract #4 Durrbach A et al Am J Transplant 9; 9(Suppl 2):199; Abstract #27 18 ITT Population Mean Calculated GFR Calculated GFR Over Time: BENEFIT Slope (95%CI), ml/min/1.73 m 2 /year Bela MI (.7, 2.58) Bela LI (-.1, 2.44) (-3.22, -.7) from from Belatacept MI Belatacept LI Cyclosporine from Months Patients with Measurements Bela MI Bela LI ITT Population Mean Calculated GFR Calculated GFR Over Time: BENEFIT-EXTEXT 7 6 Slope (95%CI), ml/min/1.73 m 2 /year Bela MI -.59 (-2.7,.9) Bela LI -.85 (-2.32,.62) -2.1 (-3.49, -.53) Belatacept MI Belatacept LI Cyclosporine 3 from from from Months Patients with Measurements Bela MI Bela LI

6 Belatacept Phase 3 Clinical Trial Results: Incidence of Acute Rejection Prognostic Features of Rejection Episodes BENEFIT BENEFIT-EXT Worse Graft Outcomes Better Graft Outcomes Did not meet % NI margin ^ Met % NI margin Both belatacept groups met % NI margin vs. High Banff grade Low Banff grade Associated with anti-hla antibodies Not associated with anti-hla antibodies Late Early Recurrent Single Banff Grade Mild acute (IA) 7(3) 4(2) 3(1) Mild acute (IB) 3(1) 8(4) 5(2) Moderate acute (IIA) 17(8) 16(7) 6(3) Moderate acute (IIB) (9) (4) 2(1) Severe Acute (III) 2(1) 1(<1) Vincenti F et al Am J Transplant 9; 9(Suppl 2):191; Abstract #4 Durrbach A et al Am J Transplant 9; 9(Suppl 2):199; Abstract #27 IA 4(2) 2(1) IB 7(4) 2(1) 2(1) IIA (5) 17() 17(9) IIB 16(9) 8(5) 5(3) III 21 Poor renal function after rejection Tanaka et a.l; Transplant Intl 4; 17:59-64 Vereerstraeten et al.; Transplantation 1997;63: Opelz; Transplantation 8; 85:661-6 Racusen et al.; Amer J Transplantation 3; 3:78-14 Everly et al; Amer J Transplantation 9;9:63-71 Good renal function after rejection 22 Phase 3 Studies; ITT Population; Year 1 DBL Prevalence of CAN / IFTA at Month 12 Study -8 Study -27 Pooled 7 Percent of Patients (95% CI) Bela MI Bela LI Belatacept and CV Risk Factors N in analysis CAN=chronic allograft nephropathy; P<.2 vs cyclosporine P<.27 vs cyclosporine

7 Phase 3 Studies; ITT Population New-Onset Diabetes at Month 12 Phase 3 Studies; ITT Population Blood Pressure at Month 12 Percent of Patients (95% CI) N in analysis BENEFIT BENEFIT-EXTEXT Pooled Analysis NODAT was defined as treatment with anti-diabetic medication for a duration of 3 days or at least two fasting plasma glucose (FPG) tests indicating FPG 126 mg/dl (7. mmol/l); NODAT was assessed only after Week 4; P=.3 vs cyclosporine; P<.2 vs cyclosporine Bela MI Bela LI 25 BENEFIT BENEFIT-EXT Systolic Diastolic Systolic Diastolic Bela MI Bela LI Bela MI Bela LI Bela MI Bela LI Bela MI Bela LI N Mean (mmhg) Difference from (97.3% CI) mmhg 26 Phase 3 Studies; ITT Population Changes in Serum Lipids at Month 12 PTLD Risk Concentrated in EBV (-) Recipients Mean change from baseline (mg/dl) (SE) BENEFIT Study -27 BENEFIT-EXT P<.1 vs cyclosporine Bela MI Bela LI N = Non-HDL cholesterol LDL cholesterol Triglycerides Non-HDL cholesterol LDL cholesterol Triglycerides

8 Pooled Core Studies; SCS Safety Population; Safety Update DBL PTLD 2-year Incidence Rates by Recipient EBV Serostatus Incidence rates per p-y (95% CI) EBV (+) recipients EBV ( ) recipients CMS.28 (.22,.34) 1.3 (.78, 1.36) UNOS.11 (.8,.13).7 (.55,.87) Belatacept core studies.33 (.11,.77) 4.9 (1.64, 8.42) Summary of the Phase III Belatacept Trials LI has better overall safety profile than MI and is the recommended registered regimen The risk of PTLD is minimized by selecting patients who are known to be EBV + and reversing episodes of acute rejection with steroid rather than antilymphocyte agents Including LDT induction, treatment with any immunosuppressant, Comprehensive Benefit-Risk Assessment: EBV+, Eff 24M Absolute Difference between Belatacept LI and (%) Death/Graft Loss Death CKD Stage 4/5 Rejection Rejection w/ckd 4/ Belatacept better better Summary of the Phase III Belatacept Trials LI has better overall safety profile than MI and is the recommended registered regimen The risk of PTLD is minimized by selecting patients who are known to be EBV + and reversing episodes of acute rejection with steroid rather than antilymphocyte agents Serious Infections Malignancy PTLD Pooled Core Studies

9 Study Design (Exploratory, Phase II) Immunosuppression with Belatacept-Based, Based, CNI- Avoiding and Steroid-Avoiding Regimens vs a Tacrolimus-Based, Steroid-Avoiding Regimen in Kidney Transplant Patients: Results of a 1-Year, Randomized Study Ronald Ferguson, Flavio Vincenti, Dixon B Kaufman, E Steve Woodle, Brad A Marder, Franco Citterio, Wiliam Marks, Mamta Agarwal, Yuping Dong, Pushkal Garg, Josep Grinyó De novo renal Tx Randomized, open-label, multicenter study of belatacept- based steroid-avoiding regimens Primary Clinical Endpoint 1 month 3 months 6 months LTE 1 year 3 years Thymoglobulin + Belatacept + MMF N = 33 Thymoglobulin + Belatacept + Sirolimus N = 26 Thymoglobulin + Tacrolimus + MMF N = 3 34 Acute Rejection by Month 12 Mean MDRD GFR Over Time 8 Belatacept + MMF Belatacept + SRL TAC + MMF Banff grade, n (%) Mild acute (IA) Mild acute (IB) Moderate acute (IIA) Moderate acute (IIB) Belatacept + MMF 2 (6) 1 (3) Belatacept + SRL 1 (4) TAC + MMF 1 (3) Mean calculated GFR (95% CI) Month 64 ml/min 62 ml/min 54 ml/min Severe acute (III) 1 (3) Biopsies were read centrally

10 Patients Steroid-free by Month Belatacept Monotherapy (ITN Trial) 93 S.Creat. mg/dl Daclizumab Patients (%) 25 steroids Sirolimus (8-12 µg/ml) Belatacept - mg/kg at day, 4, weeks 2, 4, 8 and 12. Then, 5 mg/kg monthly. n/n 24/32 /26 28/3 Belatacept+MMF (n = 33) Belatacept+SRL (n = 26) TAC+MMF (n = 3) 37 Day Transplant 12 M 24 M 36 M 48 M 59-year old with Type II diabetes. Kidney biopsy at one year was normal. No presence of DSA. 38 TASOCITINIB (CP69,5) A JANUS Kinase 3 Inhibitor The JANUS KINASES JAK1 JAK2 JAK3 Tyk2 39 Roman God of Gates

11 Cytokine receptors that share γc subunit and their functions Cytokine Signaling of JAK Control of perhipheral self-tolerance Development of T- regulatory cells Differentiation of helper and cytotoxic T cells In-vitro expansion and differentiation of antigen-selected T and NK cells Regulation of B-cell function in concert with IL-21 Immunoglobulin class switching T-helper cell differentiation to Th2 Co-stimulant for growth in T, B and mast cells Thymic development and survival of T cells Homeostasis of perpheral lymphocytes Growth and survival of B-cell progenitors (mouse) Goblet cell hyperplasia Mucus production Development, differentiation, survival and activation of NK cells Expansion of CD8 memory cells Homeostasis of peripheral T cells Regulation of immunoglobulin production Proliferation and activation of NK cells Proliferation of B and T cells Cytokine α β γ STAT P JAK JAK P P STAT P STAT blocks phosphorylation of STAT and downstream activation P STAT mrna JAK inhibition suppresses signaling of multiple cytokines including IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 Pesu M, et al. Immunological Reviews 5; 3: CNI, calcineurin inhibitor; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription 42 Mutations of the γchain or JAK3 Result in Severe Combined Immunodeficiency CP 3 mg bid BK & CMV CP 15 mg bid more favorable dose Inhibition of the γ chain/jak3 pathway is likely to induce patient immunosuppression Pesu M, et al. Immunological Reviews 5; 3:

12 Study Design Patient Baseline Characteristics As Treated Day 1 to Month 12 Extension 1-6 months (n=5) 1-3 months (n=7) (n=9) Screening Day -3 to Transplant -ME mg BID mg BID Day 1 Month 3 Month 6 Month 9 Month 12 (Interim analysis) Concomitant immunosuppressive agents across all arms Basiliximab induction (days and 4), MPA products (Cellcept or Myfortic), corticosteroid taper Primary efficacy endpoint (non-inferiority vs., NI margin 12%) Biopsy-proven acute rejection (BPAR) rate at Month 6, or BPAR meeting Scr criteria at Month 6» BPAR associated with an increase in Scr of.3 mg/dl and % from pre-rejection baseline Primary safety endpoint (superiority vs ) Measured GFR (iohexol serum clearance) at Month 6 Sex, n (%) Male Female Mean age, years (SD) Age range, years Race, n (%) White Black Asian Other Donor source, n (%) Living Deceased Mean recipient PRA, % (SD) EBV serostatus, n (%) Negative CMV D+R- n, (%) Diabetic pretransplant n, (%) On-dialysis pretransplant n, (%) 82 (78.1) 23 (21.9) 48.1 (11.8) (61.9) 16 (15.2) 15 (14.3) 9 (8.6) 41 (39.) 64 (61.) 1.5 (4.2) 7 (7.) 17 (17.) 21 (19.8) 98 (92.5) International study including 15 countries and 57 Centers 8 (74.8) 27 (25.2) 45.8 (12.6) (66.4) 21 (19.6) 11 (.3) 4 (3.7) 42 (39.3) 65 (6.7) 1. (3.6) 7 (7.) 16 (15.2) 26 (24.1) 96 (89.7) 7 (64.2) 39 (35.8) 47.1 (12.9) (71.6) 12 (11.) (9.2) 9 (8.3) 42 (38.5) 67 (61.5) 2. (6.) 11 (.) 11 (.1) 24 (22.4) 91 (83.5) BID, twice-daily dosing;, cyclosporine A; MMF, mycophenolate mofetil; MPA, mycophenolic acid; Scr, serum creatinine CMV, cytomegalovirus; EBV, Epstein Barr virus; MPA, mycophenolic acid; PRA, panel-reactive antibody; SD, standard deviation Patient Disposition /Patient and Graft Survival Primary Efficacy Endpoints: BPAR and BPAR Meeting Scr Criteria at Month 6 Patients, n (%) 1-6 months 1-3 months Randomized and treated Discontinued (all reasons) 44 (.) 45 (.5) 28 (25.5) Discontinued (due to insufficient clinical response or acute rejection) from study phase 13 (12.4) 11 (.3) 12 (11.) 6-month patient survival (%) month graft survival (%) month K-M rate % 15 mg 1-6 months 15 mg 1-3 months BPAR BPAR meeting Scr criteria Non-inferiority was demonstrated between each of the tasocitinib groups and in BPAR and BPAR meeting Scr criteria. Scr, serum creatinine

13 Infections and Post-Transplant Lymphoproliferative Disorder Hemoglobin and Absolute Neutrophil Counts 1-6 months 1-3 months Hemoglobin Absolute Neutrophil Counts Clinically significant infection at Month 6, % Serious infection at Month 6, % month incidence of CMV disease including CMV syndrome, % Polyomavirus-associated nephropathy, % Post-transplant lymphoproliferative disorder (PTLD), n Hgb (g/dl) 1-6 months 1-3 months 16 ANC (K/µL) Baseline Day Baseline Day Month Month 6-month incidence of anemia, neutropenia, and leukopenia (reported as adverse events) for tasocitinib 1-6 months, tasocitinib 1-3 months, and, respectively, n (%) 1-6 months 1-3 months All three PTLD cases occurred approximately months post-transplant; 2/3 cases occurred after data cut-off date for the 6-month interim analysis Serious infection defined as an infection reported as a serious adverse event Anemia: 48 (45.7); 43 (.2); 27 (24.8), respectively Neutropenia: 14 (13.3); 6 (5.6); 2 (1.8), respectively Leukopenia: 28 (26.7); 18 (16.8); 12 (11.), respectively Erythropoeitin was prohibited after Month 3 Error bars are ± SD; ANC, absolute neutrophil counts; Hgb, hemoglobin 49 New-onset Diabetes and Serum Lipids Blood Pressure and Use of Antihypertensive Medications at Month 6 K-M Rates of Patients with NODAT2 and NODAT2/IFG at Month 6 Serum Lipid Concentrations at Month 6 Systolic and Diastolic Blood Pressure Use of Antihypertensive Medications K-M 25 rate (%) 15 5 NODAT2 NODAT2/IFG mg/dl months 1-3 months mm/hg Month months 1-3 months NODAT2: patients who required treatment for diabetes for 3 consecutive days or with fasting serum glucose 126 mg/dl IFG: defined as fasting serum glucose mg/dl HDL, high-density lipoprotein; IFG, impaired fasting glycemia; LDL, low-density lipoprotein; NODAT, new-onset diabetes after transplantation 6 Systolic Diastolic 1-6 months 1-3 months p value = difference in least squares mean (tasocitinib vs ) p< % Subjects Using Any Antihypertensive Meds

14 Exposure-response analysis results: 6-month Kaplan- Meier rates by tasocitinib exposure Exposure BCAR % CMV disease, % group (divided into 2 groups of TWC2) Serious Infections, % Low (n=88) High (n=88) group (divided into quartiles of TWC2) 1 st quartile (n=44) nd quartile (n=44) rd quartile (n=44) th quartile (n=44) Group N~ Summary (6-month Interim Analysis) The primary objectives of the interim analysis were met as demonstrated by non-inferiority in the incidence of BPAR rates and statistically significantly higher measured GFR at Month 6 in each of the tasocitinib groups compared with the control group There was also evidence of over-immunosuppression (higher incidence of serious infections and opportunistic viral infections) and excessive myelosuppression (higher incidence of anemia, neutropenia, and leukopenia) in the tasocitinib groups compared with the group. Lower dosage based on TDM may improve the safety without jeopardizing efficacy. There were trends for improved glycemic control and lower systolic and diastolic blood pressures in the tasocitinib groups, compared with the group Q1: 43-96; Q2: ; Q3: ; Q4: ng/ml CMV disease, CMV-related event or isolated CMV viremia reported as an adverse event BCAR biopsy-confirmed acute rejection; CMV, cytomegalovirus;, cyclosporine A; LDAR, locally diagnosed acute rejection; TWC2, time-weighted average tasocitinib concentration at 2 hours postdose CONCLUSION The past decade has not witnessed the approval of a new drug in transplantation The drugs in the new pipeline provide efficacy while preserving renal function, decreasing CV risk factors and the promise of improving long term outcome 55 14